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Interleukin 22 (IL-22) has an important role in colorectal tumorigenesis and many colorectal diseases such as inflammatory bowel disease and certain infections. However, the regulation of IL-22 production in the intestinal system is still unclear. Here, we present evidence that butyrophilin-like protein 2 (BTNL2) is required for colorectal IL-22 production, and BTNL2 knockout mice show decreased colonic tumorigenesis and more severe colitis phenotypes than control mice due to defective production of IL-22. Mechanistically, BTNL2 acts on group 3 innate lymphoid cells (ILC3s), CD4+ T cells, and γδ T cells to promote the production of IL-22. Importantly, we find that a monoclonal antibody against BTNL2 attenuates colorectal tumorigenesis in mice and that the mBTNL2-Fc recombinant protein has a therapeutic effect in a dextran sulfate sodium (DSS)-induced colitis model. This study not only identifies a regulatory mechanism of IL-22 production in the colorectal system but also provides a potential therapeutic target for the treatment of human colorectal cancer and inflammatory bowel diseases.
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Colite , Neoplasias Colorretais , Humanos , Camundongos , Animais , Imunidade Inata , Linfócitos , Carcinogênese , Transformação Celular Neoplásica , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais de Doenças , Butirofilinas , Interleucina 22RESUMO
The receptor tyrosine kinase EPHB2 (EPH receptor B2) is highly expressed in many human cancer types, especially in gastrointestinal cancers, such as colorectal cancer. Several coding mutations of the EPHB2 gene have been identified in many cancer types, suggesting that EPHB2 plays a critical role in carcinogenesis. However, the exact functional mechanism of EPHB2 in carcinogenesis remains unknown. In this study, we find that EPHB2 is required for TNF-induced signaling activation and proinflammatory cytokine production in colorectal epithelial cells. Mechanistically, after TNF stimulation, EPHB2 is ubiquitinated by its E3 ligase RNF186. Then, ubiquitinated EPHB2 recruits and further phosphorylates TAB2 at nine tyrosine sites, which is a critical step for the binding between TAB2 and TAK1. Due to defects in TNF signaling in RNF186-knockout colorectal epithelial cells, the phenotype of colitis-propelled colorectal cancer model in RNF186-knockout mice is significantly reduced compared with that in wild-type control mice. Moreover, we find that a genetic mutation in EPHB2 identified in a family with colorectal cancer is a gain-of-function mutation that promoted TNF signaling activation compared with wild-type EPHB2. We provide evidence that the EPHB2-RNF186-TAB2-TAK1 signaling cascade plays an essential role in TNF-mediated signal transduction in colorectal epithelial cells and the carcinogenesis of colorectal cancer, which may provide potential targets for the treatment of colorectal cancer.
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Neoplasias Colorretais , Receptor EphA1 , Animais , Humanos , Camundongos , Carcinogênese , Neoplasias Colorretais/genética , Citocinas , Células Epiteliais/metabolismo , Receptor EphA1/metabolismo , Transdução de Sinais , Tirosina , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Receptor EphB2RESUMO
Opportunistic fungal infections have become one of the leading causes of death among immunocompromised patients, resulting in an estimated 1.5 million deaths each year worldwide. The molecular mechanisms that promote host defense against fungal infections remain elusive. Here, we find that Myosin IF (MYO1F), an unconventional myosin, promotes the expression of genes that are critical for antifungal innate immune signaling and proinflammatory responses. Mechanistically, MYO1F is required for dectin-induced α-tubulin acetylation, acting as an adaptor that recruits both the adaptor AP2A1 and α-tubulin N-acetyltransferase 1 to α-tubulin; in turn, these events control the membrane-to-cytoplasm trafficking of spleen tyrosine kinase and caspase recruitment domain-containing protein 9 Myo1f-deficient mice are more susceptible than their wild-type counterparts to the lethal sequelae of systemic infection with Candida albicans Notably, administration of Sirt2 deacetylase inhibitors, namely AGK2, AK-1, or AK-7, significantly increases the dectin-induced expression of proinflammatory genes in mouse bone marrow-derived macrophages and microglia, thereby protecting mice from both systemic and central nervous system C. albicans infections. AGK2 also promotes proinflammatory gene expression in human peripheral blood mononuclear cells after Dectin stimulation. Taken together, our findings describe a key role for MYO1F in promoting antifungal immunity by regulating the acetylation of α-tubulin and microtubules, and our findings suggest that Sirt2 deacetylase inhibitors may be developed as potential drugs for the treatment of fungal infections.
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Candida albicans/fisiologia , Candidíase/imunologia , Imunidade Inata/imunologia , Leucócitos Mononucleares/imunologia , Microtúbulos/imunologia , Miosina Tipo I/metabolismo , Miosina Tipo I/fisiologia , Acetilação , Animais , Antifúngicos/farmacologia , Candidíase/tratamento farmacológico , Candidíase/metabolismo , Candidíase/microbiologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Microtúbulos/microbiologia , Miosina Tipo I/genética , Transdução de SinaisRESUMO
In brief: Impaired spermatogenesis resulting from disturbed cholesterol metabolism due to intake of high-fat diet (HFD) has been widely recognized, however, the role of preprotein invertase subtilin 9 (PCSK9), which is a negative regulator of cholesterol metabolism, has never been reported. This study aims to reveal the role of PCSK9 on spermatogenesis induced by HFD in mice. Abstract: Long-term consumption of a high-fat diet (HFD) is an important factor that leads to impaired spermatogenesis exhibiting poor sperm quantity and quality. However, the mechanism of this is yet to be elucidated. Disrupted cholesterol homeostasis is one of many crucial pathological factors which could contribute to impaired spermatogenesis. As a negative regulator of cholesterol metabolism, preprotein invertase subtilin 9 (PCSK9) mediates low density lipoprotein receptor (LDLR) degradation to the lysosome, thereby reducing the expression of LDLR on the cell membrane and increasing serum low-density lipoprotein cholesterol level, resulting in lipid metabolism disorders. Here, we aim to study whether PCSK9 is a pathological factor for impaired spermatogenesis induced by HFD and the underlying mechanism. To meet the purpose of our study, we utilized wild-type C57BL/6 male mice and PCSK9 knockout mice with same background as experimental subjects and alirocumab, a PCSK9 inhibitor, was used for treatment. Results indicated that HFD induced higher PCSK9 expression in serum, liver, and testes, and serum PCSK9 is negatively correlated with spermatogenesis, while both PCSK9 inhibitor treatment and PCSK9 knockout methodologies ameliorated impaired lipid metabolism and spermatogenesis in mice fed a HFD. This could be due to the overexpression of PCSK9 induced by HFD leading to dyslipidemia, resulting in testicular lipotoxicity, thus activating the Bcl-2-Bax-Caspase3 apoptosis signaling pathway in testes, particularly in Leydig cells. Our study demonstrates that PCSK9 is an important pathological factor in the dysfunction of spermatogenesis in mice induced by HFD. This finding could provide innovative ideas for the diagnosis and treatment of male infertility.
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Dieta Hiperlipídica , Pró-Proteína Convertase 9 , Animais , Masculino , Camundongos , beta-Frutofuranosidase , Colesterol , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pró-Proteína Convertase 9/genética , SêmenRESUMO
Invasive fungal infections have become a leading cause of death among immunocompromised patients, leading to around 1.5 million deaths per year globally. The molecular mechanisms by which hosts defend themselves against fungal infection remain largely unclear, which impedes the development of antifungal drugs and other treatment options. In this article, we show that the tyrosine kinase receptor EPH receptor B2 (EPHB2), together with dectin-1, recognizes ß-glucan and activates downstream signaling pathways. Mechanistically, we found that EPHB2 is a kinase for Syk and is required for Syk phosphorylation and activation after dectin-1 ligand stimulation, whereas dectin-1 is critical for the recruitment of Syk. Ephb2-deficient mice are susceptible to Candida albicans-induced fungemia model, which also supports the role of EPHB2 in antifungal immunity. Overall, we provide evidence that EPHB2 is a coreceptor for the recognition of dectin-1 ligands and plays an essential role in antifungal immunity by phosphorylating Syk.
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Candida albicans/fisiologia , Candidíase/imunologia , Receptor EphB2/metabolismo , Animais , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Humanos , Lectinas Tipo C/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Receptor EphB2/genética , Transdução de Sinais , Quinase Syk/metabolismo , Células THP-1RESUMO
IL-17A plays an essential role in the pathogenesis of many autoimmune diseases, including psoriasis and multiple sclerosis. Act1 is a critical adaptor in the IL-17A signaling pathway. In this study, we report that an anti-sense long noncoding RNA, TRAF3IP2-AS1, regulates Act1 expression and IL-17A signaling by recruiting SRSF10, which downregulates the expression of IRF1, a transcriptional factor of Act1. Interestingly, we found that a psoriasis-susceptible variant of TRAF3IP2-AS1 A4165G (rs13210247) is a gain-of-function mutant. Furthermore, we identified a mouse gene E130307A14-Rik that is homologous to TRAF3IP2-AS1 and has a similar ability to regulate Act1 expression and IL-17A signaling. Importantly, treatment with lentiviruses expressing E130307A14-Rik or SRSF10 yielded therapeutic effects in mouse models of psoriasis and experimental autoimmune encephalomyelitis. These findings suggest that TRAF3IP2-AS1 and/or SRSF10 may represent attractive therapeutic targets in the treatment of IL-17-related autoimmune diseases, such as psoriasis and multiple sclerosis.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Fator Regulador 1 de Interferon/metabolismo , Interleucina-17/metabolismo , Psoríase/metabolismo , RNA Longo não Codificante/metabolismo , RNA/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Processamento de Serina-Arginina/metabolismo , Transdução de Sinais/genética , Animais , Proteínas de Ciclo Celular/genética , Técnicas de Inativação de Genes , Células HaCaT , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , RNA/genética , RNA Longo não Codificante/genética , Proteínas Repressoras/genética , Fatores de Processamento de Serina-Arginina/genética , TransfecçãoRESUMO
Uterine receptivity to the embryo is crucial for successful implantation. The establishment of uterine receptivity requires a large amount of energy, and abnormal energy regulation causes implantation failure. Glucose metabolism in the endometrium is tissue specific. Glucose is largely stored in the form of glycogen, which is the main energy source for the endometrium. AMP-activated protein kinase (AMPK), an important energy-sensing molecule, is a key player in the regulation of glucose metabolism and its regulation is also tissue specific. However, the mechanism of energy regulation in the endometrium for the establishment of uterine receptivity remains to be elucidated. In this study, we aimed to investigate the energy regulation mechanism of mouse uterine receptivity and its significance in embryo implantation. The results showed that the AMPK, p-AMPK, glycogen synthase 1, and glycogen phosphorylase M levels and the glycogen content in mouse endometrial epithelium varied in a periodic manner under regulation by the ovarian hormone. Specifically, progesterone significantly activated AMPK, promoted glycogenolysis, and upregulated glycogen phosphorylase M expression. AMPK regulated glycogen phosphorylase M expression and promoted glycogenolysis. AMPK was also found to be activated by changes in the energy or glycogen of the endometrial epithelial cells. The inhibition of AMPK activity or glycogenolysis altered the uterine receptivity markers during the window of implantation and ultimately interfered with implantation. In summary, consistency and synchronization of AMPK and glycogen metabolism constitute the core regulatory mechanism in mouse endometrial epithelial cells involved in the establishment of uterine receptivity.
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Proteínas Quinases Ativadas por AMP , Glicogênio , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Implantação do Embrião/fisiologia , Endométrio/metabolismo , Células Epiteliais/metabolismo , Feminino , Glicogênio/metabolismo , CamundongosRESUMO
The incidence of polycystic ovary syndrome (PCOS) due to high-fat diet (HFD) consumption has been increasing significantly. However, the mechanism by which a HFD contributes to the pathogenesis of PCOS has not been elucidated. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein that regulates cholesterol metabolism. Our previous study revealed abnormally high PCSK9 levels in serum from patients with PCOS and in serum and hepatic and ovarian tissues from PCOS model mice, suggesting that PCSK9 is involved in the pathogenesis of PCOS. However, the factor that induces high PCSK9 expression in PCOS remains unclear. In this study, Pcsk9 knockout mice were used to further explore the role of PCSK9 in PCOS. We also studied the effects of a HFD on the expression of PCSK9 and sterol regulatory element-binding protein 2 (SREBP2), a regulator of cholesterol homeostasis and a key transcription factor that regulates the expression of PCSK9, and the roles of these proteins in PCOS pathology. Our results indicated HFD may play an important role by inducing abnormally high PCSK9 expression via SREBP2 upregulation. We further investigated the effects of an effective SREBP inhibitor, fatostain, and found that it could reduce HFD-induced PCSK9 expression, ameliorate hyperlipidemia and improve follicular development in PCOS model mice. Our study thus further elucidates the important role of an HFD in the pathogenesis of PCOS and provides a new clue in the prevention and treatment of this disorder.
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Síndrome do Ovário Policístico , Pró-Proteína Convertase 9 , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Camundongos , Camundongos Knockout , Síndrome do Ovário Policístico/etiologia , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Regulação para CimaRESUMO
To evaluate the efficacy and safety of Chinese patent medicines in the treatment of insomnia by frequency network Meta-analysis. Randomized controlled trials of Chinese patent medicines for insomnia were retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase and Cochrane Library databases from the time of database establishment to October 2020. The quality of the included RCTs was evaluated according to the Cochrane bias risk standard, and the data was analyzed by RevMan 5.3 and Stata/MP 15.1. A total of 11 kinds of Chinese patent medicines in 27 RCTs were included. According to Meta-analysis, in term of the effective rate, Tianmeng Liquid, Zaoren Anshen Capsules, Shumian Capsules, Shensong Yangxin Capsules, Shenqi Wuweizi Tablets, Shugan Jieyu Capsules, Anshen Bunao Liquid and Qiye Anshen Tablets combined with nonbenzodiazepine drugs(NBZDs) were superior to NBZDs alone. In term of the improvement of Pittsburg sleeping quality index(PSQI) score, Tianmeng Liquid, Shumian Capsules, Shensong Yangxin Capsules, Bailemian Capsules, Shenqi Wuweizi Tablets, Shugan Jieyu Capsules, Yangxue Qingnao Granules and Yindan Xinnaotong Capsules combined with NBZDs were superior to NBZDs alone. In terms of the safety, Shumian Capsules, Shensong Yangxin Capsules, Shenqi Wuweizi Tablets and Qiye Anshen Tablets combined with NBZDs were superior to NBZDs alone. In terms of the avoidance of dizziness and headache, Qiye Anshen Tablets combined with NBZDs were superior to NBZDs alone. The results of Network Meta-analysis indicated that in term of the effective rate, top three optimal medication regimens were NBZDs combined with Shugan Jieyu Capsules, combined with Zaoren Anshen Capsules and combined with Shensong Yangxin Capsules in the order from high to low. With the respect of improvement of PSQI score, top three optimal medication regimens were NBZDs combined with Yangxue Qingnao Granules, combined with Tianmeng Liquid and combined with Yindan Xinnaotong Capsules in the order from high to low. In terms of the safety, top three optimal medication regimens were NBZDs combined with Qiye Anshen Tablets, combined with Shensong Yangxin Capsules and combined with Shenqi Wuweizi Tablets in the order from high to low. In terms of the avoidance of dizziness and headache, top three optimal medication regimens were NBZDs combined with Qiye Anshen Tablets, combined with Zaoren Anshen Capsules and combined with Shumian Capsules in the order from high to low. In terms of the avoidance of fatigue, top three optimal medication regimens were NBZDs combined with Shensong Yangxin Capsules, combined with Shumian Capsules and combined with Qiye Anshen Tablets in the order from high to low. In conclusion, Chinese patent medicines combined with NBZDs can effectively alleviate the symptoms of insomnia with a high safety. However, the conclusion of this study needs to be verified by more high-quality studies because of the low methodological quality of the included studies.
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Medicamentos de Ervas Chinesas , Medicina Tradicional do Leste Asiático , Distúrbios do Início e da Manutenção do Sono , China , Humanos , Metanálise em Rede , Medicamentos sem Prescrição , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológicoRESUMO
This study aims to study the effects of adenosine A2A receptor (A2AR) on hippocampal cell apoptosis and the putative mechanisms in a mouse model of chronic hypoxic-hypercapnia. Wild-type (WT) or A2AR knockout (A2AR KO) mice were randomly divided into normal control (NC) groups and chronic hypoxic-hypercapnia (4HH) groups. Compared with their corresponding NC groups (WT-NC and KO-NC), the apoptosis index (AI), caspase-3 activity, Bax mRNA and P-p38 protein expression in the hippocampus of 4HH groups (WT-4HH and KO-4HH) were significantly increased, while Bcl2 mRNA expression was significantly decreased (P < 0.05). Moreover, A2AR deficiency significantly rescued the effect of chronic hypoxic-hypercapnia on apoptosis when compared with the WT-4HH group (P < 0.05). A2AR deficiency inhibits hippocampal cell apoptosis in mice exposed to chronic hypoxic-hypercapnia, which might be associated with dampened p38 MAPK activation and Bax mRNA expression, and augmented Bcl-2 mRNA expression.
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Apoptose , Hipocampo/metabolismo , Hipercapnia/patologia , Hipóxia/patologia , Receptor A2A de Adenosina/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Doença Crônica , Ativação Enzimática , Hipocampo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , RNA Mensageiro/genética , Proteína X Associada a bcl-2/genéticaRESUMO
We report here an enzymatic strategy for asparaginyl endopeptidase-mediated peptide cyclization. Incorporation of chloroacetyl groups into the recognition sequence of OaAEP1 enabled intramolecular cyclization with Cys residues. Combining this strategy and phage display, we identified nanomolar macrocyclic peptide ligands targeting TEAD4. One of the bicyclic peptides binds to TEAD4 with a KD value of 139 nM, 16 times lower than its linear analogue, demonstrating the utility of this platform in discovering high-affinity macrocyclic peptide ligands.
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Bacteriófagos , Peptídeos , Ciclização , Peptídeos/química , Cisteína Endopeptidases , Ligantes , Bacteriófagos/metabolismo , Biblioteca de Peptídeos , Peptídeos Cíclicos/químicaRESUMO
With the increasing attention paid to macrocyclic scaffolds in peptide drug development, genetically encoded peptide macrocycle libraries have become invaluable sources for the discovery of high-affinity peptide ligands targeting disease-associated proteins. The traditional phage display technique of constructing disulfide-tethered macrocycles by cysteine oxidation has the inherent drawback of reduction instability of the disulfide bond. Chemical macrocyclization solves the problem of disulfide bond instability, but the involved highly electrophilic reagents are usually toxic to phages and may bring undesirable side reactions. Here, we report a unique Sortase-mediated Peptide Ligation and One-pot Cyclization strategy (SPLOC) to generate peptide macrocycle libraries, avoiding the undesired reactions of electrophiles with phages. The key to this platform is to mine the unnatural promiscuity of sortase on the X residue of the pentapeptide recognition sequence (LPXTG). Low reactive electrophiles are incorporated into the X-residue side chain, enabling intramolecular cyclization with the cysteine residue of the phage-displayed peptide library. Utilizing the genetically encoded peptide macrocycle library constructed by the SPLOC platform, we found a high-affinity bicyclic peptide binding TEAD4 with a nanomolar KD value (63.9 nM). Importantly, the binding affinity of the bicyclic peptide ligand is 102-fold lower than that of the acyclic analogue. To our knowledge, this is the first time to mine the unnatural promiscuity of ligases to generate peptide macrocycles, providing a new avenue for the construction of genetically encoded cyclic peptide libraries.
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We describe a simple and robust oxidation strategy for preparing N-terminal thiazolidine-containing peptide thioesters from peptide hydrazides. We find for the first time that l-thioproline can be used as a protective agent to prevent the nitrosation of N-terminal thiazolidine during peptide hydrazide oxidation. The thioproline-based oxidation strategy has been successfully applied to the chemical synthesis of CC chemokine ligand-2 (69aa) and omniligase-C (113aa), thereby demonstrating its utility in hydrazide-based native chemical ligation.
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Oxirredução , Peptídeos , Tiazolidinas , Tiazolidinas/química , Tiazolidinas/síntese química , Estrutura Molecular , Peptídeos/química , Peptídeos/síntese química , Hidrazinas/química , Prolina/química , Ésteres/química , Compostos de Sulfidrila/químicaRESUMO
OBJECTIVE: To study the protective effect of cerebrospinal fluid containing Qingxin Kaiqiao Fang on sodium dithionite (Na2S2O4)-induced PC12 cell injury, in order to provide basis for clinical application of the prescription. METHOD: SD rats were orally administered with water decoction of Qingxin Kaiqiao Fang (7. 9 g . kg-1) once every 12 h, for a total of 7 times, in order to prepare cerebrospinal fluid containing Qingxin Kaiqiao Fang. The neurocyte injury model was established by adding Na2S2O4 with the final concentration of 8 m mol . L-1 into PC12 cells. With nimodipine (1 x 10(7)mol . L-1 ) as the positive control group, MTT method test was adopted to detect the impact of cerebrospinal fluid containing Qingxin Kaiqiao Fang on the activity of PC12 cells. The expression of Bax, Bel-2 and Caspase-3 mRNA was detected by RT-PCR. RESULT: The cerebrospinal fluid containing Qingxin Kaiqiao Fang groups showed a significantly higher activity in PC12 cells than the model group, with decrease in expressions of Bax mRNA and Caspase-3 mRNA and increase in expression of Bel-2 mRNA. There were significant differences compared with the model group (P< 0. 05,P <0. 01). CONCLUSION: Qingxin Kaiqiao Fang shows a notable protective effect on Na2S2 04-induced neurocyte injury.
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Líquido Cefalorraquidiano/química , Ditionita/toxicidade , Medicamentos de Ervas Chinesas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Células PC12 , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Introduction: Autosomal recessive dystrophic epidermolysis bullosa (RDEB) is a rare disease with an early onset and severe phenotype. The pathogenic mechanism associated with mutations in the gene COL7A1 has been widely studied and many related cases have been reported, but prenatal cases are rare. Here, we report the prenatal diagnosis of a sporadic case of RDEB. Methods: In this study, the fetus with abnormal skin manifestations, which were determined during a prenatal ultrasound, was evaluated based on the ultrasound and autopsy findings and the results of molecular diagnostic analyses. Samples of the fetus and the parents were subjected to trio whole-exome sequencing, and in vitro functional analyses were conducted to analyze the pathogenicity of the detected mutation. Results: During the conventional prenatal ultrasound, the fetus showed abnormal epidermal lines on both lower limbs and the plantar skin as well as an interruption of the continuity of the lateral epidermal line below the ankle of the right lower limb. Gene testing revealed a homozygous nonsense mutation in COL7A1 (c.7411C>T, p.Arg2471Ter), which gave rise to RDEB in the fetus. Further, the results of the in vitro functional experiments confirmed that the mutation might lead to protein degradation. Conclusion: Most prenatal diagnoses of RDEB are the result of targeted molecular analyses carried out based on family history, and prenatal ultrasound reports of severe RDEB phenotypes are extremely rare. Our case suggests that the observation of abnormal epidermal lines should be given due consideration during prenatal diagnosis, as they may be a sign of possible epidermolysis bullosa.
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Calcium and vitamin D have well-established roles in maintaining calcium balance and bone health. Decades of research in human subjects and animals have revealed that calcium and vitamin D also have effects on many other organs including male reproductive organs. The presence of calcium-sensing receptor, vitamin D receptor, vitamin D activating and inactivating enzymes and calcium channels in the testes, male reproductive tract and human spermatozoa suggests that vitamin D and calcium may modify male reproductive function. Functional animal models have shown that vitamin D deficiency in male rodents leads to a decrease in successful mating and fewer pregnancies, often caused by impaired sperm motility and poor sperm morphology. Human studies have to a lesser extent validated these findings; however, newer studies suggest a positive effect of vitamin D supplementation on semen quality in cases with vitamin D deficiency, which highlights the need for initiatives to prevent vitamin D deficiency. Calcium channels in male reproductive organs and spermatozoa contribute to the regulation of sperm motility and capacitation, both essential for successful fertilisation, which supports a need to avoid calcium deficiency. Studies have demonstrated that vitamin D, as a regulator of calcium homoeostasis, influences calcium influx in the testis and spermatozoa. Emerging evidence suggests a potential link between vitamin D deficiency and male infertility, although further investigation is needed to establish a definitive causal relationship. Understanding the interplay between vitamin D, calcium and male reproductive health may open new avenues for improving fertility outcomes in men.
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AIMS: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in the women of childbearing age. It is characterized by hyperandrogenism and abnormal follicular growth and ovulation. The polyol pathway is a glucose metabolism bypass pathway initiated by aldose reductase (ADR). Androgen induces the expression of ADR in the male reproductive tract, which has a general physiological significance for male reproductive function. Here we investigate whether hyperandrogenemia in PCOS leads to increased flux of the polyol pathway in ovarian tissue, which in turn affects follicular maturation and ovulation through oxidative stress. MAIN METHODS: We used clinical epidemiological methods to collect serum and granulosa cells from clinical subjects for a clinical case-control study. At the same time, cell biology and molecular biology techniques were used to conduct animal and cell experiments to further explore the mechanism of hyperandrogen-induced ovarian polyol pathway hyperactivity and damage to ovarian function. KEY FINDINGS: Here, we find that hyperandrogenism of PCOS can induce the expression of ovarian aldose reductase, which leads to the increase of the polyol pathway flux, and affects ovarian function through excessive oxidative stress. SIGNIFICANCE: Our research has enriched the pathological mechanism of PCOS and may provide a new clue for the clinical treatment of PCOS.
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Hiperandrogenismo , Síndrome do Ovário Policístico , Humanos , Animais , Feminino , Masculino , Síndrome do Ovário Policístico/metabolismo , Hiperandrogenismo/metabolismo , Aldeído Redutase/metabolismo , Estudos de Casos e Controles , Estresse OxidativoRESUMO
Soybean frogeye leaf spot (FLS) is a worldwide fungal disease. Its higher occurrence frequency and wider distribution range always led to severe yield losses of soybean, therefore, breeding new cultivars with FLS resistance has been an important breeding goal for soybean breeders. In this study, an association panel of 183 representative soybean accessions was used to evaluate their resistance to FLS race 1, and to identify quantitative trait nucleotides (QTNs) and candidate genes based on genome-wide association study (GWAS) and high-throughput single-nucleotide polymorphisms (SNPs). A total of 23,156 high-quality SNPs were developed using the specific locus-amplified fragment sequencing (SLAF-seq) approach. Finally, 13 novel association signals associated with FLS race 1 resistance were identified by the compressed mixed linear model (CMLM). In addition, 119 candidate genes were found within the 200-kb flanking genomic region of these 13 peak SNPs. Based on the gene-based association analysis, haplotype analysis, expression pattern analysis, and virus-induced gene silencing (VIGS) systems, four genes (Glyma.05G121100, Glyma.17G228300, Glyma.19G006900, and Glyma.19G008700) were preliminarily proved to play an important role in the soybean resistance to FLS race 1.
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We report a new pattern of a bicyclic helical peptide constructed through head-to-tail cross-linking. The described bicyclic helical peptide has a head-to-tail cross-linking arm and a C-terminal i, i + 4 cross-linking arm. This scaffold will provide a promising scaffold for designing a proteolytically resistant helix-constrained peptide.
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PeptídeosRESUMO
Common variants of the T-cell activation Rho GTPase-activating protein (TAGAP) are associated with the susceptibility to human inflammatory bowel diseases (IBDs); however, the underlying mechanisms are still unknown. Here, we show that TAGAP deficiency or TAGAP expression downregulation caused by TAGAP gene polymorphism leads to decreased production of antimicrobial peptides (AMPs), such as reg3g, which subsequently causes dysregulation of the gut microbiota, which includes Akkermansia muciniphila and Bacteroides acidifaciens strains. These two strains can polarize T helper cell differentiation in the gut, and aggravate systemic disease associated with the dextran sodium sulfate-induced (DSS) disease's phenotype in mice. More importantly, we demonstrated that recombinant reg3g protein or anti-p40 monoclonal antibody exerted therapeutic effects for the treatment of DSS-induced colitis in wild-type and TAGAP-deficient mice, suggesting that they are potential medicines for human IBD treatment, and they may also have a therapeutic effect for the patients who carry the common variant of TAGAP rs212388.