Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors(HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen se...Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors(HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen sensing EGLN prolyl hydroxylases.Hypoxia affects many aspects of cellular growth through both redox effects and through the stabilization of HIFs. The HIF isoforms likely have differential effects on tumor growth via alteration of metabolism, growth, and self-renewal and are likely highly context-dependent. In some tumors such as renal cell carcinoma, the EGLN/HIF axis appears to drive tumorigenesis,while in many others HIF1 and HIF2 may actually have a tumor suppressive role. An emerging role of HIF biology is its effects on the tumor microenvironment. The EGLN/HIF axis plays a key role in regulating the function of the various components of the tumor microenvironment, which include cancer-associated fibroblasts, endothelial cells, immune cells, and the extracellular matrix(ECM). Here, we discuss hypoxia and the diverse roles of HIFs in the setting of tumorigenesis and the maintenance of the tumor microenvironment as well as possible future directions of the field.展开更多
Chaperone-mediated autophagy （CMA）, one of the main pathways of lysosomal proteolysis, is characterized by the selective targeting and direct translocation into the lysosomal lumen of substrate proteins containing a...Chaperone-mediated autophagy （CMA）, one of the main pathways of lysosomal proteolysis, is characterized by the selective targeting and direct translocation into the lysosomal lumen of substrate proteins containing a targeting motif biochemically related to the pentapeptide KFERQ. Along with the other two lysosomal pathways, macro- and micro-autophagy, CMA is essential for maintaining cellular homeostasis and survival by selectively degrading misfolded, oxidized, or damaged cytosolic proteins. CMA plays an important role in pathologies such as cancer, kidney disorders, and neurodegenerative diseases. Neurons are post-mitotic and highly susceptible to dysfunction of cellular quality-control systems. Maintaining a balance between protein synthesis and degradation is critical for neuronal functions and homeostasis. Recent studies have revealed several new mechanisms by which CMA protects neurons through regulating factors critical for their viability and homeostasis. In the current review, we summarize recent advances in the understanding of the regulation and physiology of CMA with a specific focus on its possible roles in neuroprotection.展开更多
The malignant processes deviate from the healthy homeostatic control, and various “tricks” enable malignant cells to avoid the healthy regulation. Consequently, the malignant structures miss the apoptosis and prolif...The malignant processes deviate from the healthy homeostatic control, and various “tricks” enable malignant cells to avoid the healthy regulation. Consequently, the malignant structures miss the apoptosis and proliferate without restriction, and without the formation of communication networks in the newly formed cells. The modulation supports the homeostatic control to rearrange the health regulation processes in various ways. The modulation acts with stochastic processes, using stochastic resonances for molecular excitations, supporting the regulative enzymatic processes. The number of stochastic resonant frequencies is as many as the number of enzymatic reactions. The malignant cells differ structurally and dynamically in their connections and interactions from their healthy host tissues. The radiofrequency carrier is modulated with an appropriate time-fractal (1/f) noise to select the autonomic cancer-cells, destroy them, or force the precancerous, semi-individual cells to participate in the networking connections. The modulation in this way limits the cellular autonomy of malignant cells and boosts the healthy control. The resonant energy triggers apoptotic processes and helps immunogenic actions deliver extracellular genetic information for antigen-presentation. The modulation is applied in clinical practice. The therapy (modulated electro-hyperthermia, mEHT) is intensively used in oncology in complementary applications and for palliative stages, and occasionally even as a monotherapy.展开更多
Over the past century,age-related diseases,such as cancer,type-2 diabetes,obesity,and mental illness,have shown a significant increase,negatively impacting overall quality of life.Studies on aged animal models have un...Over the past century,age-related diseases,such as cancer,type-2 diabetes,obesity,and mental illness,have shown a significant increase,negatively impacting overall quality of life.Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels,including transcriptional,translational,and post-translational processes,resulting from cellular stress and circadian derangements.The circadian clock emerges as a key regulator,sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes,such as stem-cell function,cellular stress responses,and inter-tissue communication,which become disrupted during aging.Given the crucial role of hypothalamic circuits in regulating organismal physiology,metabolic control,sleep homeostasis,and circadian rhythms,and their dependence on these processes,strategies aimed at enhancing hypothalamic and circadian function,including pharmacological and non-pharmacological approaches,offer systemic benefits for healthy aging.Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions,like the hypothalamus,while reducing side effects associated with systemic drug delivery,thereby presenting new therapeutic possibilities for diverse age-related conditions.展开更多
Heat shock transcription factor(HSF)are essential regulators of heat shock protein(HSP)gene expression in plants and algae,contributing to their resilience against biotic and abiotic stresses.However,the localization,...Heat shock transcription factor(HSF)are essential regulators of heat shock protein(HSP)gene expression in plants and algae,contributing to their resilience against biotic and abiotic stresses.However,the localization,structure,phylogenetic relationship,and characteristics of PtHSF genes in microalgae,especially in diatom Phaeodactylum tricornutum,remain largely unexplored.This study presents a comprehensive analysis of the PtHSF gene family in P.tricornutum.A genome-wide analysis identified 68 PtHSF genes,which were classified into two distinct subfamilies:traditional and untraditional.Motif and structure analyses revealed evidence of multiple duplication events within the PtHSF gene family.Expression profiling revealed diurnal patterns,with 34 genes being downregulated during the light period and upregulated during the dark period,while 19 genes exhibited the opposite pattern.These findings suggest that PtHSF genes may have specialized functions during the diurnal cycle and play a crucial role in maintaining cellular homeostasis in response to various stresses.Notably,PtHSF16,30,and 43 genes exhibited higher expression levels,suggesting their potential importance.This study provides a valuable foundation for future investigations into the specific functions of HSFs under different stress conditions and their regulatory mechanisms in P.tricornutum and other microalgae.展开更多
Foxtail millet (Setaria italica L.) is a drought-tolerant millet crop of arid and semi-arid regions. Aldo-keto reductases (AKRs) are significant part of plant defence mechanism, having an ability to confer multiple st...Foxtail millet (Setaria italica L.) is a drought-tolerant millet crop of arid and semi-arid regions. Aldo-keto reductases (AKRs) are significant part of plant defence mechanism, having an ability to confer multiple stress tolerance. In this study, AKR1 gene expression was studied in roots and leaves of foxtail millet subjected to different regimes of PEG- and NaCl-stress for seven days. The quantitative Real-time PCR expression analysis in both root and leaves showed upregulation of AKR1 gene during PEG and salt stress. A close correlation exits between expression of AKR1 gene and the rate of lipid peroxidation along with the retardation of growth. Tissue-specific differences were found in the AKR1 gene expression to the stress intensities studied. The reduction in root and shoot growth under both stress conditions were dependent on stress severity. The level of lipid peroxidation as indicated by MDA formation was significantly increased in roots and leaves along with increased stress levels. Finally, these findings support the early responsive nature of AKR1 gene and seem to be associated at least in part with its ability to contribute in antioxidant defence related pathways which could provide a better protection against oxidative stress under stress conditions.展开更多
Ubiquitination plays a crucial role in retinoic acid-inducible gene I(RIG-I)-induced antiviral responses.However, the precise regulatory mechanisms of RIG-I activity mediated by conjugated and unanchored ubiquitin cha...Ubiquitination plays a crucial role in retinoic acid-inducible gene I(RIG-I)-induced antiviral responses.However, the precise regulatory mechanisms of RIG-I activity mediated by conjugated and unanchored ubiquitin chains remain to be determined. In this study, we discovered that T55 of RIG-I was required for its binding ability for the unanchored ubiquitin chains. Experimental and mathematical analysis showed that unanchored ubiquitin chains associated with RIG-I were essential for sustained activation of type I interferon(IFN) signaling. Transcriptomics study revealed that the binding of RIG-I with unanchored ubiquitin chains additionally regulated the expression of a subset of metabolic and cell fate decision genes. Moreover, we found that ubiquitin-specific peptidase 21(USP21) and USP3 deubiquitinate conjugated and unanchored ubiquitin chains on RIG-I respectively. Taken together, characterization of the regulation mode and functions of conjugated ubiquitination and the unconjugated ubiquitin chainbinding of RIG-I may provide means to fine-tune RIG-I-mediated type I IFN signaling.展开更多
基金supported by funding from Cancer Prevention & Research Institute of Texas (CPRIT, RR140012)V Foundation (V2015-2022)+1 种基金Sabin Family Foundation Fellowship at MD Anderson (2016-00052285)generous support from the McNair Foundation
文摘Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors(HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen sensing EGLN prolyl hydroxylases.Hypoxia affects many aspects of cellular growth through both redox effects and through the stabilization of HIFs. The HIF isoforms likely have differential effects on tumor growth via alteration of metabolism, growth, and self-renewal and are likely highly context-dependent. In some tumors such as renal cell carcinoma, the EGLN/HIF axis appears to drive tumorigenesis,while in many others HIF1 and HIF2 may actually have a tumor suppressive role. An emerging role of HIF biology is its effects on the tumor microenvironment. The EGLN/HIF axis plays a key role in regulating the function of the various components of the tumor microenvironment, which include cancer-associated fibroblasts, endothelial cells, immune cells, and the extracellular matrix(ECM). Here, we discuss hypoxia and the diverse roles of HIFs in the setting of tumorigenesis and the maintenance of the tumor microenvironment as well as possible future directions of the field.
基金partially supported by the FMMU Research FoundationNational Basic Research Development Program of China (2011CB510000)the National Natural Science Foundation of China (31371400)
文摘Chaperone-mediated autophagy （CMA）, one of the main pathways of lysosomal proteolysis, is characterized by the selective targeting and direct translocation into the lysosomal lumen of substrate proteins containing a targeting motif biochemically related to the pentapeptide KFERQ. Along with the other two lysosomal pathways, macro- and micro-autophagy, CMA is essential for maintaining cellular homeostasis and survival by selectively degrading misfolded, oxidized, or damaged cytosolic proteins. CMA plays an important role in pathologies such as cancer, kidney disorders, and neurodegenerative diseases. Neurons are post-mitotic and highly susceptible to dysfunction of cellular quality-control systems. Maintaining a balance between protein synthesis and degradation is critical for neuronal functions and homeostasis. Recent studies have revealed several new mechanisms by which CMA protects neurons through regulating factors critical for their viability and homeostasis. In the current review, we summarize recent advances in the understanding of the regulation and physiology of CMA with a specific focus on its possible roles in neuroprotection.
文摘The malignant processes deviate from the healthy homeostatic control, and various “tricks” enable malignant cells to avoid the healthy regulation. Consequently, the malignant structures miss the apoptosis and proliferate without restriction, and without the formation of communication networks in the newly formed cells. The modulation supports the homeostatic control to rearrange the health regulation processes in various ways. The modulation acts with stochastic processes, using stochastic resonances for molecular excitations, supporting the regulative enzymatic processes. The number of stochastic resonant frequencies is as many as the number of enzymatic reactions. The malignant cells differ structurally and dynamically in their connections and interactions from their healthy host tissues. The radiofrequency carrier is modulated with an appropriate time-fractal (1/f) noise to select the autonomic cancer-cells, destroy them, or force the precancerous, semi-individual cells to participate in the networking connections. The modulation in this way limits the cellular autonomy of malignant cells and boosts the healthy control. The resonant energy triggers apoptotic processes and helps immunogenic actions deliver extracellular genetic information for antigen-presentation. The modulation is applied in clinical practice. The therapy (modulated electro-hyperthermia, mEHT) is intensively used in oncology in complementary applications and for palliative stages, and occasionally even as a monotherapy.
基金supported by National Council of Science and Technology(CONACYT)(grants FC 2016/2672 and FOSISS 272757),INMEGEN(09/2017/I)the Ministry of Education,Science,Technology and Innovation of Mexico City(SECTEI)(grant 228/2021).
文摘Over the past century,age-related diseases,such as cancer,type-2 diabetes,obesity,and mental illness,have shown a significant increase,negatively impacting overall quality of life.Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels,including transcriptional,translational,and post-translational processes,resulting from cellular stress and circadian derangements.The circadian clock emerges as a key regulator,sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes,such as stem-cell function,cellular stress responses,and inter-tissue communication,which become disrupted during aging.Given the crucial role of hypothalamic circuits in regulating organismal physiology,metabolic control,sleep homeostasis,and circadian rhythms,and their dependence on these processes,strategies aimed at enhancing hypothalamic and circadian function,including pharmacological and non-pharmacological approaches,offer systemic benefits for healthy aging.Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions,like the hypothalamus,while reducing side effects associated with systemic drug delivery,thereby presenting new therapeutic possibilities for diverse age-related conditions.
基金fundings of educational and scientific research projects for young and middle-aged teachers in Fujian Province(Grant number:2022JAT220693)Natural Science Foundation of Guangdong Province(Grant numbers:2024A1515013029 and 2022A1515012141).
文摘Heat shock transcription factor(HSF)are essential regulators of heat shock protein(HSP)gene expression in plants and algae,contributing to their resilience against biotic and abiotic stresses.However,the localization,structure,phylogenetic relationship,and characteristics of PtHSF genes in microalgae,especially in diatom Phaeodactylum tricornutum,remain largely unexplored.This study presents a comprehensive analysis of the PtHSF gene family in P.tricornutum.A genome-wide analysis identified 68 PtHSF genes,which were classified into two distinct subfamilies:traditional and untraditional.Motif and structure analyses revealed evidence of multiple duplication events within the PtHSF gene family.Expression profiling revealed diurnal patterns,with 34 genes being downregulated during the light period and upregulated during the dark period,while 19 genes exhibited the opposite pattern.These findings suggest that PtHSF genes may have specialized functions during the diurnal cycle and play a crucial role in maintaining cellular homeostasis in response to various stresses.Notably,PtHSF16,30,and 43 genes exhibited higher expression levels,suggesting their potential importance.This study provides a valuable foundation for future investigations into the specific functions of HSFs under different stress conditions and their regulatory mechanisms in P.tricornutum and other microalgae.
文摘Foxtail millet (Setaria italica L.) is a drought-tolerant millet crop of arid and semi-arid regions. Aldo-keto reductases (AKRs) are significant part of plant defence mechanism, having an ability to confer multiple stress tolerance. In this study, AKR1 gene expression was studied in roots and leaves of foxtail millet subjected to different regimes of PEG- and NaCl-stress for seven days. The quantitative Real-time PCR expression analysis in both root and leaves showed upregulation of AKR1 gene during PEG and salt stress. A close correlation exits between expression of AKR1 gene and the rate of lipid peroxidation along with the retardation of growth. Tissue-specific differences were found in the AKR1 gene expression to the stress intensities studied. The reduction in root and shoot growth under both stress conditions were dependent on stress severity. The level of lipid peroxidation as indicated by MDA formation was significantly increased in roots and leaves along with increased stress levels. Finally, these findings support the early responsive nature of AKR1 gene and seem to be associated at least in part with its ability to contribute in antioxidant defence related pathways which could provide a better protection against oxidative stress under stress conditions.
基金supported by the National Key Research and Development Program of China(2020YFA0908700)the National Natural Science Foundation of China(31870862,31700760,31770978,and 91742109)+4 种基金China Postdoctoral Science Foundation(2019M663225)Science and Technology Planning Project of GuangzhouChina(201804010385)Fundamental Research Funds for the Central Universities(18lgpy49)Guangdong Basic and Applied Basic Research Foundation(2019A1515110508)。
文摘Ubiquitination plays a crucial role in retinoic acid-inducible gene I(RIG-I)-induced antiviral responses.However, the precise regulatory mechanisms of RIG-I activity mediated by conjugated and unanchored ubiquitin chains remain to be determined. In this study, we discovered that T55 of RIG-I was required for its binding ability for the unanchored ubiquitin chains. Experimental and mathematical analysis showed that unanchored ubiquitin chains associated with RIG-I were essential for sustained activation of type I interferon(IFN) signaling. Transcriptomics study revealed that the binding of RIG-I with unanchored ubiquitin chains additionally regulated the expression of a subset of metabolic and cell fate decision genes. Moreover, we found that ubiquitin-specific peptidase 21(USP21) and USP3 deubiquitinate conjugated and unanchored ubiquitin chains on RIG-I respectively. Taken together, characterization of the regulation mode and functions of conjugated ubiquitination and the unconjugated ubiquitin chainbinding of RIG-I may provide means to fine-tune RIG-I-mediated type I IFN signaling.
