AIM: To evaluate which patients with hepatocellular carcinoma (HCC) are most likely to respond to thalidomide treatment. METHODS: From July 2002 to July 2004, patients with HCC who received thalidomide treatment, were...AIM: To evaluate which patients with hepatocellular carcinoma (HCC) are most likely to respond to thalidomide treatment. METHODS: From July 2002 to July 2004, patients with HCC who received thalidomide treatment, were enrolled. We extracted relevant data from the patients’ medical records, including history and type of hepatitis, comorbidity, serum α-fetoprotein (α-FP) level, volumetric changes in tumor, length of survival, and the dose, duration, side effects of thalidomide treatment. The tumor response was evaluated. On the basis of these data, the patients were divided into two groups: those with either partial response or stable disease (PR + SD group) and those with progressive disease (PD group). RESULTS: Two of 42 (5%) patients had a partial tumor response after treatment with thalidomide, 200 mg/d, and 9 (21%) had stable disease. Patients in the PR + SD group all had cirrhosis. Comparing patients with and without cirrhosis, the former were more likely to respond to thalidomide therapy (PR + SD: 100% vs PD: 64.5%, P = 0.041 < 0.05). Thalidomide was significantly more likely to be effective in tumors smaller than 5 cm (PR + SD: 63.6% vs PD: 25.8%, P = 0.034 < 0.05). Compared with patients with progressive disease (PD), patients in the PR + SD group had a higher total dose of thalidomide (13 669.4 ± 8446.0 mg vs 22 022.7 ± 11 461.4 mg, P = 0.023 < 0.05) and a longer survival (181.0 ± 107.1 d vs 304.4 ± 167.1 d, P = 0.047 < 0.05). Patients with comorbid disease had a significantly greater incidence of adverse reactions than those without (93.8% vs 60.0%, P = 0.021 < 0.05). The average number of adverse reactions in each person with a comorbid condition was twice as high as in those without other diseases (2.2 ± 1.3 vs 1.1 ± 1.2; P = 0.022 < 0.05). CONCLUSION: Thalidomide therapy is most likely to beeffective in patients with early stage small HCC, espe- cially in those with other underlying diseases. A low dose (200 mg/d) of thalidomide is recommended to continue the treatment long enough to make it展开更多
The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant.However,despite the long use of tacrolimus in clinical practice,the best way to use this agent is still a matter...The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant.However,despite the long use of tacrolimus in clinical practice,the best way to use this agent is still a matter of intense debate.The start of the genomic era has generated new research areas,such as pharmacogenetics,which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body.This variability seems to be correlated with the presence of genetic polymorphisms.Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus;also,unlike phenotypic tests,the genotype is a stable characteristic that needs to be determined only once for any given gene.However,prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication.At present,research has been able to reliably show that the CYP3A5 genotype,but not the CYP3A4 or ABCB1 ones,can modify the pharmacokinetics of tacrolimus.However,it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity.For these reasons,pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing.展开更多
Sirtuin 3(SIRT3)is a deacetylase that modulates proteins that control metabolism and protects against oxidative stress.Modulation of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating ...Sirtuin 3(SIRT3)is a deacetylase that modulates proteins that control metabolism and protects against oxidative stress.Modulation of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating metabolic diseases and associated cardiac disturbances.In this study,we investigated the role of SIRT3 in inflammation and fibrosis in the heart using male mice with constitutive and systemic deletion of SIRT3 and human cardiac AC16 cells.SIRT3 knockout mice showed cardiac fibrosis and inflammation that was characterized by augmented transcriptional activity of AP-1.Consistent with this,SIRT3 overexpression in human and neonatal rat cardiomyocytes partially prevented the inflammatory and profibrotic response induced by TNF-α.Notably,these effects were associated with a decrease in the mRNA and protein levels of FOS and the DNA-binding activity of AP-1.Finally,we demonstrated that SIRT3 inhibits FOS transcription through specific histone H3 lysine K27 deacetylation at its promoter.These findings highlight an important function of SIRT3 in mediating the often intricate profibrotic and proinflammatory responses of cardiac cells through the modulation of the FOS/AP-1 pathway.Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy,heart failure,and diabetic cardiomyopathy,our results point to SIRT3 as a potential target for treating these diseases.展开更多
The pathogenesis of glaucoma is still not fully clarified but a growing body of evidence suggests that neuroinflammation and immune response are part of the sequence of pathological events leading to the optic neuropa...The pathogenesis of glaucoma is still not fully clarified but a growing body of evidence suggests that neuroinflammation and immune response are part of the sequence of pathological events leading to the optic neuropathy. Indeed, inflammation-involving the activation and proliferation of resident glial cells(astrocytes, Muller cells and microglia) and the release of a plethora of anti-and pro-inflammatory cytokines, chemokines and reactive oxygen species-has been reported as common features in clinical and experimental glaucoma. In the insulted retina, as for other neuronal tissues, pathogenic and reparative aspects coexist in the inflammatory process, with extent and persistency affecting the final outcome. In view of this, therapies aimed at modulating the immune and inflammatory responses may represent a promising approach for limiting the optic nerve damage and the loss of retinal ganglion cells associated with glaucoma.展开更多
Mesenchymal stem cells(MSCs)are multipotent stem cells and capable of differentiating into multiple cell types including osteoblastic,chondrogenic and adipogenic lineages.We previously identified BMP9 as one of the mo...Mesenchymal stem cells(MSCs)are multipotent stem cells and capable of differentiating into multiple cell types including osteoblastic,chondrogenic and adipogenic lineages.We previously identified BMP9 as one of the most potent BMPs that induce osteoblastic differentiation of MSCs although exact molecular mechanism through which BMP9 regulates osteogenic differentiation remains to be fully understood.Here,we seek to develop a recombinant adenovirus system to optimally silence mouse BMP9 and then characterize the important role of BMP9 in osteogenic differentiation of MSCs.Using two different siRNA bioinformatic prediction programs,we design five siRNAs targeting mouse BMP9(or simB9),which are expressed under the control of the converging H1 and U6 promoters in recombinant adenovirus vectors.We demonstrate that two of the five siRNAs,simB9-4 and simB9-7,exhibit the highest efficiency on silencing exogenous mouse BMP9 in MSCs.Furthermore,simB9-4 and simB9-7 act synergistically in inhibiting BMP9-induced expression of osteogenic markers,matrix mineralization and ectopic bone formation from MSCs.Thus,our findings demonstrate the important role of BMP9 in osteogenic differentiation of MSCs.The characterized simB9 siRNAs may be used as an important tool to investigate the molecular mechanism behind BMP9 osteogenic signaling.Our results also indicate that recombinant adenovirus-mediated expression of siRNAs is efficient and sustained,and thus may be used as an effective delivery vehicle of siRNA therapeutics.展开更多
Breast cancer is the most common cancer among women. In recent years, many in vitro and in vivo studies indicate that green tea possesses anti-cancer effects. The epidemiological studies, however, have produced inconc...Breast cancer is the most common cancer among women. In recent years, many in vitro and in vivo studies indicate that green tea possesses anti-cancer effects. The epidemiological studies, however, have produced inconclusive results in humans. Likewise, results from animal models about the preventive or therapeutic effects of green tea components are inconclusive. The mechanisms by which green tea intake may influence the risk of breast cancer in humans remain elusive. Here, we review recent studies of green tea polyphenols and their applications in the prevention and treatment of breast cancer. Furthermore, we discuss the effect of green tea components on breast cancer by reviewing epidemiological studies, animal model studies and clinical trials. At last, we discuss the mechanisms by which green tea components suppress the develop-ment and recurrence of breast cancer. A better understanding of the mechanisms will improve the utilization of green tea in breast cancer prevention and therapy and pave the way to novel prevention and treatment strategies for breast cancer.展开更多
BACKGROUND The use of network pharmacology and blood metabolomics to study the patho-genesis of violent aggression in patients with schizophrenia and the related drug mechanisms of action provides new directions for r...BACKGROUND The use of network pharmacology and blood metabolomics to study the patho-genesis of violent aggression in patients with schizophrenia and the related drug mechanisms of action provides new directions for reducing the risk of violent aggression and optimizing treatment plans.AIM To explore the metabolic regulatory mechanism of olanzapine in treating patients with schizophrenia with a moderate to high risk of violent aggression.METHODS Metabolomic technology was used to screen differentially abundant metabolites in patients with schizophrenia with a moderate to high risk of violent aggression before and after olanzapine treatment,and the related metabolic pathways were identified.Network pharmacology was used to establish protein-protein interaction networks of the core targets of olanzapine.Gene Ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were subsequently performed.RESULTS Compared with the healthy group,the patients with schizophrenia group presented significant changes in the levels of 24 metabolites related to the disruption of 9 metabolic pathways,among which the key pathways were the alanine,aspartate and glutamate metabolism and arginine biosynthesis pathways.After treatment with olanzapine,the levels of 10 differentially abundant metabolites were significantly reversed in patients with schizophrenia.Olanzapine effectively regulated six metabolic pathways,among which the key pathways were alanine,aspartate and glutamate metabolism and arginine biosynthesis pathways.Ten core targets of olanzapine were involved in several key pathways.CONCLUSION The metabolic pathways of alanine,aspartate,and glutamate metabolism and arginine biosynthesis are the key pathways involved in olanzapine treatment for aggressive schizophrenia.展开更多
Background:Phytochemicals encompass a diverse array of bioactive substances originating from plants,exhibit-ing a broad spectrum of possible health-promoting effects.Nonetheless,the clinical uses of these compounds ar...Background:Phytochemicals encompass a diverse array of bioactive substances originating from plants,exhibit-ing a broad spectrum of possible health-promoting effects.Nonetheless,the clinical uses of these compounds are restricted due to their limited solubility,stability,bioavailability,and target selectivity.Nanotechnology-based delivery methods present a viable approach to address these problems and enhance the properties and biological activity of phytochemicals.Nanoformulations have the potential to augment the solubility,bioavailability,and pharmacokinetics of phytochemicals by means of several methods.One potential approach to enhance the surface area and solubility of phytochemicals is by lowering their particle size.The process of adsorption of surfactants onto phytochemical particles can lead to the formation of micelles,which exhibit solubility in water.Nanofor-mulations have the potential to enhance the uptake of phytochemicals across many biological barriers,including the intestinal epithelium.Objective:To study the potential of nanoformulation in enhancing the therapeutic action of phytochemicals Method:Systemic review was performed while considering some aspects of PRISM guidelines.Result:The nanoparticles have a great potential in delivering the phytochemicals and could of great help in the management of various diseases.Although,exhaustive research and clinical trials are yet demanded to provide the evidential proof for the same.Conclusion:In conclusion,the utilisation of ligand-functionalized nanoparticles enables the precise targeting of phytochemicals to particular cells or tissues.The field of nanotechnology has significant promise in transform-ing the advancement and administration of phytochemicals for medicinal and preventative applications.The utilisation of nanotechnology holds promise in addressing the obstacles related to the physicochemical charac-teristics of phytochemicals,hence enabling the development of enhanced and precise delivery systems for these advantageous molecules.展开更多
Background:Male infertility poses a growing challenge to the healthcare system,with its prevalence on the rise.Unhealthy lifestyle,food,and addictions such as smoking,alcoholism,etc.accelerate the occurrence.While sev...Background:Male infertility poses a growing challenge to the healthcare system,with its prevalence on the rise.Unhealthy lifestyle,food,and addictions such as smoking,alcoholism,etc.accelerate the occurrence.While several approaches are being investigated to prevent and treat this condition,each therapeutic approach has its drawbacks.Traditional medications continue to play a crucial role in the healthcare system.In recent years,there has been a shift towards determining the efficacy of phytochemicals(or,herbal drugs)as remedies.Objective:To evaluate the effect of various herbs,plant,metabolites,or a part of plant in management of non-genetic male infertility.Methods:The male infertility-associated keywords were searched in PubMed,excluding those non-English writen papers.A total of 146 pertinent and closely connected records were included for full reading and inclusion in the systemic evaluation.Results:The manuscript focuses on individual herbal drug components,their active ingredients,their role in improving the condition and quality of life,and decreasing the prevalence of male infertility.Conclusion:Herbal medicinal plants show promising outcomes to treat male infertility.Herbal alternatives are appealing and have regained popularity.The future holds promise for some of these herbal treatments to advance with many showing improved outcomes in males with infertility issues.展开更多
Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has ev...Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has evolved as a potential therapeutic option for treating Alzheimer’s disease,owing to its rapid advancement over the recent decade.Small interfering ribonucleic acid has recently garnered considerable attention in gene therapy owing to its ability to down-regulate genes with high sequence specificity and an almost limitless number of therapeutic targets,including those that were once considered undruggable.However,lackluster cellular uptake and the destabilization of small interfering ribonucleic acid in its biological environment restrict its therapeutic application,necessitating the development of a vector that can safeguard the genetic material from early destruction within the bloodstream while effectively delivering therapeutic genes across the bloodbrain barrier.Nanotechnology has emerged as a possible solution,and several delivery systems utilizing nanoparticles have been shown to bypass key challenges regarding small interfering ribonucleic acid delivery.By reducing the enzymatic breakdown of genetic components,nanomaterials as gene carriers have considerably enhanced the efficiency of gene therapy.Liposomes,polymeric nanoparticles,magnetic nanoparticles,dendrimers,and micelles are examples of nanocarriers that have been designed,and each has its own set of features.Furthermore,recent advances in the specific delivery of neurotrophic compounds via gene therapy have provided promising results in relation to augmenting cognitive abilities.In this paper,we highlight the use of different nanocarriers in targeted gene delivery and small interfering ribonucleic acid-mediated gene silencing as a potential platform for treating Alzheimer’s disease.展开更多
Background:Breast cancer is one of the most common malignancies affecting women worldwide,emphasizing the need for effective therapeutic strategies.Phytochemicals derived from plants have gained significant attention ...Background:Breast cancer is one of the most common malignancies affecting women worldwide,emphasizing the need for effective therapeutic strategies.Phytochemicals derived from plants have gained significant attention due to their potential anticancer properties.Objective:This review aims to comprehensively assess the existing literature on using phytochemical-loaded for-mulations as a therapeutic approach for breast cancer.By analyzing the available evidence,we aim to determine the potential benefits and limitations of these formulations in terms of their anticancer activity,bioavailability,and safety.Methods:A systematic search of relevant databases was conducted to identify studies investigating phytochemical-loaded formulations in the context of breast cancer treatment.The inclusion criteria encompassed clinical trials,preclinical studies,and in-vitro experiments that reported using phytochemicals in various formulations for breast cancer treatment.Data extraction was performed to ensure the reliability and validity of the included studies.Results:The review highlights the diverse range of phytochemicals used in different formulations for breast cancer treatment.Findings suggest that these formulations exhibit promising anticancer effects by targeting mul-tiple signaling pathways in breast cancer progression,including cell proliferation,apoptosis,angiogenesis,and metastasis.Moreover,various delivery systems,such as nanoparticles,liposomes,and micelles,have enhanced phytochemicals’bioavailability and targeted delivery.Conclusion:Phytochemical-loaded formulations hold immense potential as a therapeutic approach for breast cancer treatment.The reviewed evidence indicates their ability to inhibit tumor growth,enhance chemotherapy effectiveness,and reduce adverse effects.However,further research is warranted to optimize the formulation strategies,investigate the long-term safety profiles,and conduct large-scale clinical trials to establish their efficacy and applicability in clinical settings.These findings contr展开更多
Background:Several trials have been conducted since the beginning of the COVID-19 pandemic to establish possible clinical treatments for the infected individuals.However,many these approaches have failed to demonstrat...Background:Several trials have been conducted since the beginning of the COVID-19 pandemic to establish possible clinical treatments for the infected individuals.However,many these approaches have failed to demonstrate positive results in human clinical trials.In the middle of this investigation,essential oils attracted interest due to their numerous benefits and possible role in management of illness.Essential oils have virucidal effects at nontoxic quantities due to their tiny molecular size,high lipophilicity,and quick commencement of action.Furthermore,the pulmonary exhalation,lower respiratory stimulus,and deep lung transport properties of essential oils increase their potential medicinal usefulness.Objective:The present review aimd to evaluate the potential efficacy of essential oil in management of COVID-19.Methods:Following the Preferred Reporting Items for Systematic Review and Meta-Analysis(PRISMA)guidelines,studies published in English up to January 2024 were searched in the PubMed,Scifinder,and Scopus database,using relevant keywords,such as“Essential oil and COVID-19”,“Essential Oil and Viral Infection”,etc.Those non-English articles,abstracts,conference papers,book chapters,and reviews were excluded.Results:A total of 108 potentially relevant articles were included for full-text review,with the emphasis is on scrutinizing the probable antiviral action of essential oils to inhibit the replication of viruses.We tried to provide an opinion based on different studies performed using the same concept in different corners of the world.Conclusion:Various essential oils hold a great potential to work as an adjuvant therapy in management and prevention of COVID-19.展开更多
The role of copper element has been an increasingly relevant topic in recent years in the fields of human and animal health, for both the study of new drugs and innovative food and feed supplements. This metal plays a...The role of copper element has been an increasingly relevant topic in recent years in the fields of human and animal health, for both the study of new drugs and innovative food and feed supplements. This metal plays an important role in the central nervous system, where it is associated with glutamatergic signaling, and it is widely involved in inflammatory processes. Thus, diseases involving copper(Ⅱ) dyshomeostasis often have neurological symptoms, as exemplified by Alzheimer's and other diseases(such as Parkinson's and Wilson's diseases). Moreover, imbalanced copper ion concentrations have also been associated with diabetes and certain types of cancer, including glioma. In this paper, we propose a comprehensive overview of recent results that show the importance of these metal ions in several pathologies, mainly Alzheimer's disease, through the lens of the development and use of copper chelators as research compounds and potential therapeutics if included in multi-target hybrid drugs. Seeing how copper homeostasis is important for the well-being of animals as well as humans, we shortly describe the state of the art regarding the effects of copper and its chelators in agriculture, livestock rearing, and aquaculture, as ingredients for the formulation of feed supplements as well as to prevent the effects of pollution on animal productions.展开更多
BACKGROUND: Agitation occurs frequently among critically ill patients admitted to the intensive care unit(ICU). We aimed to evaluate the frequency, predisposing factors and outcomes of agitation in trauma ICU. METHODS...BACKGROUND: Agitation occurs frequently among critically ill patients admitted to the intensive care unit(ICU). We aimed to evaluate the frequency, predisposing factors and outcomes of agitation in trauma ICU. METHODS: A retrospective analysis was conducted to include patients who were admitted to the trauma ICU between April 2014 and March 2015. Data included patient's demographics, initial vitals, associated injuries, Ramsey Sedation Scale, Glasgow Coma Scale, head injury lesions, use of sedatives and analgesics, head interventions, ventilator days, and ICU length of stay. Patients were divided into two groups based on the agitation status.RESULTS: A total of 102 intubated patients were enrolled; of which 46(45%) experienced agitation. Patients in the agitation group were 7 years younger, had significantly lower GCS and sustained higher frequency of head injuries(P<0.05). Patients who developed agitation were more likely to be prescribed propofol alone or in combination with midazolam and to have frequent ICP catheter insertion, longer ventilatory days and higher incidence of pneumonia(P<0.05). On multivariate analysis, use of propofol alone(OR=4.97; 95% CI=1.35–18.27), subarachnoid hemorrhage(OR=5.11; 95% CI=1.38–18.91) and ICP catheter insertion for severe head injury(OR=4.23; 95% CI=1.16–15.35) were independent predictors for agitation(P<0.01).CONCLUSION: Agitation is a frequent problem in trauma ICU and is mainly related to the type of sedation and poor outcomes in terms of prolonged mechanical ventilation and development of nosocomial pneumonia. Therefore, understanding the main predictors of agitation facilitates early risk-stratification and development of better therapeutic strategies in trauma patients.展开更多
The RON receptor tyrosine kinase, a member of the MET proto-oncogene family, is a pathogenic factor im- plicated in tumor malignancy. Specifically, aberrations in RON signaling result in increased cancer cell growth, ...The RON receptor tyrosine kinase, a member of the MET proto-oncogene family, is a pathogenic factor im- plicated in tumor malignancy. Specifically, aberrations in RON signaling result in increased cancer cell growth, survival, invasion, angiogenesis, and drug resistance. Biochemical events such as ligand binding, receptor over- expression, generation of structure-defected variants, and point mutations in the kinase domain contribute to RON signaling activation. Recently, functional crosstalk between RON and signaling proteins such as MET and EFGR has emerged as an additional mechanism for RON activation, which is critical for tumorigenic develop- ment. The RON signaling crosstalk acts either as a regulatory feedback loop that strengthens or enhances tumor- igenic phenotype of cancer cells or serves as a signaling compensatory pathway providing a growth/survival ad- vantage for cancer cells to escape targeted therapy. Moreover, viral oncoproteins derived from Friend leukemia or Epstein-Barr viruses interact with RON to drive viral oncogenesis. In cancer cells, RON signaling is integrated into cellular signaling network essential for cancer cell growth and survival. These activities provide the mo- lecular basis of targeting RON for cancer treatment. In this review, we will discuss recent data that uncover the mechanisms of RON activation in cancer cells, review evidence of RON signaling crosstalk relevant to cancer malignancy, and emphasize the significance of the RON signaling addiction by cancer cells for tumor therapy. Understanding aberrant RON signaling will not only provide insight into the mechanisms of tumor pathogenesis, but also lead to the development of novel strategies for molecularly targeted cancer treatment.展开更多
Various vaccine platforms are geared against COVID-19 vaccine development to produce immunogens in cells.To design a recombinant protein-based COVID-19 vaccine,Vaxine pty Ltd used computer models of the spike protein ...Various vaccine platforms are geared against COVID-19 vaccine development to produce immunogens in cells.To design a recombinant protein-based COVID-19 vaccine,Vaxine pty Ltd used computer models of the spike protein and its human receptor,ACE2,to identify how the virus infects human cells.Based on this,the COVAX-19 ■vaccine is synthesized.It does reduce not only COVID-19 disease but also blocks virus shedding and transmission.Researchers are optimistic that this vaccine candidate could be clinically available soon with sufficient vaccine efficacy with a considerable amount of reduction in vaccination-related side effects.展开更多
Endocrine therapy using estrogen receptor-u （ER-α） antagonists for attenuating horm2one-driven cell proliferation is a major treatment modality for breast cancers. To exploit any DNA repair deficiencies associated ...Endocrine therapy using estrogen receptor-u （ER-α） antagonists for attenuating horm2one-driven cell proliferation is a major treatment modality for breast cancers. To exploit any DNA repair deficiencies associated with endocrine therapy, we investigated the functional and physical interactions of ER-α with O^6-methylguanine DNA methyltransferase （MGMT）, a unique DNA repair protein that confers tumor resistance to various anticancer alkylating agents. The ER-α -positive breast cancer cell lines （MCF-7, T47D） and ER- negative cell lines （MDAMB- 468, MDAMB-231）, and established inhibitors of ER-α and MGMT, namely, ICI-182,780 （Faslodex） and O^6- benzylguanine, respectively, were used to study MGMT- ER interactions. The MGMT gene promoter was found to harbor one full and two half estrogen-responsive elements （EREs） and two antioxidant-responsive elements （AREs）. MGMT expression was upregulated by estrogen, downregulated by tamoxifen in Western blot and promoter-linked reporter assays. Similarly, both transient and stable transfections of Nrf-2 （nuclear factor-erythroid 2-related factor-2） increased the levels of MGMT protein and activity 3 to 4-fold reflecting novel regulatory nodes for this dragresistance determinant. Of the different ER-α antagonists tested, the pure anti-estrogen fulvestrant was most potent in inhibiting the MGMT activity in a dose, time and ER-α dependent manner, similar to O^6-benzylguanine. Interestingly, fulvestrant exposure led to a degradation of both ER-α and MGMT proteins and O^6-benzylguanine also induced a specific loss of ER-a and MGMT proteins in MCF-7 and T47D breast cancer cells with similar kinetics. Immunoprecipitation revealed a specific association of ER-a and MGMT proteins in breast cancer cells. Furthermore, silencing of MGMT gene expression triggered a decrease in the levels of both MGMT and ER-a proteins. The involvement of proteasome in the drug-induced degradation of both proteins was also demonstrated. Fulvestrant enhanced the cytotox展开更多
Clustered regulatory interspaced short palindromic repeats(CRISPR)has changed biomedical research and provided entirely new models to analyze every aspect of biomedical sciences during the last decade.In the study of ...Clustered regulatory interspaced short palindromic repeats(CRISPR)has changed biomedical research and provided entirely new models to analyze every aspect of biomedical sciences during the last decade.In the study of cancer,the CRISPR/CRISPR-associated protein(Cas)system opens new avenues into issues that were once unknown in our knowledge of the non-coding genome,tumor heterogeneity,and precision medicines.CRISPR/Cas-based geneediting technology now allows for the precise and permanent targeting of mutations and provides an opportunity to target small non-coding RNAs such as microRNAs(miRNAs).However,the development of effective and safe cancer gene editing therapy is highly dependent on proper design to be innocuous to normal cells and prevent introducing other abnormalities.This study aims to highlight the cutting-edge approaches in cancer-gene editing therapy based on the CRISPR/Cas technology to target miRNAs in cancer therapy.Furthermore,we highlight the potential challenges in CRISPR/Cas-mediated miRNA gene editing and offer advanced strategies to overcome them.展开更多
Bone tissue engineering requires a combination of materials,cells,growth factors and mechanical cues to recapitulate bone formation.In this study we evaluated hybrid hydrogels for minimally invasive bone formation by ...Bone tissue engineering requires a combination of materials,cells,growth factors and mechanical cues to recapitulate bone formation.In this study we evaluated hybrid hydrogels for minimally invasive bone formation by combining biomaterials with skeletal stem cells and staged release of growth factors together with mechanotransduction.Hybrid hydrogels consisting of alginate and decellularized,demineralised bone extracellular matrix(ALG/ECM)were seeded with Stro-1t human bone marrow stromal cells(HBMSCs).Dual combinations of growth factors within staged-release polylactic-co-glycolic acid(PLGA)microparticles were added to hydrogels to mimic,in part,the signalling events in bone regeneration:VEGF,TGF-β_(3),PTHrP(fast release),or BMP-2,vitamin D_(3)(slow release).Mechanotransduction was initiated using magnetic fields to remotely actuate superparamagnetic nanoparticles(MNP)targeted to TREK1 ion channels.Hybrid hydrogels were implanted subcutaneously within mice for 28 days,and evaluated for bone formation using micro-CT and histology.Control hydrogels lacking HBMSCs,growth factors,or MNP became mineralised,and neither growth factors,HBMSCs,nor mechanotransduction increased bone formation.However,structural differences in the newly-formed bone were influenced by growth factors.Slow release of BMP-2 induced thick bone trabeculae and PTHrP or VitD_(3)increased bone formation.However,fast-release of TGF-β_(3)and VEGF resulted in thin trabeculae.Mechanotransduction reversed the trabecular thinning and increased collagen deposition with PTHrP and VitD_(3).Our findings demonstrate the potential of hybrid ALG/ECM hydrogel–cell–growth factor constructs to repair bone in combination with mechanotransduction for fine-tuning bone structure.This approach may form a minimally invasive reparative strategy for bone tissue engineering applications.展开更多
In recent years,a lot of research has been done on silver nanoparticles(SNP)due to their numerous applications in the biomedical,pharmaceutical,and drug delivery industries.In this present study SNP were green synthes...In recent years,a lot of research has been done on silver nanoparticles(SNP)due to their numerous applications in the biomedical,pharmaceutical,and drug delivery industries.In this present study SNP were green synthesized using Melicope lunu-ankenda(M.lunu-ankenda)leaf extract.The addition of AgNO3 causes a color change.L-arginine addition results in further colour changes confirming conjugation.A UV–Vis spectrophotometric examination showed that the absorption peak for SNP was 435 nm,while the peak for L-arginine SNP(cSNP)was 422 nm.FTIR analysis confirmed the association of amides and amines with nanoparticles.The spherical nature of the silver was disclosed by SEM,and its elemental character is verified by EDS.The thermal stability of the nanoparticles is determined by TGA analysis,while TEM examination verifies their spherical shape.Using the MTT assay,these cSNP exhibited outstanding toxicity analysis(IC5038.72μg/ml)against MDA-MB-231 cells.These cSNP causes damage to the mitochondria(JC1 staining),which causes oxidative stress and the production of ROS with 83%of DCF expression in cancer cells.Furthermore,as demonstrated by the Comet assay and DAPI,these cSNP cause good DNA damage in the treated cells.Additionally,using flow cytometry,cSNPs potentially trigger apoptosis by triggering the expression of caspase 3 and caspase 8 proteins.Additionally,through CAM,cSNP demonstrated strong anti-angiogenesis activity by reducing the number of blood vessel branches.These findings suggest that cSNP may be crucial for drug delivery and cancer treatment.展开更多
文摘AIM: To evaluate which patients with hepatocellular carcinoma (HCC) are most likely to respond to thalidomide treatment. METHODS: From July 2002 to July 2004, patients with HCC who received thalidomide treatment, were enrolled. We extracted relevant data from the patients’ medical records, including history and type of hepatitis, comorbidity, serum α-fetoprotein (α-FP) level, volumetric changes in tumor, length of survival, and the dose, duration, side effects of thalidomide treatment. The tumor response was evaluated. On the basis of these data, the patients were divided into two groups: those with either partial response or stable disease (PR + SD group) and those with progressive disease (PD group). RESULTS: Two of 42 (5%) patients had a partial tumor response after treatment with thalidomide, 200 mg/d, and 9 (21%) had stable disease. Patients in the PR + SD group all had cirrhosis. Comparing patients with and without cirrhosis, the former were more likely to respond to thalidomide therapy (PR + SD: 100% vs PD: 64.5%, P = 0.041 < 0.05). Thalidomide was significantly more likely to be effective in tumors smaller than 5 cm (PR + SD: 63.6% vs PD: 25.8%, P = 0.034 < 0.05). Compared with patients with progressive disease (PD), patients in the PR + SD group had a higher total dose of thalidomide (13 669.4 ± 8446.0 mg vs 22 022.7 ± 11 461.4 mg, P = 0.023 < 0.05) and a longer survival (181.0 ± 107.1 d vs 304.4 ± 167.1 d, P = 0.047 < 0.05). Patients with comorbid disease had a significantly greater incidence of adverse reactions than those without (93.8% vs 60.0%, P = 0.021 < 0.05). The average number of adverse reactions in each person with a comorbid condition was twice as high as in those without other diseases (2.2 ± 1.3 vs 1.1 ± 1.2; P = 0.022 < 0.05). CONCLUSION: Thalidomide therapy is most likely to beeffective in patients with early stage small HCC, espe- cially in those with other underlying diseases. A low dose (200 mg/d) of thalidomide is recommended to continue the treatment long enough to make it
文摘The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant.However,despite the long use of tacrolimus in clinical practice,the best way to use this agent is still a matter of intense debate.The start of the genomic era has generated new research areas,such as pharmacogenetics,which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body.This variability seems to be correlated with the presence of genetic polymorphisms.Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus;also,unlike phenotypic tests,the genotype is a stable characteristic that needs to be determined only once for any given gene.However,prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication.At present,research has been able to reliably show that the CYP3A5 genotype,but not the CYP3A4 or ABCB1 ones,can modify the pharmacokinetics of tacrolimus.However,it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity.For these reasons,pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing.
基金supported by funds from the Spanish Ministry of Economy and Competitiveness(SAF2015-64146-R and RTI2018-093999-B-100)and the“FundacióLa Maratóde TV3”to M.V.-C.
文摘Sirtuin 3(SIRT3)is a deacetylase that modulates proteins that control metabolism and protects against oxidative stress.Modulation of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating metabolic diseases and associated cardiac disturbances.In this study,we investigated the role of SIRT3 in inflammation and fibrosis in the heart using male mice with constitutive and systemic deletion of SIRT3 and human cardiac AC16 cells.SIRT3 knockout mice showed cardiac fibrosis and inflammation that was characterized by augmented transcriptional activity of AP-1.Consistent with this,SIRT3 overexpression in human and neonatal rat cardiomyocytes partially prevented the inflammatory and profibrotic response induced by TNF-α.Notably,these effects were associated with a decrease in the mRNA and protein levels of FOS and the DNA-binding activity of AP-1.Finally,we demonstrated that SIRT3 inhibits FOS transcription through specific histone H3 lysine K27 deacetylation at its promoter.These findings highlight an important function of SIRT3 in mediating the often intricate profibrotic and proinflammatory responses of cardiac cells through the modulation of the FOS/AP-1 pathway.Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy,heart failure,and diabetic cardiomyopathy,our results point to SIRT3 as a potential target for treating these diseases.
文摘The pathogenesis of glaucoma is still not fully clarified but a growing body of evidence suggests that neuroinflammation and immune response are part of the sequence of pathological events leading to the optic neuropathy. Indeed, inflammation-involving the activation and proliferation of resident glial cells(astrocytes, Muller cells and microglia) and the release of a plethora of anti-and pro-inflammatory cytokines, chemokines and reactive oxygen species-has been reported as common features in clinical and experimental glaucoma. In the insulted retina, as for other neuronal tissues, pathogenic and reparative aspects coexist in the inflammatory process, with extent and persistency affecting the final outcome. In view of this, therapies aimed at modulating the immune and inflammatory responses may represent a promising approach for limiting the optic nerve damage and the loss of retinal ganglion cells associated with glaucoma.
基金The reported work was supported in part by research grants from the National Institutes of Health(CA226303,DE020140 to TCH and RRR)the U.S.Department of Defense(OR130096 to JMW)+1 种基金the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust(RRR,TCH),the Scoliosis Research Society(TCH and MJL)the National Key Research and Development Program of China(2016YFC1000803 and 2011CB707906 to TCH).
文摘Mesenchymal stem cells(MSCs)are multipotent stem cells and capable of differentiating into multiple cell types including osteoblastic,chondrogenic and adipogenic lineages.We previously identified BMP9 as one of the most potent BMPs that induce osteoblastic differentiation of MSCs although exact molecular mechanism through which BMP9 regulates osteogenic differentiation remains to be fully understood.Here,we seek to develop a recombinant adenovirus system to optimally silence mouse BMP9 and then characterize the important role of BMP9 in osteogenic differentiation of MSCs.Using two different siRNA bioinformatic prediction programs,we design five siRNAs targeting mouse BMP9(or simB9),which are expressed under the control of the converging H1 and U6 promoters in recombinant adenovirus vectors.We demonstrate that two of the five siRNAs,simB9-4 and simB9-7,exhibit the highest efficiency on silencing exogenous mouse BMP9 in MSCs.Furthermore,simB9-4 and simB9-7 act synergistically in inhibiting BMP9-induced expression of osteogenic markers,matrix mineralization and ectopic bone formation from MSCs.Thus,our findings demonstrate the important role of BMP9 in osteogenic differentiation of MSCs.The characterized simB9 siRNAs may be used as an important tool to investigate the molecular mechanism behind BMP9 osteogenic signaling.Our results also indicate that recombinant adenovirus-mediated expression of siRNAs is efficient and sustained,and thus may be used as an effective delivery vehicle of siRNA therapeutics.
基金Supported by National Natural Science Foundation of China,No.81001587
文摘Breast cancer is the most common cancer among women. In recent years, many in vitro and in vivo studies indicate that green tea possesses anti-cancer effects. The epidemiological studies, however, have produced inconclusive results in humans. Likewise, results from animal models about the preventive or therapeutic effects of green tea components are inconclusive. The mechanisms by which green tea intake may influence the risk of breast cancer in humans remain elusive. Here, we review recent studies of green tea polyphenols and their applications in the prevention and treatment of breast cancer. Furthermore, we discuss the effect of green tea components on breast cancer by reviewing epidemiological studies, animal model studies and clinical trials. At last, we discuss the mechanisms by which green tea components suppress the develop-ment and recurrence of breast cancer. A better understanding of the mechanisms will improve the utilization of green tea in breast cancer prevention and therapy and pave the way to novel prevention and treatment strategies for breast cancer.
基金Supported by Henan Provincial Science and Technology Research Project,No.242102310203.
文摘BACKGROUND The use of network pharmacology and blood metabolomics to study the patho-genesis of violent aggression in patients with schizophrenia and the related drug mechanisms of action provides new directions for reducing the risk of violent aggression and optimizing treatment plans.AIM To explore the metabolic regulatory mechanism of olanzapine in treating patients with schizophrenia with a moderate to high risk of violent aggression.METHODS Metabolomic technology was used to screen differentially abundant metabolites in patients with schizophrenia with a moderate to high risk of violent aggression before and after olanzapine treatment,and the related metabolic pathways were identified.Network pharmacology was used to establish protein-protein interaction networks of the core targets of olanzapine.Gene Ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were subsequently performed.RESULTS Compared with the healthy group,the patients with schizophrenia group presented significant changes in the levels of 24 metabolites related to the disruption of 9 metabolic pathways,among which the key pathways were the alanine,aspartate and glutamate metabolism and arginine biosynthesis pathways.After treatment with olanzapine,the levels of 10 differentially abundant metabolites were significantly reversed in patients with schizophrenia.Olanzapine effectively regulated six metabolic pathways,among which the key pathways were alanine,aspartate and glutamate metabolism and arginine biosynthesis pathways.Ten core targets of olanzapine were involved in several key pathways.CONCLUSION The metabolic pathways of alanine,aspartate,and glutamate metabolism and arginine biosynthesis are the key pathways involved in olanzapine treatment for aggressive schizophrenia.
文摘Background:Phytochemicals encompass a diverse array of bioactive substances originating from plants,exhibit-ing a broad spectrum of possible health-promoting effects.Nonetheless,the clinical uses of these compounds are restricted due to their limited solubility,stability,bioavailability,and target selectivity.Nanotechnology-based delivery methods present a viable approach to address these problems and enhance the properties and biological activity of phytochemicals.Nanoformulations have the potential to augment the solubility,bioavailability,and pharmacokinetics of phytochemicals by means of several methods.One potential approach to enhance the surface area and solubility of phytochemicals is by lowering their particle size.The process of adsorption of surfactants onto phytochemical particles can lead to the formation of micelles,which exhibit solubility in water.Nanofor-mulations have the potential to enhance the uptake of phytochemicals across many biological barriers,including the intestinal epithelium.Objective:To study the potential of nanoformulation in enhancing the therapeutic action of phytochemicals Method:Systemic review was performed while considering some aspects of PRISM guidelines.Result:The nanoparticles have a great potential in delivering the phytochemicals and could of great help in the management of various diseases.Although,exhaustive research and clinical trials are yet demanded to provide the evidential proof for the same.Conclusion:In conclusion,the utilisation of ligand-functionalized nanoparticles enables the precise targeting of phytochemicals to particular cells or tissues.The field of nanotechnology has significant promise in transform-ing the advancement and administration of phytochemicals for medicinal and preventative applications.The utilisation of nanotechnology holds promise in addressing the obstacles related to the physicochemical charac-teristics of phytochemicals,hence enabling the development of enhanced and precise delivery systems for these advantageous molecules.
文摘Background:Male infertility poses a growing challenge to the healthcare system,with its prevalence on the rise.Unhealthy lifestyle,food,and addictions such as smoking,alcoholism,etc.accelerate the occurrence.While several approaches are being investigated to prevent and treat this condition,each therapeutic approach has its drawbacks.Traditional medications continue to play a crucial role in the healthcare system.In recent years,there has been a shift towards determining the efficacy of phytochemicals(or,herbal drugs)as remedies.Objective:To evaluate the effect of various herbs,plant,metabolites,or a part of plant in management of non-genetic male infertility.Methods:The male infertility-associated keywords were searched in PubMed,excluding those non-English writen papers.A total of 146 pertinent and closely connected records were included for full reading and inclusion in the systemic evaluation.Results:The manuscript focuses on individual herbal drug components,their active ingredients,their role in improving the condition and quality of life,and decreasing the prevalence of male infertility.Conclusion:Herbal medicinal plants show promising outcomes to treat male infertility.Herbal alternatives are appealing and have regained popularity.The future holds promise for some of these herbal treatments to advance with many showing improved outcomes in males with infertility issues.
基金supported by the Intramural Research Program National Institute on Aginq,NIH。
文摘Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has evolved as a potential therapeutic option for treating Alzheimer’s disease,owing to its rapid advancement over the recent decade.Small interfering ribonucleic acid has recently garnered considerable attention in gene therapy owing to its ability to down-regulate genes with high sequence specificity and an almost limitless number of therapeutic targets,including those that were once considered undruggable.However,lackluster cellular uptake and the destabilization of small interfering ribonucleic acid in its biological environment restrict its therapeutic application,necessitating the development of a vector that can safeguard the genetic material from early destruction within the bloodstream while effectively delivering therapeutic genes across the bloodbrain barrier.Nanotechnology has emerged as a possible solution,and several delivery systems utilizing nanoparticles have been shown to bypass key challenges regarding small interfering ribonucleic acid delivery.By reducing the enzymatic breakdown of genetic components,nanomaterials as gene carriers have considerably enhanced the efficiency of gene therapy.Liposomes,polymeric nanoparticles,magnetic nanoparticles,dendrimers,and micelles are examples of nanocarriers that have been designed,and each has its own set of features.Furthermore,recent advances in the specific delivery of neurotrophic compounds via gene therapy have provided promising results in relation to augmenting cognitive abilities.In this paper,we highlight the use of different nanocarriers in targeted gene delivery and small interfering ribonucleic acid-mediated gene silencing as a potential platform for treating Alzheimer’s disease.
文摘Background:Breast cancer is one of the most common malignancies affecting women worldwide,emphasizing the need for effective therapeutic strategies.Phytochemicals derived from plants have gained significant attention due to their potential anticancer properties.Objective:This review aims to comprehensively assess the existing literature on using phytochemical-loaded for-mulations as a therapeutic approach for breast cancer.By analyzing the available evidence,we aim to determine the potential benefits and limitations of these formulations in terms of their anticancer activity,bioavailability,and safety.Methods:A systematic search of relevant databases was conducted to identify studies investigating phytochemical-loaded formulations in the context of breast cancer treatment.The inclusion criteria encompassed clinical trials,preclinical studies,and in-vitro experiments that reported using phytochemicals in various formulations for breast cancer treatment.Data extraction was performed to ensure the reliability and validity of the included studies.Results:The review highlights the diverse range of phytochemicals used in different formulations for breast cancer treatment.Findings suggest that these formulations exhibit promising anticancer effects by targeting mul-tiple signaling pathways in breast cancer progression,including cell proliferation,apoptosis,angiogenesis,and metastasis.Moreover,various delivery systems,such as nanoparticles,liposomes,and micelles,have enhanced phytochemicals’bioavailability and targeted delivery.Conclusion:Phytochemical-loaded formulations hold immense potential as a therapeutic approach for breast cancer treatment.The reviewed evidence indicates their ability to inhibit tumor growth,enhance chemotherapy effectiveness,and reduce adverse effects.However,further research is warranted to optimize the formulation strategies,investigate the long-term safety profiles,and conduct large-scale clinical trials to establish their efficacy and applicability in clinical settings.These findings contr
文摘Background:Several trials have been conducted since the beginning of the COVID-19 pandemic to establish possible clinical treatments for the infected individuals.However,many these approaches have failed to demonstrate positive results in human clinical trials.In the middle of this investigation,essential oils attracted interest due to their numerous benefits and possible role in management of illness.Essential oils have virucidal effects at nontoxic quantities due to their tiny molecular size,high lipophilicity,and quick commencement of action.Furthermore,the pulmonary exhalation,lower respiratory stimulus,and deep lung transport properties of essential oils increase their potential medicinal usefulness.Objective:The present review aimd to evaluate the potential efficacy of essential oil in management of COVID-19.Methods:Following the Preferred Reporting Items for Systematic Review and Meta-Analysis(PRISMA)guidelines,studies published in English up to January 2024 were searched in the PubMed,Scifinder,and Scopus database,using relevant keywords,such as“Essential oil and COVID-19”,“Essential Oil and Viral Infection”,etc.Those non-English articles,abstracts,conference papers,book chapters,and reviews were excluded.Results:A total of 108 potentially relevant articles were included for full-text review,with the emphasis is on scrutinizing the probable antiviral action of essential oils to inhibit the replication of viruses.We tried to provide an opinion based on different studies performed using the same concept in different corners of the world.Conclusion:Various essential oils hold a great potential to work as an adjuvant therapy in management and prevention of COVID-19.
文摘The role of copper element has been an increasingly relevant topic in recent years in the fields of human and animal health, for both the study of new drugs and innovative food and feed supplements. This metal plays an important role in the central nervous system, where it is associated with glutamatergic signaling, and it is widely involved in inflammatory processes. Thus, diseases involving copper(Ⅱ) dyshomeostasis often have neurological symptoms, as exemplified by Alzheimer's and other diseases(such as Parkinson's and Wilson's diseases). Moreover, imbalanced copper ion concentrations have also been associated with diabetes and certain types of cancer, including glioma. In this paper, we propose a comprehensive overview of recent results that show the importance of these metal ions in several pathologies, mainly Alzheimer's disease, through the lens of the development and use of copper chelators as research compounds and potential therapeutics if included in multi-target hybrid drugs. Seeing how copper homeostasis is important for the well-being of animals as well as humans, we shortly describe the state of the art regarding the effects of copper and its chelators in agriculture, livestock rearing, and aquaculture, as ingredients for the formulation of feed supplements as well as to prevent the effects of pollution on animal productions.
文摘BACKGROUND: Agitation occurs frequently among critically ill patients admitted to the intensive care unit(ICU). We aimed to evaluate the frequency, predisposing factors and outcomes of agitation in trauma ICU. METHODS: A retrospective analysis was conducted to include patients who were admitted to the trauma ICU between April 2014 and March 2015. Data included patient's demographics, initial vitals, associated injuries, Ramsey Sedation Scale, Glasgow Coma Scale, head injury lesions, use of sedatives and analgesics, head interventions, ventilator days, and ICU length of stay. Patients were divided into two groups based on the agitation status.RESULTS: A total of 102 intubated patients were enrolled; of which 46(45%) experienced agitation. Patients in the agitation group were 7 years younger, had significantly lower GCS and sustained higher frequency of head injuries(P<0.05). Patients who developed agitation were more likely to be prescribed propofol alone or in combination with midazolam and to have frequent ICP catheter insertion, longer ventilatory days and higher incidence of pneumonia(P<0.05). On multivariate analysis, use of propofol alone(OR=4.97; 95% CI=1.35–18.27), subarachnoid hemorrhage(OR=5.11; 95% CI=1.38–18.91) and ICP catheter insertion for severe head injury(OR=4.23; 95% CI=1.16–15.35) were independent predictors for agitation(P<0.01).CONCLUSION: Agitation is a frequent problem in trauma ICU and is mainly related to the type of sedation and poor outcomes in terms of prolonged mechanical ventilation and development of nosocomial pneumonia. Therefore, understanding the main predictors of agitation facilitates early risk-stratification and development of better therapeutic strategies in trauma patients.
基金supported in part by National Institutes of Health grantR01 CA91980 (MHW)a grant from the Amarillo Area Foundation(MHW)supported by NIH grants R01 CA112029 and CA121211
文摘The RON receptor tyrosine kinase, a member of the MET proto-oncogene family, is a pathogenic factor im- plicated in tumor malignancy. Specifically, aberrations in RON signaling result in increased cancer cell growth, survival, invasion, angiogenesis, and drug resistance. Biochemical events such as ligand binding, receptor over- expression, generation of structure-defected variants, and point mutations in the kinase domain contribute to RON signaling activation. Recently, functional crosstalk between RON and signaling proteins such as MET and EFGR has emerged as an additional mechanism for RON activation, which is critical for tumorigenic develop- ment. The RON signaling crosstalk acts either as a regulatory feedback loop that strengthens or enhances tumor- igenic phenotype of cancer cells or serves as a signaling compensatory pathway providing a growth/survival ad- vantage for cancer cells to escape targeted therapy. Moreover, viral oncoproteins derived from Friend leukemia or Epstein-Barr viruses interact with RON to drive viral oncogenesis. In cancer cells, RON signaling is integrated into cellular signaling network essential for cancer cell growth and survival. These activities provide the mo- lecular basis of targeting RON for cancer treatment. In this review, we will discuss recent data that uncover the mechanisms of RON activation in cancer cells, review evidence of RON signaling crosstalk relevant to cancer malignancy, and emphasize the significance of the RON signaling addiction by cancer cells for tumor therapy. Understanding aberrant RON signaling will not only provide insight into the mechanisms of tumor pathogenesis, but also lead to the development of novel strategies for molecularly targeted cancer treatment.
文摘Various vaccine platforms are geared against COVID-19 vaccine development to produce immunogens in cells.To design a recombinant protein-based COVID-19 vaccine,Vaxine pty Ltd used computer models of the spike protein and its human receptor,ACE2,to identify how the virus infects human cells.Based on this,the COVAX-19 ■vaccine is synthesized.It does reduce not only COVID-19 disease but also blocks virus shedding and transmission.Researchers are optimistic that this vaccine candidate could be clinically available soon with sufficient vaccine efficacy with a considerable amount of reduction in vaccination-related side effects.
基金supported by grants from the Cancer Prevention Research Institute of Texas(RP130266)the Carson-Leslie Foundation and the Association for Research of Childhood Cancer
文摘Endocrine therapy using estrogen receptor-u （ER-α） antagonists for attenuating horm2one-driven cell proliferation is a major treatment modality for breast cancers. To exploit any DNA repair deficiencies associated with endocrine therapy, we investigated the functional and physical interactions of ER-α with O^6-methylguanine DNA methyltransferase （MGMT）, a unique DNA repair protein that confers tumor resistance to various anticancer alkylating agents. The ER-α -positive breast cancer cell lines （MCF-7, T47D） and ER- negative cell lines （MDAMB- 468, MDAMB-231）, and established inhibitors of ER-α and MGMT, namely, ICI-182,780 （Faslodex） and O^6- benzylguanine, respectively, were used to study MGMT- ER interactions. The MGMT gene promoter was found to harbor one full and two half estrogen-responsive elements （EREs） and two antioxidant-responsive elements （AREs）. MGMT expression was upregulated by estrogen, downregulated by tamoxifen in Western blot and promoter-linked reporter assays. Similarly, both transient and stable transfections of Nrf-2 （nuclear factor-erythroid 2-related factor-2） increased the levels of MGMT protein and activity 3 to 4-fold reflecting novel regulatory nodes for this dragresistance determinant. Of the different ER-α antagonists tested, the pure anti-estrogen fulvestrant was most potent in inhibiting the MGMT activity in a dose, time and ER-α dependent manner, similar to O^6-benzylguanine. Interestingly, fulvestrant exposure led to a degradation of both ER-α and MGMT proteins and O^6-benzylguanine also induced a specific loss of ER-a and MGMT proteins in MCF-7 and T47D breast cancer cells with similar kinetics. Immunoprecipitation revealed a specific association of ER-a and MGMT proteins in breast cancer cells. Furthermore, silencing of MGMT gene expression triggered a decrease in the levels of both MGMT and ER-a proteins. The involvement of proteasome in the drug-induced degradation of both proteins was also demonstrated. Fulvestrant enhanced the cytotox
文摘Clustered regulatory interspaced short palindromic repeats(CRISPR)has changed biomedical research and provided entirely new models to analyze every aspect of biomedical sciences during the last decade.In the study of cancer,the CRISPR/CRISPR-associated protein(Cas)system opens new avenues into issues that were once unknown in our knowledge of the non-coding genome,tumor heterogeneity,and precision medicines.CRISPR/Cas-based geneediting technology now allows for the precise and permanent targeting of mutations and provides an opportunity to target small non-coding RNAs such as microRNAs(miRNAs).However,the development of effective and safe cancer gene editing therapy is highly dependent on proper design to be innocuous to normal cells and prevent introducing other abnormalities.This study aims to highlight the cutting-edge approaches in cancer-gene editing therapy based on the CRISPR/Cas technology to target miRNAs in cancer therapy.Furthermore,we highlight the potential challenges in CRISPR/Cas-mediated miRNA gene editing and offer advanced strategies to overcome them.
基金supported by the BBSRC(sLOLA grant BB/G010579/1)an EU ERC Advanced Grant DYNACEUTICS(grant no.789119).
文摘Bone tissue engineering requires a combination of materials,cells,growth factors and mechanical cues to recapitulate bone formation.In this study we evaluated hybrid hydrogels for minimally invasive bone formation by combining biomaterials with skeletal stem cells and staged release of growth factors together with mechanotransduction.Hybrid hydrogels consisting of alginate and decellularized,demineralised bone extracellular matrix(ALG/ECM)were seeded with Stro-1t human bone marrow stromal cells(HBMSCs).Dual combinations of growth factors within staged-release polylactic-co-glycolic acid(PLGA)microparticles were added to hydrogels to mimic,in part,the signalling events in bone regeneration:VEGF,TGF-β_(3),PTHrP(fast release),or BMP-2,vitamin D_(3)(slow release).Mechanotransduction was initiated using magnetic fields to remotely actuate superparamagnetic nanoparticles(MNP)targeted to TREK1 ion channels.Hybrid hydrogels were implanted subcutaneously within mice for 28 days,and evaluated for bone formation using micro-CT and histology.Control hydrogels lacking HBMSCs,growth factors,or MNP became mineralised,and neither growth factors,HBMSCs,nor mechanotransduction increased bone formation.However,structural differences in the newly-formed bone were influenced by growth factors.Slow release of BMP-2 induced thick bone trabeculae and PTHrP or VitD_(3)increased bone formation.However,fast-release of TGF-β_(3)and VEGF resulted in thin trabeculae.Mechanotransduction reversed the trabecular thinning and increased collagen deposition with PTHrP and VitD_(3).Our findings demonstrate the potential of hybrid ALG/ECM hydrogel–cell–growth factor constructs to repair bone in combination with mechanotransduction for fine-tuning bone structure.This approach may form a minimally invasive reparative strategy for bone tissue engineering applications.
文摘In recent years,a lot of research has been done on silver nanoparticles(SNP)due to their numerous applications in the biomedical,pharmaceutical,and drug delivery industries.In this present study SNP were green synthesized using Melicope lunu-ankenda(M.lunu-ankenda)leaf extract.The addition of AgNO3 causes a color change.L-arginine addition results in further colour changes confirming conjugation.A UV–Vis spectrophotometric examination showed that the absorption peak for SNP was 435 nm,while the peak for L-arginine SNP(cSNP)was 422 nm.FTIR analysis confirmed the association of amides and amines with nanoparticles.The spherical nature of the silver was disclosed by SEM,and its elemental character is verified by EDS.The thermal stability of the nanoparticles is determined by TGA analysis,while TEM examination verifies their spherical shape.Using the MTT assay,these cSNP exhibited outstanding toxicity analysis(IC5038.72μg/ml)against MDA-MB-231 cells.These cSNP causes damage to the mitochondria(JC1 staining),which causes oxidative stress and the production of ROS with 83%of DCF expression in cancer cells.Furthermore,as demonstrated by the Comet assay and DAPI,these cSNP cause good DNA damage in the treated cells.Additionally,using flow cytometry,cSNPs potentially trigger apoptosis by triggering the expression of caspase 3 and caspase 8 proteins.Additionally,through CAM,cSNP demonstrated strong anti-angiogenesis activity by reducing the number of blood vessel branches.These findings suggest that cSNP may be crucial for drug delivery and cancer treatment.
