Efficient immune responses against invading pathogens often involve coordination between cells from both the innate and adaptive immune systems.For multiple decades,it has been believed that CD8+memory T cells and nat...Efficient immune responses against invading pathogens often involve coordination between cells from both the innate and adaptive immune systems.For multiple decades,it has been believed that CD8+memory T cells and natural killer(NK)cells constantly and uniformly recirculate.Only recently was the existence of noncirculating memory T and NK cells that remain resident in the peripheral tissues,termed tissue-resident memory T(TRM)cells and tissue-resident NK(trNK)cells,observed in various organs owing to improved techniques.TRM cells populate a wide range of peripheral organs,including the skin,sensory ganglia,gut,lungs,brain,salivary glands,female reproductive tract,and others.Recent findings have demonstrated the existence of TRM in the secondary lymphoid organs(SLOs)as well,leading to revision of the classic theory that they exist only in peripheral organs.trNK cells have been identified in the uterus,skin,kidney,adipose tissue,and salivary glands.These tissue-resident lymphocytes do not recirculate in the blood or lymphatic system and often adopt a unique phenotype that is distinct from those of circulating immune cells.In this review,we will discuss the recent findings on the tissue residency of both innate and adaptive lymphocytes,with a particular focus on CD8+memory T cells,and describe some advances regarding unconventional T cells(invariant NKT cells,mucosal-associated invariant T cells(MAIT),andγδT cells)and the emerging family of trNK cells.Specifically,we will focus on the phenotypes and functions of these subsets and discuss their implications in anti-viral and anti-tumor immunity.展开更多
Innate immunity is critical for the control of virus infection and operates to restrict viral susceptibility and direct antiviral immunity for protection from acute or chronic viral-associated diseases including cance...Innate immunity is critical for the control of virus infection and operates to restrict viral susceptibility and direct antiviral immunity for protection from acute or chronic viral-associated diseases including cancer. RIG-I like receptors(RLRs) are cytosolic RNA helicases that function as pathogen recognition receptors to detect RNA pathogen associated molecular patterns(PAMPs) of virus infection. The RLRs include RIG-I, MDA5, and LGP2. They function to recognize and bind to PAMP motifs within viral RNA in a process that directs the RLR to trigger downstream signaling cascades that induce innate immunity that controls viral replication and spread. Products of RLR signaling also serve to modulate the adaptive immune response to infection. Recent studies have additionally connected RLRs to signaling cascades that impart inflammatory and apoptotic responses to virus infection. Viral evasion of RLR signaling supports viral outgrowth and pathogenesis, including the onset of viral-associated cancer.展开更多
Most Aloe species are used as new food or functional food ingredient.Even though widely known for its health benefits,the anti-inflammatory effects and underlying mechanisms of Aloin(Alo),an anthraquinone compound iso...Most Aloe species are used as new food or functional food ingredient.Even though widely known for its health benefits,the anti-inflammatory effects and underlying mechanisms of Aloin(Alo),an anthraquinone compound isolated from plant species of the genus Aloe,remain unidentified.Here,we investigated the protective effects of Alo against cecal ligation and puncture(CLP)-induced sepsis and microflora in mice.Alo significantly improved CLP-induced sepsis and the survival rate of septic mice,downregulated the expression of proinflammatory factors,and decreased the infiltration of inflammatory cells in tissues.Alo upregulated the proportion of peritoneal macrophages,reduced the number of peritoneal bacteria,decreased the content of short-chain fatty acids and bile acids in the abdominal cavity,and suppressed Toll-like receptor(TLR)-2/4/nuclear factor kappa-B(NF-κB)/NOD-like receptor thermal protein domain associated protein 3(NLRP3)/Caspase-1/3/8 signaling.Furthermore,Alo altered the composition of the microbiome and promoted the growth of Lactobacillus,which showed a stronger anti-inflammatory effect.Whole-genome analysis identified the genes Saa3,Il10,Fpr1,and Eif4a1 associated with the protective effects of Alo in mice with CLP-induced sepsis.Overall,our results provide novel insights into the therapeutic potential and mechanism of action of Alo in the treatment of sepsis.展开更多
Multiple morphological abnormalities of sperm flagella(MMAF)is a severe form of asthenoteratozoospermia,characterized by morphological abnormalities and reduced motility of sperm,causing male infertility.Although appr...Multiple morphological abnormalities of sperm flagella(MMAF)is a severe form of asthenoteratozoospermia,characterized by morphological abnormalities and reduced motility of sperm,causing male infertility.Although approximately 60%of MMAF cases can be explained genetically,the etiology of the remaining cases is unclear.Here,we identified two novel compound heterozygous variants in the gene,dynein axonemal heavy chain 10(DNAH10),in three patients from two unrelated Pakistani families using whole-exome sequencing(WES),including one compound heterozygous mutation(DNAH10:c.9409C>A[p.P3137T];c.12946G>C[p.D4316H])in family 1 and another compound heterozygous mutation(DNAH10:c.8849G>A[p.G2950D];c.11509C>T[p.R3687W])in family 2.All the identified variants are absent or rare in public genome databases and are predicted to have deleterious effects according to multiple bioinformatic tools.Sanger sequencing revealed that these variants follow an autosomal recessive mode of inheritance.Hematoxylin and eosin(H&E)staining revealed MMAF,including sperm head abnormalities,in the patients.In addition,immunofluorescence staining revealed loss of DNAH10 protein signals along sperm flagella.These findings broaden the spectrum of DNAH10 variants and expand understanding of the genetic basis of male infertility associated with the MMAF phenotype.展开更多
Multiple morphological abnormalities of the flagella(MMAF)represent a severe form of sperm defects leading to asthenozoospermia and male infertility.In this study,we identified a novel homozygous splicing mutation(c.8...Multiple morphological abnormalities of the flagella(MMAF)represent a severe form of sperm defects leading to asthenozoospermia and male infertility.In this study,we identified a novel homozygous splicing mutation(c.871-4 ACA>A)in the adenylate kinase 7(AK7)gene by whole-exome sequencing in infertile individuals.Spermatozoa from affected individuals exhibited typical MMAF characteristics,including coiled,bent,short,absent,and irregular flagella.Transmission electron microscopy analysis showed disorganized axonemal structure and abnormal mitochondrial sheets in sperm flagella.Immunofluorescence staining confirmed the absence of AK7 protein from the patients’spermatozoa,validating the pathogenic nature of the mutation.This study provides direct evidence linking the AK7 gene to MMAF-associated asthenozoospermia in humans,expanding the mutational spectrum of AK7 and enhancing our understanding of the genetic basis of male infertility.展开更多
Discoidin domain receptor 1(DDR1)is overexpressed in various tumors,such as triple-negative breast cancer(TNBC),and is rarely expressed in normal tissues.These characteristics make DDR1 a preferable target candidate f...Discoidin domain receptor 1(DDR1)is overexpressed in various tumors,such as triple-negative breast cancer(TNBC),and is rarely expressed in normal tissues.These characteristics make DDR1 a preferable target candidate for the construction of an antibody-drug conjugate(ADC)for targeted therapy.Here,we investigated the preparation and preclinical efficacy of DDR1-DX8951,an ADC that includes an anti-DDR1 monoclonal antibody conjugated to DX8951 by a cleavable Gly-Gly-Phe-Gly(GGFG)linker.The anti-DDR1 monoclonal antibody was coupled to DX8951(i.e.,DDR1-DX8951),producing the targeted therapy ADC.The antitumor activities of DDR1-DX8951 monotherapy or DDR1-DX8951 plus pembrolizumab were assessed in TNBC mouse models.DDR1-DX8951 can specifically target DDR1,be quickly internalized by TNBC cells,and reduce the viability of TNBC cells in vitro.The potent antitumor activity of DDR1-DX8951 was revealed in TNBC xenograft models.Importantly,our investigation demonstrated that DDR1-DX8951 plus pembrolizumab not only revealed the inhibitory efficacy on tumor growth and metastasis but also played an important role in improving the immunosuppressive tumor microenvironment(TME)of TNBC.Taken together,this investigation provides justification for large-sample studies to further assess the safety and efficacy of DDR1-DX8951 plus pembrolizumab for TNBC clinical trials.展开更多
Carrimycin(CA),sanctioned by China’s National Medical Products Administration(NMPA)in 2019 for treating acute bronchitis and sinusitis,has recently been observed to exhibit multifaceted biological activities,encompas...Carrimycin(CA),sanctioned by China’s National Medical Products Administration(NMPA)in 2019 for treating acute bronchitis and sinusitis,has recently been observed to exhibit multifaceted biological activities,encompassing anti-inflammatory,antiviral,and anti-tumor properties.Despite these applications,its efficacy in sepsis treatment remains unexplored.This study introduces a novel function of CA,demonstrating its capacity to mitigate sepsis induced by lipopolysaccharide(LPS)and cecal ligation and puncture(CLP)in mice models.Our research employed in vitro assays,real-time quantitative polymerase chain reaction(RT-qPCR),and RNA-seq analysis to establish that CA significantly reduces the levels of pro-inflammatory cytokines,namely tumor necrosis factor-alpha(TNF-α),interleukin 1 beta(IL-1β),and interleukin 6(IL-6),in response to LPS stimulation.Additionally,Western blotting and immunofluorescence assays revealed that CA impedes Nuclear Factor Kappa B(NF-κB)activation in LPS-stimulated RAW264.7 cells.Complementing these findings,in vivo experiments demonstrated that CA effectively alleviates LPS-and CLP-triggered organ inflammation in C57BL/6 mice.Further insights were gained through 16S sequencing,highlighting CA’s pivotal role in enhancing gut microbiota diversity and modulating metabolic pathways,particularly by augmenting the production of short-chain fatty acids in mice subjected to CLP.Notably,a comparative analysis revealed that CA’s anti-inflammatory efficacy surpasses that of equivalent doses of aspirin(ASP)and TIENAM.Collectively,these findings suggest that CA exhibits significant therapeutic potential in sepsis treatment.This discovery provides a foundational theoretical basis for the clinical application of CA in sepsis management.展开更多
Objective: The human cluster of differentiation(CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer(...Objective: The human cluster of differentiation(CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer(NK) cells targeting hematologic malignancies(HMs).Methods: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine(PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients.Results: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS–CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an “exhausted” phenotype of intratumoral NK cells in patients with HMs or solid tumors.Conclusions: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.展开更多
Objective Hepatocellular carcinoma(HCC)is the third leading cause of cancer-associated death worldwide.As a first-line drug for advanced HCC treatment,lenvatinib faces a significant hurdle due to the development of bo...Objective Hepatocellular carcinoma(HCC)is the third leading cause of cancer-associated death worldwide.As a first-line drug for advanced HCC treatment,lenvatinib faces a significant hurdle due to the development of both intrinsic and acquired resistance among patients,and the underlying mechanism remains largely unknown.The present study aims to identify the pivotal gene responsible for lenvatinib resistance in HCC,explore the potential molecular mechanism,and propose combinatorial therapeutic targets for HCC management.Methods Cell viability and colony formation assays were conducted to evaluate the sensitivity of cells to lenvatinib and dicoumarol.RNA-Seq was used to determine the differences in transcriptome between parental cells and lenvatinib-resistant(LR)cells.The upregulated genes were analyzed by GO and KEGG analyses.Then,qPCR and Western blotting were employed to determine the relative gene expression levels.Afterwards,the intracellular reactive oxygen species(ROS)and apoptosis were detected by flow cytometry.Results PLC-LR and Hep3B-LR were established.There was a total of 116 significantly upregulated genes common to both LR cell lines.The GO and KEGG analyses indicated that these genes were involved in oxidoreductase and dehydrogenase activities,and reactive oxygen species pathways.Notably,NAD(P)H:quinone oxidoreductase 1(NQO1)was highly expressed in LR cells,and was involved in the lenvatinib resistance.The high expression of NQO1 decreased the production of ROS induced by lenvatinib,and subsequently suppressed the apoptosis.The combination of lenvatinib and NQO1 inhibitor,dicoumarol,reversed the resistance of LR cells.Conclusion The high NQO1 expression in HCC cells impedes the lenvatinib-induced apoptosis by regulating the ROS levels,thereby promoting lenvatinib resistance in HCC cells.展开更多
Toll and Toll-like receptors(TLRs)are pivotal components of the innate immune system,playing a crucial role in the early defense against invading pathogens.These receptors basically recognize microbial components and ...Toll and Toll-like receptors(TLRs)are pivotal components of the innate immune system,playing a crucial role in the early defense against invading pathogens.These receptors basically recognize microbial components and thus spread the presence of pathogens to the host and activate signaling pathways that lead to an appropriate immune response.Their discoveries and studies in the late 80s/early90s have initiated the understanding of how organisms detect and respond to microbial infections(Hoffmann et al.,1999;Medzhitov and Janeway,2000;Akira et al.,2006;Nusslein-Volhard,2021).展开更多
The host antimicrobial immune response relies on a complex interplay of molecular mechanisms to effectively combat microbial infections.Herein,we investigate the functional role of Cullin-3(Cul3),one critical constitu...The host antimicrobial immune response relies on a complex interplay of molecular mechanisms to effectively combat microbial infections.Herein,we investigate the functional role of Cullin-3(Cul3),one critical constituent of Cullin-RING ubiquitin ligases,in the Drosophila melanogaster(fruit fly)antimicrobial immune defense.Weshow that silencing of Cul3 leads to a decreased induction of antimicrobial peptides and high mortality in adult flies after bacterial infection.Through biochemical approaches,we demonstrate that Cul3 predominantly relies on its BTB-binding domain and neddylation domain to physically associate with death-associated inhibitor of apoptosis 2(Diap2).Importantly,Cul3 ameliorates the Diap2-mediated ubiquitination of death-related ced-3/Nedd2-like caspase(Dredd),a process essential for robust immune deficiency signaling upon bacterial infection.Taken together,our findings highlight a previously unrecognized regulatory axis of Cul3/Diap2/Dredd in the fly antimicrobial immune defense,providing potential insights into therapeutic strategies for combating bacterial infections in humans.展开更多
In their natural habitats,bacteria thrive in densely populated environments(such as soil and the human gut)and compete with other microorganisms for ecological niches[1].Secretion systems enable bacteria to export pro...In their natural habitats,bacteria thrive in densely populated environments(such as soil and the human gut)and compete with other microorganisms for ecological niches[1].Secretion systems enable bacteria to export proteins into their surroundings and play key roles in interbacterial competition,development,nutrient acquisition,and virulence[2–4].Type VII secretion system b(T7SSb)has been primarily identified in low-G+C Firmicutes,which exhibit significant inter-and intraspecies heterogeneity in secreting putative toxin effectors.展开更多
Microglia,which are tissue-resident macrophages in the brain,play a central role in the brain innate immunity and contribute to the maintenance of brain homeostasis.Lipopolysaccharide is a component of the outer membr...Microglia,which are tissue-resident macrophages in the brain,play a central role in the brain innate immunity and contribute to the maintenance of brain homeostasis.Lipopolysaccharide is a component of the outer membrane of gram-negative bacteria,and activates immune cells including microglia via Toll-like receptor 4 signaling.Lipopolysaccharide is generally known as an endotoxin,as administration of highdose lipopolysaccharide induces potent systemic inflammation.Also,it has long been recognized that lipopolysaccharide exacerbates neuroinflammation.In contrast,our study revealed that oral administration of lipopolysaccharide ameliorates Alzheimer’s disease pathology and suggested that neuroprotective microglia are involved in this phenomenon.Additionally,other recent studies have accumulated evidence demonstrating that controlled immune training with low-dose lipopolysaccharide prevents neuronal damage by transforming the microglia into a neuroprotective phenotype.Therefore,lipopolysaccharide may not a mere inflammatory inducer,but an immunomodulator that can lead to neuroprotective effects in the brain.In this review,we summarized current studies regarding neuroprotective microglia transformed by immune training with lipopolysaccharide.We state that microglia transformed by lipopolysaccharide preconditioning cannot simply be characterized by their general suppression of proinflammatory mediators and general promotion of anti-inflammatory mediators,but instead must be described by their complex profile comprising various molecules related to inflammatory regulation,phagocytosis,neuroprotection,anti-apoptosis,and antioxidation.In addition,microglial transformation seems to depend on the dose of lipopolysaccharide used during immune training.Immune training of neuroprotective microglia using lowdose lipopolysaccharide,especially through oral lipopolysaccharide administration,may represent an innovative prevention or treatment for neurological diseases;however more vigorous studies are still required to properly modulate these treatments.展开更多
Accumulating evidence has shown that the hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating breast cancer progression and metastasis. The effects of hypoxia-inducible...Accumulating evidence has shown that the hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating breast cancer progression and metastasis. The effects of hypoxia-inducible factor 1 （HIF-1）, a master regulator of the hypoxic response, have been extensively studied during these processes. In this review, we focus on the roles of HIF-1 in regulating breast cancer cell metastasis, specifically its effects on multiple key steps of metastasis, such as epithelial-mesenchymal transition （EMT）, invasion, extravasation, and metastatic niche formation. We also discuss the roles of HIF-l-regulated non-coding RNAs in breast cancer metastasis, and therapeutic opportunities for breast cancer through targeting the HIF-1 pathway,展开更多
A group of impressive immunotherapies for cancer treatment, including immune checkpoint-blocking antibodies,gene therapy and immune cell adoptive cellular immunotherapy, have been established, providing new weapons to...A group of impressive immunotherapies for cancer treatment, including immune checkpoint-blocking antibodies,gene therapy and immune cell adoptive cellular immunotherapy, have been established, providing new weapons to fight cancer. Natural killer（NK） cells are a component of the first line of defense against tumors and virus infections. Studies have shown dysfunctional NK cells in patients with cancer. Thus, restoring NK cell antitumor functionality could be a promising therapeutic strategy. NK cells that are activated and expanded ex vivo can supplement malfunctional NK cells in tumor patients. Therapeutic antibodies, chimeric antigen receptor（CAR）, or bispecific proteins can all retarget NK cells precisely to tumor cells. Therapeutic antibody blockade of the immune checkpoints of NK cells has been suggested to overcome the immunosuppressive signals delivered to NK cells.Oncolytic virotherapy provokes antitumor activity of NK cells by triggering antiviral immune responses. Herein,we review the current immunotherapeutic approaches employed to restore NK cell antitumor functionality for the treatment of cancer.展开更多
The novel coronavirus disease(COVID-19)pandemic is emerging as a global health threat and shows a higher risk for men than women.Thus far,the studies on andrological consequences of COVID-19 are limited.To ascertain t...The novel coronavirus disease(COVID-19)pandemic is emerging as a global health threat and shows a higher risk for men than women.Thus far,the studies on andrological consequences of COVID-19 are limited.To ascertain the consequences of COVID-19 on sperm parameters after recovery,we recruited 41 reproductive-aged male patients who had recovered from COVID-19,and analyzed their semen parameters and serum sex hormones at a median time of 56 days after hospital discharge.For longitudinal analysis,a second sampling was obtained from 22 of the 41 patients after a median time interval of 29 days from first sampling.Compared with controls who had not suffered from COVID-19,the total sperm count,sperm concentration,and percentages of motile and progressively motile spermatozoa in the patients were significantly lower at first sampling,while sperm vitality and morphology were not affected.The total sperm count,sperm concentration,and number of motile spermatozoa per ejaculate were significantly increased and the percentage of morphologically abnormal sperm was reduced at the second sampling compared with those at first in the 22 patients examined.Though there were higher prolactin and lower progesterone levels in patients at first sampling than those in controls,no significant alterations were detected for any sex hormones examined over time following COVID-19 recovery in the 22 patients.Although it should be interpreted carefully,these findings indicate an adverse but potentially reversible consequence of COVID-19 on sperm quality.展开更多
Punlcalagin is isolated from pomegranate and widely used for the treatment of different diseases in Chinese traditional medicine. This study aimed to evaluate the effect of Punicalagin （purity L〉98%） on oxidative s...Punlcalagin is isolated from pomegranate and widely used for the treatment of different diseases in Chinese traditional medicine. This study aimed to evaluate the effect of Punicalagin （purity L〉98%） on oxidative stress induced testicular damage and its effect on fertility. We detected the antioxidant potential of punicalagin in lipopolysaccharide （LPS） induced oxidative stress damage in testes, also tried to uncover the boosting fertility effect of Punicalagin （PU） against oxidative stress-induced infertility. Results demonstrated that 9 mg kg-1 for 7 days treatment significantly decreases LPS induced oxidative damage in testes and nitric oxide production. The administration of oxidative stress resulted in a significant reduction in testes antioxidants GSH, T-SOD, and CAT raised LPO, but treatment with punicalagin for 7 days increased antioxidant defense GSH, T-SOD, and CAT by the end of the experiment and reduced LPO level as well. PU also significantly activates Nrf2, which is involved in regulation of antioxidant defense systems. Hence, the present research categorically elucidates the protective effect of punicalagin against LPS induced oxidative stress induced perturbation in the process of spermatogenesis and significantly increased sperm health and number. Moreover, fertility success significantly decreased in LPS-injected mice compared to controls. Mice injected with LPS had fertility indices of 12.5%, while others treated with a combination of PU ＋ LPS exhibited 75% indices. By promoting fertility and eliminating oxidative stress and inflammation, PU may be a useful nutrient for the treatment of infertility.展开更多
Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using world...Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.Methods:We constructed a trispecific killer engager(TriKE)consisting of anti-CD16,IL-15,and anti-CD19.This TriKE was designed to attract CD19^(+)tumor cells to CD16^(+)NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK cells.Results:Treatment with 161519 TriKE in the presence of CD19^(+)targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK cells.NK cells"armed"with 161519 TriKE showed stronger cytolysis against CD19+targets compared with that of"unarmed"NK cells.A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 BiKE.Combined use of IL-2 was a more effective treatment with 1619 BiKE,when compared with that using 161519 TriKE.Conclusions:The newly generated 161519 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19+tumor cells.The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.展开更多
Inflammatory bowel diseases(IBDs),such as ulcerative colitis and Crohn's disease,are chronic pathologies associated with a deregulated immune response in the intestinal mucosa,and they are triggered by environment...Inflammatory bowel diseases(IBDs),such as ulcerative colitis and Crohn's disease,are chronic pathologies associated with a deregulated immune response in the intestinal mucosa,and they are triggered by environmental factors in genetically susceptible individuals.Exogenous glucocorticoids(GCs)are widely used as anti-inflammatory therapy in IBDs.In the past,patients with moderate or severe states of inflammation received GCs as a first line therapy with an important effectiveness in terms of reduction of the disease activity and the induction of remission.However,this treatment often results in detrimental side effects.This downside drove the development of second generation GCs and more precise(non-systemic)drugdelivery methods.Recent clinical trials show that most of these new treatments have similar effectiveness to first generation GCs with fewer adverse effects.The remaining challenge in successful treatment of IBDs concerns the refractoriness and dependency that some patients encounter during GCs treatment.A deeper understanding of the molecular mechanisms underlying GC response is key to personalizing drug choice for IBDs patients to optimize their response to treatment.In this review,we examine the clinical characteristics of treatment with GCs,followed by an in depth analysis of the proposed molecular mechanisms involved in its resistance and dependence associated with IBDs.This thorough analysis of current clinical and biomedical literature may help guide physicians in determining a course of treatment for IBDs patients and identifies important areas needing further study.展开更多
Objective:NK cells play crucial roles in the immune defense mechanisms against viral infections and transformed cells.However,the developmental progression,transcriptomic landscape,and functional subtypes of liver NK ...Objective:NK cells play crucial roles in the immune defense mechanisms against viral infections and transformed cells.However,the developmental progression,transcriptomic landscape,and functional subtypes of liver NK cells are not well defined.Hepatocellular carcinoma(HCC)accounts for approximately 80%of primary liver cancer worldwide,yet the biological characteristics of NK cells in the HCC environment are unclear.Therefore,we aimed to determine these cells’roles in tumorigenesis and prognosis.Methods:We compared the single-cell RNA sequencing profiles of NK cells purified from blood(n=1),healthy liver tissues(n=3),HCC tumor tissues(n=4),and peritumor liver tissues(n=1)to identify NK cell subsets.Furthermore,we performed bioinformatics analysis by using The Cancer Genome Atlas(TCGA)data to identify prognostic biomarkers simultaneously overexpressed in the blood and tumor tissues of patients with HCC.Results:Transcriptomic analysis revealed 5 NK cell subsets(L1-NK-CD56bright,L2-NK-CD56dim,L3-NK-HLA,L4-LrNK-FCGR3A,and L5-LrNK-XCL1)in the healthy liver tissues.However,the transitional L3 subset and the CXCR6+CD16+L4 subset with strong anti-tumor activity were absent in the HCC and peritumor liver tissues.Furthermore,4 common prognosis-associated genes(RHOB,TALDO1,HLA-DPA1,and TKT)were significantly overexpressed in the paired tumor tissue and blood.Conclusions:Our study revealed 5 specific subsets of NK cells in healthy human liver tissues.However,only 3 of the 5 NK cell subsets were present in HCC and peritumor tissues.The cytotoxic NK cell subsets were absent in HCC tissues.Furthermore,we identified 4 potential non-invasive prognostic biomarkers in patients with HCC.展开更多
基金by the National Key R&D Program of China(2018YFA0507403)the National Natural Science Foundation of China(81788101,81701631,31390433,and 31670908)the Chinese Academy of Sciences(XDB29030000).
文摘Efficient immune responses against invading pathogens often involve coordination between cells from both the innate and adaptive immune systems.For multiple decades,it has been believed that CD8+memory T cells and natural killer(NK)cells constantly and uniformly recirculate.Only recently was the existence of noncirculating memory T and NK cells that remain resident in the peripheral tissues,termed tissue-resident memory T(TRM)cells and tissue-resident NK(trNK)cells,observed in various organs owing to improved techniques.TRM cells populate a wide range of peripheral organs,including the skin,sensory ganglia,gut,lungs,brain,salivary glands,female reproductive tract,and others.Recent findings have demonstrated the existence of TRM in the secondary lymphoid organs(SLOs)as well,leading to revision of the classic theory that they exist only in peripheral organs.trNK cells have been identified in the uterus,skin,kidney,adipose tissue,and salivary glands.These tissue-resident lymphocytes do not recirculate in the blood or lymphatic system and often adopt a unique phenotype that is distinct from those of circulating immune cells.In this review,we will discuss the recent findings on the tissue residency of both innate and adaptive lymphocytes,with a particular focus on CD8+memory T cells,and describe some advances regarding unconventional T cells(invariant NKT cells,mucosal-associated invariant T cells(MAIT),andγδT cells)and the emerging family of trNK cells.Specifically,we will focus on the phenotypes and functions of these subsets and discuss their implications in anti-viral and anti-tumor immunity.
基金supported by National Institutes of Health grants AI083019, AI104002, and AI88778
文摘Innate immunity is critical for the control of virus infection and operates to restrict viral susceptibility and direct antiviral immunity for protection from acute or chronic viral-associated diseases including cancer. RIG-I like receptors(RLRs) are cytosolic RNA helicases that function as pathogen recognition receptors to detect RNA pathogen associated molecular patterns(PAMPs) of virus infection. The RLRs include RIG-I, MDA5, and LGP2. They function to recognize and bind to PAMP motifs within viral RNA in a process that directs the RLR to trigger downstream signaling cascades that induce innate immunity that controls viral replication and spread. Products of RLR signaling also serve to modulate the adaptive immune response to infection. Recent studies have additionally connected RLRs to signaling cascades that impart inflammatory and apoptotic responses to virus infection. Viral evasion of RLR signaling supports viral outgrowth and pathogenesis, including the onset of viral-associated cancer.
基金supported by the National Natural Science Foundation of China(81803547)the Natural Science Foundation of Fujian Province,China(2021J01204)Fujian Provincial Regional Development Project(2021N3005)。
文摘Most Aloe species are used as new food or functional food ingredient.Even though widely known for its health benefits,the anti-inflammatory effects and underlying mechanisms of Aloin(Alo),an anthraquinone compound isolated from plant species of the genus Aloe,remain unidentified.Here,we investigated the protective effects of Alo against cecal ligation and puncture(CLP)-induced sepsis and microflora in mice.Alo significantly improved CLP-induced sepsis and the survival rate of septic mice,downregulated the expression of proinflammatory factors,and decreased the infiltration of inflammatory cells in tissues.Alo upregulated the proportion of peritoneal macrophages,reduced the number of peritoneal bacteria,decreased the content of short-chain fatty acids and bile acids in the abdominal cavity,and suppressed Toll-like receptor(TLR)-2/4/nuclear factor kappa-B(NF-κB)/NOD-like receptor thermal protein domain associated protein 3(NLRP3)/Caspase-1/3/8 signaling.Furthermore,Alo altered the composition of the microbiome and promoted the growth of Lactobacillus,which showed a stronger anti-inflammatory effect.Whole-genome analysis identified the genes Saa3,Il10,Fpr1,and Eif4a1 associated with the protective effects of Alo in mice with CLP-induced sepsis.Overall,our results provide novel insights into the therapeutic potential and mechanism of action of Alo in the treatment of sepsis.
基金supported by the National Natural Science Foundation of China(No.32100689)the National Key Research and Development Program of China(No.2021YFC2700202,No.2022YFA0806303,and No.2022YFC2702601)+1 种基金the Global Select Project(No.DJK-LX-2022010)of the Institute of Health and MedicineHefei Comprehensive National Science Center,and the Joint Fund for New Medicine of USTC(No.YD9100002034).
文摘Multiple morphological abnormalities of sperm flagella(MMAF)is a severe form of asthenoteratozoospermia,characterized by morphological abnormalities and reduced motility of sperm,causing male infertility.Although approximately 60%of MMAF cases can be explained genetically,the etiology of the remaining cases is unclear.Here,we identified two novel compound heterozygous variants in the gene,dynein axonemal heavy chain 10(DNAH10),in three patients from two unrelated Pakistani families using whole-exome sequencing(WES),including one compound heterozygous mutation(DNAH10:c.9409C>A[p.P3137T];c.12946G>C[p.D4316H])in family 1 and another compound heterozygous mutation(DNAH10:c.8849G>A[p.G2950D];c.11509C>T[p.R3687W])in family 2.All the identified variants are absent or rare in public genome databases and are predicted to have deleterious effects according to multiple bioinformatic tools.Sanger sequencing revealed that these variants follow an autosomal recessive mode of inheritance.Hematoxylin and eosin(H&E)staining revealed MMAF,including sperm head abnormalities,in the patients.In addition,immunofluorescence staining revealed loss of DNAH10 protein signals along sperm flagella.These findings broaden the spectrum of DNAH10 variants and expand understanding of the genetic basis of male infertility associated with the MMAF phenotype.
基金supported by the National Key Research and Development Program of China(No.2021YFC2700202,No.2022YFA0806303,and No.2022YFC2702601)the Global Select Project of the Institute of Health and Medicine,Hefei Comprehensive National Science Center(DJK-LX-2022010)the Joint Fund for New Medicine of USTC(YD9100002034).
文摘Multiple morphological abnormalities of the flagella(MMAF)represent a severe form of sperm defects leading to asthenozoospermia and male infertility.In this study,we identified a novel homozygous splicing mutation(c.871-4 ACA>A)in the adenylate kinase 7(AK7)gene by whole-exome sequencing in infertile individuals.Spermatozoa from affected individuals exhibited typical MMAF characteristics,including coiled,bent,short,absent,and irregular flagella.Transmission electron microscopy analysis showed disorganized axonemal structure and abnormal mitochondrial sheets in sperm flagella.Immunofluorescence staining confirmed the absence of AK7 protein from the patients’spermatozoa,validating the pathogenic nature of the mutation.This study provides direct evidence linking the AK7 gene to MMAF-associated asthenozoospermia in humans,expanding the mutational spectrum of AK7 and enhancing our understanding of the genetic basis of male infertility.
基金supported by Anhui Province Clinical Key Specialty Construction Project,China(Grant No.:2021sjlczdzk)the National Key Research and Development Program of China(Grants Nos.:2022YFC2304102 and 2022YFC2303300)the National Natural Science Foundation of China(Grant Nos.:82272301,32100745,and 31971129).
文摘Discoidin domain receptor 1(DDR1)is overexpressed in various tumors,such as triple-negative breast cancer(TNBC),and is rarely expressed in normal tissues.These characteristics make DDR1 a preferable target candidate for the construction of an antibody-drug conjugate(ADC)for targeted therapy.Here,we investigated the preparation and preclinical efficacy of DDR1-DX8951,an ADC that includes an anti-DDR1 monoclonal antibody conjugated to DX8951 by a cleavable Gly-Gly-Phe-Gly(GGFG)linker.The anti-DDR1 monoclonal antibody was coupled to DX8951(i.e.,DDR1-DX8951),producing the targeted therapy ADC.The antitumor activities of DDR1-DX8951 monotherapy or DDR1-DX8951 plus pembrolizumab were assessed in TNBC mouse models.DDR1-DX8951 can specifically target DDR1,be quickly internalized by TNBC cells,and reduce the viability of TNBC cells in vitro.The potent antitumor activity of DDR1-DX8951 was revealed in TNBC xenograft models.Importantly,our investigation demonstrated that DDR1-DX8951 plus pembrolizumab not only revealed the inhibitory efficacy on tumor growth and metastasis but also played an important role in improving the immunosuppressive tumor microenvironment(TME)of TNBC.Taken together,this investigation provides justification for large-sample studies to further assess the safety and efficacy of DDR1-DX8951 plus pembrolizumab for TNBC clinical trials.
基金supported by the Excellent Young Scholars Cultivation Project of Fujian Medical University Union Hospital in China(No.2022XH031)the National Natural Science Foundation of China(No.82203439)the Natural Science Foundation of Fujian Province(No.2022J01263).
文摘Carrimycin(CA),sanctioned by China’s National Medical Products Administration(NMPA)in 2019 for treating acute bronchitis and sinusitis,has recently been observed to exhibit multifaceted biological activities,encompassing anti-inflammatory,antiviral,and anti-tumor properties.Despite these applications,its efficacy in sepsis treatment remains unexplored.This study introduces a novel function of CA,demonstrating its capacity to mitigate sepsis induced by lipopolysaccharide(LPS)and cecal ligation and puncture(CLP)in mice models.Our research employed in vitro assays,real-time quantitative polymerase chain reaction(RT-qPCR),and RNA-seq analysis to establish that CA significantly reduces the levels of pro-inflammatory cytokines,namely tumor necrosis factor-alpha(TNF-α),interleukin 1 beta(IL-1β),and interleukin 6(IL-6),in response to LPS stimulation.Additionally,Western blotting and immunofluorescence assays revealed that CA impedes Nuclear Factor Kappa B(NF-κB)activation in LPS-stimulated RAW264.7 cells.Complementing these findings,in vivo experiments demonstrated that CA effectively alleviates LPS-and CLP-triggered organ inflammation in C57BL/6 mice.Further insights were gained through 16S sequencing,highlighting CA’s pivotal role in enhancing gut microbiota diversity and modulating metabolic pathways,particularly by augmenting the production of short-chain fatty acids in mice subjected to CLP.Notably,a comparative analysis revealed that CA’s anti-inflammatory efficacy surpasses that of equivalent doses of aspirin(ASP)and TIENAM.Collectively,these findings suggest that CA exhibits significant therapeutic potential in sepsis treatment.This discovery provides a foundational theoretical basis for the clinical application of CA in sepsis management.
基金supported by the National Key R&D Program of China (2019YFA0508502/3 and 2021YFC2300604)the Natural Science Foundation of China (Reference numbers 82388201, 82241216, and 32270963)+1 种基金the Research Funds of Center for Advanced Interdisciplinary Science and Biomedicine of IHM (QYZD20220008)the Anhui Key Research and Development Plan (Reference number 2023z04020011)。
文摘Objective: The human cluster of differentiation(CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer(NK) cells targeting hematologic malignancies(HMs).Methods: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine(PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients.Results: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS–CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an “exhausted” phenotype of intratumoral NK cells in patients with HMs or solid tumors.Conclusions: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.
基金supported by the Global Select Project(No.DJK-LX-2022001)of the Institute of Health and Medicine,Hefei Comprehensive National Science Center.
文摘Objective Hepatocellular carcinoma(HCC)is the third leading cause of cancer-associated death worldwide.As a first-line drug for advanced HCC treatment,lenvatinib faces a significant hurdle due to the development of both intrinsic and acquired resistance among patients,and the underlying mechanism remains largely unknown.The present study aims to identify the pivotal gene responsible for lenvatinib resistance in HCC,explore the potential molecular mechanism,and propose combinatorial therapeutic targets for HCC management.Methods Cell viability and colony formation assays were conducted to evaluate the sensitivity of cells to lenvatinib and dicoumarol.RNA-Seq was used to determine the differences in transcriptome between parental cells and lenvatinib-resistant(LR)cells.The upregulated genes were analyzed by GO and KEGG analyses.Then,qPCR and Western blotting were employed to determine the relative gene expression levels.Afterwards,the intracellular reactive oxygen species(ROS)and apoptosis were detected by flow cytometry.Results PLC-LR and Hep3B-LR were established.There was a total of 116 significantly upregulated genes common to both LR cell lines.The GO and KEGG analyses indicated that these genes were involved in oxidoreductase and dehydrogenase activities,and reactive oxygen species pathways.Notably,NAD(P)H:quinone oxidoreductase 1(NQO1)was highly expressed in LR cells,and was involved in the lenvatinib resistance.The high expression of NQO1 decreased the production of ROS induced by lenvatinib,and subsequently suppressed the apoptosis.The combination of lenvatinib and NQO1 inhibitor,dicoumarol,reversed the resistance of LR cells.Conclusion The high NQO1 expression in HCC cells impedes the lenvatinib-induced apoptosis by regulating the ROS levels,thereby promoting lenvatinib resistance in HCC cells.
基金support has been provided by the University of Strasbourg Institute for Advanced Study(to J.A.H.)the International Science and Technology Innovation Cooperation between Governments for National Key R&D Program Projects(2023YFE0107700)。
文摘Toll and Toll-like receptors(TLRs)are pivotal components of the innate immune system,playing a crucial role in the early defense against invading pathogens.These receptors basically recognize microbial components and thus spread the presence of pathogens to the host and activate signaling pathways that lead to an appropriate immune response.Their discoveries and studies in the late 80s/early90s have initiated the understanding of how organisms detect and respond to microbial infections(Hoffmann et al.,1999;Medzhitov and Janeway,2000;Akira et al.,2006;Nusslein-Volhard,2021).
基金supported by grants from the National Natural Science Foundation of China(32100702).
文摘The host antimicrobial immune response relies on a complex interplay of molecular mechanisms to effectively combat microbial infections.Herein,we investigate the functional role of Cullin-3(Cul3),one critical constituent of Cullin-RING ubiquitin ligases,in the Drosophila melanogaster(fruit fly)antimicrobial immune defense.Weshow that silencing of Cul3 leads to a decreased induction of antimicrobial peptides and high mortality in adult flies after bacterial infection.Through biochemical approaches,we demonstrate that Cul3 predominantly relies on its BTB-binding domain and neddylation domain to physically associate with death-associated inhibitor of apoptosis 2(Diap2).Importantly,Cul3 ameliorates the Diap2-mediated ubiquitination of death-related ced-3/Nedd2-like caspase(Dredd),a process essential for robust immune deficiency signaling upon bacterial infection.Taken together,our findings highlight a previously unrecognized regulatory axis of Cul3/Diap2/Dredd in the fly antimicrobial immune defense,providing potential insights into therapeutic strategies for combating bacterial infections in humans.
基金supported by the National Natural Science Foundation of China(82225028,82172287,32171265,31900879,and 32370185)the National Key Research and Development Program of China(2021YFC2301403)+1 种基金the high-level personnel introduction grant form Fujian Normal University(Z0210509)the Natural Science Foundation of Fujian Province(2023J011797 and 2024J010025).
文摘In their natural habitats,bacteria thrive in densely populated environments(such as soil and the human gut)and compete with other microorganisms for ecological niches[1].Secretion systems enable bacteria to export proteins into their surroundings and play key roles in interbacterial competition,development,nutrient acquisition,and virulence[2–4].Type VII secretion system b(T7SSb)has been primarily identified in low-G+C Firmicutes,which exhibit significant inter-and intraspecies heterogeneity in secreting putative toxin effectors.
基金This work was funded by Control of Innate Immunity Technology Research Association,a grant of Cross-ministerial Strategic Innovation Promotion Program,SIP-No.14533073(to GIS)from the Council for Science from Technology and Innovation(CSTI)in Cabinet Office of Japanese Government and the National Agriculture and Food Research Organization(NARO).
文摘Microglia,which are tissue-resident macrophages in the brain,play a central role in the brain innate immunity and contribute to the maintenance of brain homeostasis.Lipopolysaccharide is a component of the outer membrane of gram-negative bacteria,and activates immune cells including microglia via Toll-like receptor 4 signaling.Lipopolysaccharide is generally known as an endotoxin,as administration of highdose lipopolysaccharide induces potent systemic inflammation.Also,it has long been recognized that lipopolysaccharide exacerbates neuroinflammation.In contrast,our study revealed that oral administration of lipopolysaccharide ameliorates Alzheimer’s disease pathology and suggested that neuroprotective microglia are involved in this phenomenon.Additionally,other recent studies have accumulated evidence demonstrating that controlled immune training with low-dose lipopolysaccharide prevents neuronal damage by transforming the microglia into a neuroprotective phenotype.Therefore,lipopolysaccharide may not a mere inflammatory inducer,but an immunomodulator that can lead to neuroprotective effects in the brain.In this review,we summarized current studies regarding neuroprotective microglia transformed by immune training with lipopolysaccharide.We state that microglia transformed by lipopolysaccharide preconditioning cannot simply be characterized by their general suppression of proinflammatory mediators and general promotion of anti-inflammatory mediators,but instead must be described by their complex profile comprising various molecules related to inflammatory regulation,phagocytosis,neuroprotection,anti-apoptosis,and antioxidation.In addition,microglial transformation seems to depend on the dose of lipopolysaccharide used during immune training.Immune training of neuroprotective microglia using lowdose lipopolysaccharide,especially through oral lipopolysaccharide administration,may represent an innovative prevention or treatment for neurological diseases;however more vigorous studies are still required to properly modulate these treatments.
基金supported partially by the National Basic Research Program(973)of China(Nos.2014CB910604 and 2012CB910104)the National Natural Science Foundation of China(Nos.31171358 and 31371429)+2 种基金the Research Fund for the Doctoral Program of Higher Education of China(No.20133402110020)the Fundamental Research Funds for the Central Universities in Chinathe ‘1000 Youth Talent Program’ by the Chinese Government for Hua-feng ZHANG
文摘Accumulating evidence has shown that the hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating breast cancer progression and metastasis. The effects of hypoxia-inducible factor 1 （HIF-1）, a master regulator of the hypoxic response, have been extensively studied during these processes. In this review, we focus on the roles of HIF-1 in regulating breast cancer cell metastasis, specifically its effects on multiple key steps of metastasis, such as epithelial-mesenchymal transition （EMT）, invasion, extravasation, and metastatic niche formation. We also discuss the roles of HIF-l-regulated non-coding RNAs in breast cancer metastasis, and therapeutic opportunities for breast cancer through targeting the HIF-1 pathway,
基金supported by the Natural Science Foundation of China (No. 91429303, 31390433, 91542000, 91542114 and 31570893)the Ministry of Science & Technology of China (973 Basic Science Project 2013CB944902 and 2013CB530506)
文摘A group of impressive immunotherapies for cancer treatment, including immune checkpoint-blocking antibodies,gene therapy and immune cell adoptive cellular immunotherapy, have been established, providing new weapons to fight cancer. Natural killer（NK） cells are a component of the first line of defense against tumors and virus infections. Studies have shown dysfunctional NK cells in patients with cancer. Thus, restoring NK cell antitumor functionality could be a promising therapeutic strategy. NK cells that are activated and expanded ex vivo can supplement malfunctional NK cells in tumor patients. Therapeutic antibodies, chimeric antigen receptor（CAR）, or bispecific proteins can all retarget NK cells precisely to tumor cells. Therapeutic antibody blockade of the immune checkpoints of NK cells has been suggested to overcome the immunosuppressive signals delivered to NK cells.Oncolytic virotherapy provokes antitumor activity of NK cells by triggering antiviral immune responses. Herein,we review the current immunotherapeutic approaches employed to restore NK cell antitumor functionality for the treatment of cancer.
基金the National Key Research and Developmental Program of China(No.2018YFC1003900,2019YFA0802600,and 2018YFC1004700)a COVID-19 special task grant supported by the Chinese Academy of Science Clinical Research Hospital in Hefei(No.YD2070002020)the Fundamental Research Funds for the Central Universities(No.YD2070002006,YD9110004001,and YD9110002002).
文摘The novel coronavirus disease(COVID-19)pandemic is emerging as a global health threat and shows a higher risk for men than women.Thus far,the studies on andrological consequences of COVID-19 are limited.To ascertain the consequences of COVID-19 on sperm parameters after recovery,we recruited 41 reproductive-aged male patients who had recovered from COVID-19,and analyzed their semen parameters and serum sex hormones at a median time of 56 days after hospital discharge.For longitudinal analysis,a second sampling was obtained from 22 of the 41 patients after a median time interval of 29 days from first sampling.Compared with controls who had not suffered from COVID-19,the total sperm count,sperm concentration,and percentages of motile and progressively motile spermatozoa in the patients were significantly lower at first sampling,while sperm vitality and morphology were not affected.The total sperm count,sperm concentration,and number of motile spermatozoa per ejaculate were significantly increased and the percentage of morphologically abnormal sperm was reduced at the second sampling compared with those at first in the 22 patients examined.Though there were higher prolactin and lower progesterone levels in patients at first sampling than those in controls,no significant alterations were detected for any sex hormones examined over time following COVID-19 recovery in the 22 patients.Although it should be interpreted carefully,these findings indicate an adverse but potentially reversible consequence of COVID-19 on sperm quality.
基金This work was supported by National Natural Science Foundation of China Grants 81125005 and 81430027 （to F.S.）, the National Basic Research Program of China （2014CB943100）.
文摘Punlcalagin is isolated from pomegranate and widely used for the treatment of different diseases in Chinese traditional medicine. This study aimed to evaluate the effect of Punicalagin （purity L〉98%） on oxidative stress induced testicular damage and its effect on fertility. We detected the antioxidant potential of punicalagin in lipopolysaccharide （LPS） induced oxidative stress damage in testes, also tried to uncover the boosting fertility effect of Punicalagin （PU） against oxidative stress-induced infertility. Results demonstrated that 9 mg kg-1 for 7 days treatment significantly decreases LPS induced oxidative damage in testes and nitric oxide production. The administration of oxidative stress resulted in a significant reduction in testes antioxidants GSH, T-SOD, and CAT raised LPO, but treatment with punicalagin for 7 days increased antioxidant defense GSH, T-SOD, and CAT by the end of the experiment and reduced LPO level as well. PU also significantly activates Nrf2, which is involved in regulation of antioxidant defense systems. Hence, the present research categorically elucidates the protective effect of punicalagin against LPS induced oxidative stress induced perturbation in the process of spermatogenesis and significantly increased sperm health and number. Moreover, fertility success significantly decreased in LPS-injected mice compared to controls. Mice injected with LPS had fertility indices of 12.5%, while others treated with a combination of PU ＋ LPS exhibited 75% indices. By promoting fertility and eliminating oxidative stress and inflammation, PU may be a useful nutrient for the treatment of infertility.
基金supported by grants from the National Key R&D Program of China(Grant No.2019YFA0508502)the CAMS Innovation Fund for Medical Sciences(Grant No.2019-I2M-5-073)the National Natural Science Foundation of China(Grant Nos.81788101,81972679,and 81821001)。
文摘Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.Methods:We constructed a trispecific killer engager(TriKE)consisting of anti-CD16,IL-15,and anti-CD19.This TriKE was designed to attract CD19^(+)tumor cells to CD16^(+)NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK cells.Results:Treatment with 161519 TriKE in the presence of CD19^(+)targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK cells.NK cells"armed"with 161519 TriKE showed stronger cytolysis against CD19+targets compared with that of"unarmed"NK cells.A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 BiKE.Combined use of IL-2 was a more effective treatment with 1619 BiKE,when compared with that using 161519 TriKE.Conclusions:The newly generated 161519 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19+tumor cells.The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.
基金Supported by National Fund for Scientific and Technological Development No.1170648(MHR)Clínica Las Condes Academic Project PI2013-B002,UApoya No.560959(RQ)National Commission for Scientific and Technological Research scholarship No.21150264(DDJ),No.21120682(MOM),MECESUP Scholarship No.UCH 0714(KDC)
文摘Inflammatory bowel diseases(IBDs),such as ulcerative colitis and Crohn's disease,are chronic pathologies associated with a deregulated immune response in the intestinal mucosa,and they are triggered by environmental factors in genetically susceptible individuals.Exogenous glucocorticoids(GCs)are widely used as anti-inflammatory therapy in IBDs.In the past,patients with moderate or severe states of inflammation received GCs as a first line therapy with an important effectiveness in terms of reduction of the disease activity and the induction of remission.However,this treatment often results in detrimental side effects.This downside drove the development of second generation GCs and more precise(non-systemic)drugdelivery methods.Recent clinical trials show that most of these new treatments have similar effectiveness to first generation GCs with fewer adverse effects.The remaining challenge in successful treatment of IBDs concerns the refractoriness and dependency that some patients encounter during GCs treatment.A deeper understanding of the molecular mechanisms underlying GC response is key to personalizing drug choice for IBDs patients to optimize their response to treatment.In this review,we examine the clinical characteristics of treatment with GCs,followed by an in depth analysis of the proposed molecular mechanisms involved in its resistance and dependence associated with IBDs.This thorough analysis of current clinical and biomedical literature may help guide physicians in determining a course of treatment for IBDs patients and identifies important areas needing further study.
基金supported by the National Key R&D Program of China(Grant Nos.2021YFC2300601 and 2019YFA0508502/3)National Natural Science Foundation of China(Grant Nos.81972679 and 8202290021)+1 种基金Anhui Provincial Natural Science Foundation(Grant Nos.2008085J35 and 2008085MH252)USTC Research Funds of the Double First-Class Initiative(Grant No.YD3520002002).
文摘Objective:NK cells play crucial roles in the immune defense mechanisms against viral infections and transformed cells.However,the developmental progression,transcriptomic landscape,and functional subtypes of liver NK cells are not well defined.Hepatocellular carcinoma(HCC)accounts for approximately 80%of primary liver cancer worldwide,yet the biological characteristics of NK cells in the HCC environment are unclear.Therefore,we aimed to determine these cells’roles in tumorigenesis and prognosis.Methods:We compared the single-cell RNA sequencing profiles of NK cells purified from blood(n=1),healthy liver tissues(n=3),HCC tumor tissues(n=4),and peritumor liver tissues(n=1)to identify NK cell subsets.Furthermore,we performed bioinformatics analysis by using The Cancer Genome Atlas(TCGA)data to identify prognostic biomarkers simultaneously overexpressed in the blood and tumor tissues of patients with HCC.Results:Transcriptomic analysis revealed 5 NK cell subsets(L1-NK-CD56bright,L2-NK-CD56dim,L3-NK-HLA,L4-LrNK-FCGR3A,and L5-LrNK-XCL1)in the healthy liver tissues.However,the transitional L3 subset and the CXCR6+CD16+L4 subset with strong anti-tumor activity were absent in the HCC and peritumor liver tissues.Furthermore,4 common prognosis-associated genes(RHOB,TALDO1,HLA-DPA1,and TKT)were significantly overexpressed in the paired tumor tissue and blood.Conclusions:Our study revealed 5 specific subsets of NK cells in healthy human liver tissues.However,only 3 of the 5 NK cell subsets were present in HCC and peritumor tissues.The cytotoxic NK cell subsets were absent in HCC tissues.Furthermore,we identified 4 potential non-invasive prognostic biomarkers in patients with HCC.
