During cellular proliferation DNA undergoes frequent rep-lication cycles in which errors inevitably accumulate.DNA simultaneously faces continuous damage from endogenous sources[e.g.,reactive oxygen species(ROS)]and e...During cellular proliferation DNA undergoes frequent rep-lication cycles in which errors inevitably accumulate.DNA simultaneously faces continuous damage from endogenous sources[e.g.,reactive oxygen species(ROS)]and environmen-tal stressors,such as ultraviolet(UV)and ionizing radiation(IR).Such lesions compromise genomic stability and may escalate into DNA double-strand breaks(DSBs).Failure to repair DSBs can ultimately trigger cell death1.展开更多
In the last century,increasing knowledge about glial cells has revealed their importance in brain physiology and disease and an exciting potential target for new therapeutic interventions(Hernández et al.,2021).I...In the last century,increasing knowledge about glial cells has revealed their importance in brain physiology and disease and an exciting potential target for new therapeutic interventions(Hernández et al.,2021).Ischemic stroke is the most common of all types of stroke.As the second leading cause of disability and mortality,ischemic stroke is a serious socio-economic burden worldwide.Although it has been strongly associated with aging,during 2020 COVID-19 emerged as a new risk factor for ischemic stroke in younger patients(Cagnazzo et al.,2021).The only therapy or intervention currently available for humans is early reperfusion after the onset of the first symptoms.However,due to the high risk of brain hemorrhage,these treatments are suitable for only a small percentage of patients.Moreover,reperfusion does not prevent post-injury neurodegeneration,hence the importance of finding new therapeutic alternatives to ameliorate ischemic damage and improve post-stroke quality of life.展开更多
Photothermal therapy(PTT)induces thermoresistance through cellular heat shock response,which impairs the therapeutic efficacy of the PTT.To resolve this problem,we developed a photothermal theranostics(denoted as PMH)...Photothermal therapy(PTT)induces thermoresistance through cellular heat shock response,which impairs the therapeutic efficacy of the PTT.To resolve this problem,we developed a photothermal theranostics(denoted as PMH),which integrated the photothermal conversion agent of PdMo bimetallene with histone deacetylase 6(HDAC6)selected inhibitor(ACY-1215),showing the synergistic antitumor effect both in vitro and in vivo.Mechanistically,under the photoacoustic imaging(PA)navigation,the released ACY-1215 triggered by NIR laser irradiation decrease the heat shock proteins(HSPs)expression and weaken the HDAC6-regulated HSP90 deacetylation,thus hindering the degradation of PTT-induced misfolded or unfold proteins through proteasome dependent pathway.Moreover,mild photothermal therapy(mPTT)treatment compromised the autophagy,which induced by HDAC6 inhibition,leading to mPTTinduced misfolded or unfold proteins further accumulation.Given that inhibition of HDAC6 plus m PTT contribute to tumor eradication.This study develops a promising combination strategy based on m PTT for future cancer treatment.展开更多
Hepatocellular carcinoma(HCC)is an increasingly prevalent and deadly disease that is initiated by different etiological factors,such as alcohol-associated liver disease(ALD),metabolic dysfunction-associated steatohepa...Hepatocellular carcinoma(HCC)is an increasingly prevalent and deadly disease that is initiated by different etiological factors,such as alcohol-associated liver disease(ALD),metabolic dysfunction-associated steatohepatitis(MASH),viral hepatitis,and other hepatotoxic and hepatocarcinogenic agents.The tumor microenvironment(TME)of HCC is characterized by several different fibroblastic and immune cell types,all of which affect the initiation,progression and metastasis of this malignant cancer.This complex immune TME can be divided into an innate component that includes macrophages,neutrophils,dendritic cells,myeloid-derived suppressor cells,mucosal-associated invariant T cells,natural killer cells,natural killer T cells,and innate lymphoid cells,as well as an adaptive component that includes CD4+T cells,CD8+T cells,regulatory T cells,and B cells.In this review,we discuss the latest findings shedding light on the direct or indirect roles of these immune cells(and fibroblastic-like cells such as hepatic stellate cells)in the pathogenesis of HCC.Henceforth,further characterization of this heterogeneous TME is highly important for studying the progression of HCC and developing novel immunotherapeutic treatment options.In line with this,we also review novel groundbreaking experimental techniques and animal models aimed at specifically elucidating this complex TME and discuss emerging immune-based therapeutic strategies intended to treat HCC and predict the efficacy of these immunotherapies.展开更多
Bacteria employ diverse immune systems,such as CRISPR-Cas,to fend offphage infections.A recent study un-covered the unprecedented mechanistic features of the Kongming bacterial defense system,which uniquely ex-ploits ...Bacteria employ diverse immune systems,such as CRISPR-Cas,to fend offphage infections.A recent study un-covered the unprecedented mechanistic features of the Kongming bacterial defense system,which uniquely ex-ploits phage-derived enzymes to synthesize deoxyinosine triphosphate(dITP),thereby triggering host immunity through NAD+depletion.In response,some phages have evolved countermeasures to disrupt dITP synthesis,highlighting the ongoing evolutionary arms race between hosts and pathogens.This discovery not only deepens our understanding of bacterial defense strategies but also paves the way for new insights in biomedical research and synthetic biology.展开更多
Numerous diseases have been connected to protein arginine methylations mediated by protein arginine methyltransferase 5(PRMT5).Clinical investigations of the PRMT5-specific inhibitor GSK3326595 are currently being con...Numerous diseases have been connected to protein arginine methylations mediated by protein arginine methyltransferase 5(PRMT5).Clinical investigations of the PRMT5-specific inhibitor GSK3326595 are currently being conducted,and the results are promising for preventing cancers.However,the detailed mechanism of PRMT5 promoting colorectal cancer(CRC)malignant progression remains unclear.Here,we found that PRMT5 directly catalyzes AlkB homologue 5(ALKBH5)symmetric dimethylation at the R316 residue(meR316-ALKBH5),which enhances TRIM28-mediated ALKBH5 ubiquitination degradation.Then,an ALKBH5 decrease attenuates ALKBH5-mediated m6A demethylation on the CD276 transcript 3′untranslated region,which increases CD276 messenger RNA stability and its expression in CRC cells.Furthermore,a CD276 expression increase facilitates CRC immune evasion by inhibiting cytotoxic T-cell functions.Moreover,we revealed that PRMT5-mediated meR316-ALKBH5 activates CD276 transcription by increasing its messenger RNA m6A modification to increase CRC immune evasion in vitro and in vivo.Furthermore,we consistently showed a strong association between meR316-ALKBH5 and poor outcomes in patients with CRC.Finally,we demonstrated that combining an anti-PD1 antibody with the PRMT5 inhibitor GSK3326595 markedly halts the progression of CRC.Our findings could serve as a basis for the development of a PRMT5-meR316-ALKBH5–CD276 axis-targeting treatment approach for CRC.展开更多
Dear Editor,Chromatin modifications regulate multiple cellular progressions(Bannister and Kouzarides,2011;Zhang et al.,2021).Numerous histone modifications and their correspondent enzymes have been identified in the p...Dear Editor,Chromatin modifications regulate multiple cellular progressions(Bannister and Kouzarides,2011;Zhang et al.,2021).Numerous histone modifications and their correspondent enzymes have been identified in the past decades(Huang et al.,2014)and more histone modification sites and types have been gradually identified in recent years(Kim et al.,2019;Lu et al.,2019).展开更多
Hair growth and regeneration represents a remarkable example of stem cell function.Recent progress emphasizes the micro-and macro-environment that controls the regeneration process.There is a shift from a stem cell-ce...Hair growth and regeneration represents a remarkable example of stem cell function.Recent progress emphasizes the micro-and macro-environment that controls the regeneration process.There is a shift from a stem cell-centered view toward the various layers of regulatory mechanisms that control hair regeneration,which include local growth factors,immune and neuroendocrine signals,and dietary and environmental factors.This is better suited for clinical applica-tion in multiple forms of hair disorders:in male pattern hair loss,the stem cells are largely preserved,but androgen signaling diminishes hair growth;in alopecia areata,an immune attack is targeted toward the growing hair follicle without abrogating its regeneration capability.Genome-wide association studies further revealed the genetic bases of these disorders,although the precise pathological mechanisms of the identified loci remain largely unknown.By analyzing the dysregulation of hair regeneration under pathological conditions,we can better address the complex interactions among stem cells,the differentiated progeny,and mesenchymal components,and highlight the critical role of macroenvironment adjustment that is essential for hair growth and regeneration.The poly-genetic origin of these disorders makes the study of hair regeneration an interesting and challenging field.展开更多
Dear Editor,Tumor-associated macrophages(TAMs)are critical pro-tumor immunocytes and depletion of TAMs has been exploited for cancer therapy.1 However,the phenotypes and functions of TAMs are plastic,TAMs can also be ...Dear Editor,Tumor-associated macrophages(TAMs)are critical pro-tumor immunocytes and depletion of TAMs has been exploited for cancer therapy.1 However,the phenotypes and functions of TAMs are plastic,TAMs can also be effector cells by engulfing tumor cells and recruiting cytotoxic T cells,thus shaping the actions of TAMs is more scientific rational than depleting them indiscriminately.2 To promote the entry of reorienting TAMs into the clinical treatments of tumors,it is essential to explore the underline mechanisms controlling the anti-and pro-tumor activities of TAMs.展开更多
Etoposide is widely used for cancer chemotherapy in the clinic.However,long-term etoposide treatment can lead to adverse effects or drug resistance.To improve the situation,we evaluated the therapeutic efficiency of e...Etoposide is widely used for cancer chemotherapy in the clinic.However,long-term etoposide treatment can lead to adverse effects or drug resistance.To improve the situation,we evaluated the therapeutic efficiency of etoposide combined with inhibitors of bromodomain and extraterminal(BET)family proteins,which have recently emerged as novel anti-cancer targets due to their critical roles in cancer development.Firstly,we showed BRD4,one of the main targets of BET inhibitors,was involved in DNA damage response(DDR)via the homologous recombination(HR)repair pathway.展开更多
基金supported by grants fromthe Shenzhen Medical Research Fund(Grant No.A2302040).
文摘During cellular proliferation DNA undergoes frequent rep-lication cycles in which errors inevitably accumulate.DNA simultaneously faces continuous damage from endogenous sources[e.g.,reactive oxygen species(ROS)]and environmen-tal stressors,such as ultraviolet(UV)and ionizing radiation(IR).Such lesions compromise genomic stability and may escalate into DNA double-strand breaks(DSBs).Failure to repair DSBs can ultimately trigger cell death1.
基金funded by grants from Departamento de Biología, Facultad de Ciencias-Universidad Autónoma de Madrid(BIOUAM03-2020)Spanish Ministry of Science and Innovation(PID2020-115876GB-I00)(to MJPA)
文摘In the last century,increasing knowledge about glial cells has revealed their importance in brain physiology and disease and an exciting potential target for new therapeutic interventions(Hernández et al.,2021).Ischemic stroke is the most common of all types of stroke.As the second leading cause of disability and mortality,ischemic stroke is a serious socio-economic burden worldwide.Although it has been strongly associated with aging,during 2020 COVID-19 emerged as a new risk factor for ischemic stroke in younger patients(Cagnazzo et al.,2021).The only therapy or intervention currently available for humans is early reperfusion after the onset of the first symptoms.However,due to the high risk of brain hemorrhage,these treatments are suitable for only a small percentage of patients.Moreover,reperfusion does not prevent post-injury neurodegeneration,hence the importance of finding new therapeutic alternatives to ameliorate ischemic damage and improve post-stroke quality of life.
基金financially supported by National Key R&D Program of China(Nos.2020YFA0908800,2018YFA0704000)Basic Research Program of Shenzhen(Nos.JCYJ20200109105620482,JCYJ20180507182413022)Shenzhen Science and Technology Program(No.KQTD20190929172538530)。
文摘Photothermal therapy(PTT)induces thermoresistance through cellular heat shock response,which impairs the therapeutic efficacy of the PTT.To resolve this problem,we developed a photothermal theranostics(denoted as PMH),which integrated the photothermal conversion agent of PdMo bimetallene with histone deacetylase 6(HDAC6)selected inhibitor(ACY-1215),showing the synergistic antitumor effect both in vitro and in vivo.Mechanistically,under the photoacoustic imaging(PA)navigation,the released ACY-1215 triggered by NIR laser irradiation decrease the heat shock proteins(HSPs)expression and weaken the HDAC6-regulated HSP90 deacetylation,thus hindering the degradation of PTT-induced misfolded or unfold proteins through proteasome dependent pathway.Moreover,mild photothermal therapy(mPTT)treatment compromised the autophagy,which induced by HDAC6 inhibition,leading to mPTTinduced misfolded or unfold proteins further accumulation.Given that inhibition of HDAC6 plus m PTT contribute to tumor eradication.This study develops a promising combination strategy based on m PTT for future cancer treatment.
基金supported by the intramural program of the NIAAA(Bin Gao)the Institut Universitaire de France(IUF)(Fouad Lafdil)Xin Wei Wang was supported by the intramural program of the NCIl,NIH
文摘Hepatocellular carcinoma(HCC)is an increasingly prevalent and deadly disease that is initiated by different etiological factors,such as alcohol-associated liver disease(ALD),metabolic dysfunction-associated steatohepatitis(MASH),viral hepatitis,and other hepatotoxic and hepatocarcinogenic agents.The tumor microenvironment(TME)of HCC is characterized by several different fibroblastic and immune cell types,all of which affect the initiation,progression and metastasis of this malignant cancer.This complex immune TME can be divided into an innate component that includes macrophages,neutrophils,dendritic cells,myeloid-derived suppressor cells,mucosal-associated invariant T cells,natural killer cells,natural killer T cells,and innate lymphoid cells,as well as an adaptive component that includes CD4+T cells,CD8+T cells,regulatory T cells,and B cells.In this review,we discuss the latest findings shedding light on the direct or indirect roles of these immune cells(and fibroblastic-like cells such as hepatic stellate cells)in the pathogenesis of HCC.Henceforth,further characterization of this heterogeneous TME is highly important for studying the progression of HCC and developing novel immunotherapeutic treatment options.In line with this,we also review novel groundbreaking experimental techniques and animal models aimed at specifically elucidating this complex TME and discuss emerging immune-based therapeutic strategies intended to treat HCC and predict the efficacy of these immunotherapies.
文摘Bacteria employ diverse immune systems,such as CRISPR-Cas,to fend offphage infections.A recent study un-covered the unprecedented mechanistic features of the Kongming bacterial defense system,which uniquely ex-ploits phage-derived enzymes to synthesize deoxyinosine triphosphate(dITP),thereby triggering host immunity through NAD+depletion.In response,some phages have evolved countermeasures to disrupt dITP synthesis,highlighting the ongoing evolutionary arms race between hosts and pathogens.This discovery not only deepens our understanding of bacterial defense strategies but also paves the way for new insights in biomedical research and synthetic biology.
基金supported by grants from the Excellent Youth Foundation of Jiangsu Province,China(BK20220119)the Major Project of the University Natural Science Foundation of Jiangsu Province,China(22KJA310006)+3 种基金the Outstanding Youth Project of the University Natural Science Research in Anhui Province(2024AH020013)the Launch Foundation for High Level Talent Research of Wannan Medical College(WYRCQD2024011)the Key Project of the University Natural Science Research in Anhui Province(2023AH051774)Jiangsu Provincial Key Medical Discipline,the Project of Invigorating Health Care through Science,Technology,and Education(No.ZDXKA2016014).
文摘Numerous diseases have been connected to protein arginine methylations mediated by protein arginine methyltransferase 5(PRMT5).Clinical investigations of the PRMT5-specific inhibitor GSK3326595 are currently being conducted,and the results are promising for preventing cancers.However,the detailed mechanism of PRMT5 promoting colorectal cancer(CRC)malignant progression remains unclear.Here,we found that PRMT5 directly catalyzes AlkB homologue 5(ALKBH5)symmetric dimethylation at the R316 residue(meR316-ALKBH5),which enhances TRIM28-mediated ALKBH5 ubiquitination degradation.Then,an ALKBH5 decrease attenuates ALKBH5-mediated m6A demethylation on the CD276 transcript 3′untranslated region,which increases CD276 messenger RNA stability and its expression in CRC cells.Furthermore,a CD276 expression increase facilitates CRC immune evasion by inhibiting cytotoxic T-cell functions.Moreover,we revealed that PRMT5-mediated meR316-ALKBH5 activates CD276 transcription by increasing its messenger RNA m6A modification to increase CRC immune evasion in vitro and in vivo.Furthermore,we consistently showed a strong association between meR316-ALKBH5 and poor outcomes in patients with CRC.Finally,we demonstrated that combining an anti-PD1 antibody with the PRMT5 inhibitor GSK3326595 markedly halts the progression of CRC.Our findings could serve as a basis for the development of a PRMT5-meR316-ALKBH5–CD276 axis-targeting treatment approach for CRC.
基金supported by the National Natural Science Foundation of China(32090030,81720108027,81530074,82103270)the National Key Research and Development Program of China(2017YFA0503900)+2 种基金Science and Technology Program of Guangdong Province in China(2017B030301016)Shenzhen Municipal Commission of Science and Technology Innovation(JCYJ20170818092450901)China Postdoctoral Science Foundation(2018M643191)。
文摘Dear Editor,Chromatin modifications regulate multiple cellular progressions(Bannister and Kouzarides,2011;Zhang et al.,2021).Numerous histone modifications and their correspondent enzymes have been identified in the past decades(Huang et al.,2014)and more histone modification sites and types have been gradually identified in recent years(Kim et al.,2019;Lu et al.,2019).
基金ZY is supported by the National Natural Science Foundation of China(NSFC 31871468)the Shenzhen University Stable Support Program(20200808172413001).
文摘Hair growth and regeneration represents a remarkable example of stem cell function.Recent progress emphasizes the micro-and macro-environment that controls the regeneration process.There is a shift from a stem cell-centered view toward the various layers of regulatory mechanisms that control hair regeneration,which include local growth factors,immune and neuroendocrine signals,and dietary and environmental factors.This is better suited for clinical applica-tion in multiple forms of hair disorders:in male pattern hair loss,the stem cells are largely preserved,but androgen signaling diminishes hair growth;in alopecia areata,an immune attack is targeted toward the growing hair follicle without abrogating its regeneration capability.Genome-wide association studies further revealed the genetic bases of these disorders,although the precise pathological mechanisms of the identified loci remain largely unknown.By analyzing the dysregulation of hair regeneration under pathological conditions,we can better address the complex interactions among stem cells,the differentiated progeny,and mesenchymal components,and highlight the critical role of macroenvironment adjustment that is essential for hair growth and regeneration.The poly-genetic origin of these disorders makes the study of hair regeneration an interesting and challenging field.
文摘Dear Editor,Tumor-associated macrophages(TAMs)are critical pro-tumor immunocytes and depletion of TAMs has been exploited for cancer therapy.1 However,the phenotypes and functions of TAMs are plastic,TAMs can also be effector cells by engulfing tumor cells and recruiting cytotoxic T cells,thus shaping the actions of TAMs is more scientific rational than depleting them indiscriminately.2 To promote the entry of reorienting TAMs into the clinical treatments of tumors,it is essential to explore the underline mechanisms controlling the anti-and pro-tumor activities of TAMs.
基金supported by the National Key R&D Program of China(No.2017YFA0503900)the National Natural Science Foundation of China(No.32090033,81720108027,81530074,82103275,82002986)+3 种基金the Science and Technology Program of Guangdong Province in China(No.2017B030301016)China Postdoctoral Science Foundation(No.2019M663092)Basic and Applied Basic Research Foundation of Guangdong Province(No.2019A1515110039,2019A1515110041,2021A1515011126)Shenzhen Municipal Commission of Science and Technology Innovation(China)(No.JCYJ20170818092450901,JCYJ20200109114214463).
文摘Etoposide is widely used for cancer chemotherapy in the clinic.However,long-term etoposide treatment can lead to adverse effects or drug resistance.To improve the situation,we evaluated the therapeutic efficiency of etoposide combined with inhibitors of bromodomain and extraterminal(BET)family proteins,which have recently emerged as novel anti-cancer targets due to their critical roles in cancer development.Firstly,we showed BRD4,one of the main targets of BET inhibitors,was involved in DNA damage response(DDR)via the homologous recombination(HR)repair pathway.
