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1.
Phytomedicine ; 94: 153818, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34798521

RESUMO

BACKGROUND: Rehmannia Glutinosa Libosch. is applied for the treatment of renal and inflammatory-related diseases, and oleic acid (OA) is a compound isolated from Rehmannia Glutinosa Libosch.. Unfortunately, the pharmacological activity of OA on LPS treated acute kidney injury (AKI) has not been investigated. AIMS: The research is aiming to probe the activities of OA on LPS-induced AKI. METHODS: Information of OA effect on AKI were from network pharmacology. H&E staining, creatinine (CRE) and urea nitrogen (UN) were performed to evaluate the activities of OA on kidney function. Inflammatory factors in serum were measured by cytometric bead array. Increased ratio of reactive oxygen species (ROS) in kidney and immune cells in the peripheral blood were determined by flow cytometry (FCM). PPAR-γ, MAPK and apoptotic signaling pathways were measured by Western blot. Then, a metabolomics approach was utilized to investigate OA's response to AKI. The role of salirasib (FTS, Ras inhibitor) in OA acted on ROS, Ca2+, MMP and Ras signaling pathway in LPS treated NRK-52e cells were investigated by FCM and In-cell western. RESULTS: It is proved that OA effetively ameliorated renal function, alleviated inflammatory response and oxidative stress, and transformed apoptotic, MAPK and PPAR-γ signaling pathways in mice with AKI, regulated phenylalanine metabolism, purine metabolism, sphingolipid metabolism, taurine and hypotaurine metabolism, moreover, the role of OA in injury of NRK-52e was blocked by FTS. CONCLUSION: In a word, OA could alleviate AKI by restraining inflammation and oxidative stress via regulating the Ras/MAPKs/PPAR-γ signaling pathway, phenylalanine metabolism, purine metabolism, sphingolipid metabolism and taurine and hypotaurine metabolism, which might be a useful strategy for treating AKI.

2.
Meat Sci ; 183: 108643, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34390897

RESUMO

Slightly acidic electrolyzed water (SAEW) is often used as a disinfectant in beef preservation to ensure microbiological safety. However, it ineffectively inhibit lipid oxidation. Therefore, the combination of SAEW and tea polyphenols (TPs) was tested to inhibit lipid oxidation and microbial growth in beef preservation. SAEW and TPs were selected as the optimum sanitizer and antioxidant, respectively. Then, the inactivation efficacies of different combination treatments of SAEW and TPs of Salmonella enteritidis in beef were compared and treatment of SAEW-TPs (SAEW immersion at an available chlorine concentration of 30 mg/L for 2.5 min, followed by the TPs immersion at a 0.1% concentration for 2.5 min) was selected. Finally, the effectiveness of SAEW-TPs on the microbiological and physicochemical properties of beef during storage was evaluated. The results revealed that the required quality standard of beef treated with SAEW-TPs was prolonged by approximately 9 d at 4 °C, and this treatment had greater antimicrobial and antioxidant effects than did the single treatment.


Assuntos
Desinfetantes/farmacologia , Conservação de Alimentos/métodos , Polifenóis/farmacologia , Carne Vermelha/análise , Animais , Bovinos , Lipídeos , Oxirredução , Carne Vermelha/microbiologia , Salmonella enteritidis/efeitos dos fármacos , Hipoclorito de Sódio/farmacologia , Chá/química , Água/química
3.
Front Microbiol ; 12: 775083, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790187

RESUMO

Hepatitis E Virus (HEV) causes viral hepatitis in humans worldwide, while a subset of HEV species, avian HEV, causes hepatitis-splenomegaly syndrome in chickens. To date, there are few reports on the host proteins interacting with HEV and being involved in viral infection. Previous pull-down assay combining mass spectrometry indicated that cell division control protein 42 (CDC42), a member belonging to the Rho GTPase family, was pulled down by avian HEV capsid protein. We confirmed the direct interaction between CDC42 and avian and mammalian HEV capsid proteins. The interaction can increase the amount of active guanosine triphosphate binding CDC42 state (GTP-CDC42). Subsequently, we determined that the expression and activity of CDC42 were positively correlated with HEV infection in the host cells. Using the different inhibitors of CDC42 downstream signaling pathways, we found that CDC42-MRCK (a CDC42-binding kinase)-non-myosin IIA (NMIIA) pathway is involved in naked avian and mammalian HEV infection, CDC42-associated p21-activated kinase 1 (PAK1)-NMIIA/Cofilin pathway is involved in quasi-enveloped mammalian HEV infection and CDC42-neural Wiskott-Aldrich syndrome protein-actin-polymerizing protein Arp2/3 pathway (CDC42-(N-)WASP-Arp2/3) pathway participates in naked and quasi-enveloped mammalian HEV infection. Collectively, these results demonstrated for the first time that HEV capsid protein can directly bind to CDC42, and non- and quasi-enveloped HEV use different CDC42 downstream signaling pathways to participate in viral infection. The study provided some new insights to understand the life cycle of HEV in host cells and a new target of drug design for combating HEV infection.

5.
Front Immunol ; 12: 754208, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34733286

RESUMO

The autonomic nervous system has been studied for its involvement in the control of macrophages; however, the mechanisms underlying the interaction between the adrenergic receptors and alternatively activated macrophages (M2) remain obscure. Using FVB wild-type and beta 2 adrenergic receptors knockout, we found that ß2-AR deficiency alleviates hepatobiliary damage in mice infected with C. sinensis. Moreover, ß2-AR-deficient mice decrease the activation and infiltration of M2 macrophages and decrease the production of type 2 cytokines, which are associated with a significant decrease in liver fibrosis in infected mice. Our in vitro results on bone marrow-derived macrophages revealed that macrophages from Adrb2-/- mice significantly decrease M2 markers and the phosphorylation of ERK/mTORC1 induced by IL-4 compared to that observed in M2 macrophages from Adrb2+/+ . This study provides a better understanding of the mechanisms by which the ß2-AR enhances type 2 immune response through the ERK/mTORC1 signaling pathway in macrophages and their role in liver fibrosis.

6.
Innate Immun ; 27(7-8): 514-524, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34806444

RESUMO

This study investigated the effect and mechanism of chrysosplenol D (CD) on LPS-induced acute lung injury in mice. Histological changes in the lungs were measured by hematoxylin-eosin staining. The levels of IL-6, IL-1ß, and TNF-α in the bronchoalveolar lavage fluid were detected by ELISA. The levels of oxidative stress were detected by the cuvette assay. Immune cells in peripheral blood, the levels of reactive oxygen species, and apoptosis of primary lung cells were detected by flow cytometry. The mRNA levels of TLR4, MyD88, IL-1ß, and NLRP3 were measured by quantitative real-time polymerase chain reaction. The levels of proteins in apoptosis and the TLR4-MAPKs/NF-κB signaling pathways were detected by Western blot. Hematoxylin-eosin staining showed that CD could improve lung injury; decrease the levels of inflammatory factors, oxidative stress, reactive oxygen species, and cell apoptosis; and regulate the immune system. Moreover, CD could down-regulate the mRNA levels of TLR4, MyD88, NLRP3, and IL-1ß in lung, and the protein levels of Keap-1, Cleaved-Caspase-3/Caspase-3, Cleaved-Caspase-9/Caspase-9, TLR4, MyD88, p-ERK/ERK, p-JNK/JNK, p-p38/p38, p-p65/p65, NLRP3, and IL-1ß, and up-regulated the levels of Bcl-2/Bax, p-Nrf2/Nrf2, and HO-1. The results suggested that CD could protect mice against LPS-induced acute lung injury by inhibiting oxidative stress, inflammation, and apoptosis via the TLR4-MAPKs/NF-κB signaling pathways.

7.
Sci Rep ; 11(1): 22796, 2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34815498

RESUMO

The current severe situation of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been reversed and posed great threats to global health. Therefore, there is an urgent need to find out effective antiviral drugs. The 3-chymotrypsin-like protease (3CLpro) in SARS-CoV-2 serve as a promising anti-virus target due to its essential role in the regulation of virus reproduction. Here, we report an improved integrated approach to identify effective 3CLpro inhibitors from effective Chinese herbal formulas. With this approach, we identified the 5 natural products (NPs) including narcissoside, kaempferol-3-O-gentiobioside, rutin, vicenin-2 and isoschaftoside as potential anti-SARS-CoV-2 candidates. Subsequent molecular dynamics simulation additionally revealed that these molecules can be tightly bound to 3CLpro and confirmed effectiveness against COVID-19. Moreover, kaempferol-3-o-gentiobioside, vicenin-2 and isoschaftoside were first reported to have SARS-CoV-2 3CLpro inhibitory activity. In summary, this optimized integrated strategy for drug screening can be utilized in the discovery of antiviral drugs to achieve rapid acquisition of drugs with specific effects on antiviral targets.

8.
J Org Chem ; 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34806887

RESUMO

An interrupted Pummerer reaction of PhICl2 and sulfoxides was found to in situ generate reactive organosulfenyl chloride, which enabled the intramolecular electrophilic cyclization of 2-alkynylanilines, generating 3-sulfenylated indole with a good to excellent yield under metal-free conditions. One striking feature of the approach is that sulfoxide regeneration can be realized via the oxidation of the formed sulfides by the generated hypervalent iodine species.

9.
Proc Natl Acad Sci U S A ; 118(46)2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34772807

RESUMO

Chronic infection with liver flukes (such as Clonorchis sinensis) can induce severe biliary injuries, which can cause cholangitis, biliary fibrosis, and even cholangiocarcinoma. The release of extracellular vesicles by C. sinensis (CsEVs) is of importance in the long-distance communication between the hosts and worms. However, the biological effects of EVs from liver fluke on biliary injuries and the underlying molecular mechanisms remain poorly characterized. In the present study, we found that CsEVs induced M1-like activation. In addition, the mice that were administrated with CsEVs showed severe biliary injuries associated with remarkable activation of M1-like macrophages. We further characterized the signatures of miRNAs packaged in CsEVs and identified a miRNA Csi-let-7a-5p, which was highly enriched. Further study showed that Csi-let-7a-5p facilitated the activation of M1-like macrophages by targeting Socs1 and Clec7a; however, CsEVs with silencing Csi-let-7a-5p showed a decrease in proinflammatory responses and biliary injuries, which involved in the Socs1- and Clec7a-regulated NF-κB signaling pathway. Our study demonstrates that Csi-let-7a-5p delivered by CsEVs plays a critical role in the activation of M1-like macrophages and contributes to the biliary injuries by targeting the Socs1- and Clec7a-mediated NF-κB signaling pathway, which indicates a mechanism contributing to biliary injuries caused by fluke infection. However, molecules other than Csi-let-7a-5p from CsEVs that may also promote M1-like polarization and exacerbate biliary injuries are not excluded.

10.
Nat Commun ; 12(1): 6969, 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34845221

RESUMO

Developing low-cost and highly efficient catalysts toward the efficient oxygen evolution reaction (OER) is highly desirable for photoelectrochemical (PEC) water splitting. Herein, we demonstrated that N-incorporation could efficiently activate NiFeOx catalysts for significantly enhancing the oxygen evolution activity and stability of BiVO4 photoanodes, and the photocurrent density has been achieved up to 6.4 mA cm-2 at 1.23 V (vs. reversible hydrogen electrode (RHE), AM 1.5 G). Systematic studies indicate that the partial substitution of O sites in NiFeOx catalysts by low electronegative N atoms enriched the electron densities in both Fe and Ni sites. The electron-enriched Ni sites conversely donated electrons to V sites of BiVO4 for restraining V5+ dissolution and improving the PEC stability, while the enhanced hole-attracting ability of Fe sites significantly promotes the oxygen-evolution activity. This work provides a promising strategy for optimizing OER catalysts to construct highly efficient and stable PEC water splitting devices.

11.
Appl Microbiol Biotechnol ; 105(21-22): 8505-8516, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34633486

RESUMO

Hepatitis E, a significant global public health issue in China, is caused by sporadic infections with regional hepatitis E virus (HEV) genotypes 1, 3, and 4. To date, most immunoassays currently used to test human sera for the presence of anti-HEV antibodies cannot identify HEV at the genotype level. However, such information would be useful for identifying the source of infecting virus. Therefore, here we describe the development of a competitive enzyme-linked immunosorbent assay (ELISA) for detecting anti-genotype 1 HEV antibodies in human sera. Using recombinant genotype 1 HEV ORF3 protein as immunogen, traditional hybridoma technology was employed to generate seven monoclonal antibodies (mAbs), of which two mAbs specifically reacted with the immunogen. One of these two mAbs, 1D2, was labeled with horseradish peroxidase (HRP) for use in competitive ELISA (cELISA). After cELISA optimization using a checkerboard assay design, the amount of ORF3SAR-55 as coating antigen (100 ng/well), HRP-1D2 mAb concentration (1 µg/mL), and test serum dilution (1:10) were selected and a result ≥ 19.5 was used as the cutoff for a positive result. Importantly, cross-genotype cELISA results indicated that the cELISA could not detect anti-genotype 3 rabbit and 4 swine HEV antibodies. Moreover, human sera confirmed as negative for anti-HEV antibodies using the commercial ELISA kit were all negative via cELISA. However, because the commercial ELISA kit detects anti-all genotypes HEV antibodies and the cELISA only detects anti-genotype 1 HEV antibodies, the consistence rate of two assays detecting positive sera is low. In summary, here a cELISA for detecting anti-genotype 1 HEV antibodies was developed for use in epidemiological investigations of genotype 1 HEV infections in humans. KEY POINTS: • Seven mAbs were produced using genotype 1 HEV ORF3 protein as immunogen. • One mAb that specifically bound to genotype 1 HEV ORF3 protein was selected and labeled for use in a cELISA to detect anti-genotype 1 HEV antibodies. • The competitive ELISA developed here will aid clinical diagnosis of HEV infections and will be useful for large-scale serological testing of genotype 1 HEV infections in humans.


Assuntos
Vírus da Hepatite E , Hepatite E , Animais , Anticorpos Antivirais , Ensaio de Imunoadsorção Enzimática , Genótipo , Anticorpos Anti-Hepatite , Hepatite E/diagnóstico , Vírus da Hepatite E/genética , Coelhos , Suínos
12.
Stem Cell Res Ther ; 12(1): 546, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34674752

RESUMO

BACKGROUND: Hepatic schistosomiasis, a chronic liver injury induced by long-term Schistosoma japonicum (S. japonicum) infection, is characterized by egg granulomas and fibrotic pathology. Hepatic progenitor cells (HPCs), which are nearly absent or quiescent in normal liver, play vital roles in chronic and severe liver injury. But their role in the progression of liver injury during infection remains unknown. METHODS: In this study, the hepatic egg granulomas, fibrosis and proliferation of HPCs were analyzed in the mice model of S. japonicum infection at different infectious stages. For validating the role of HPCs in hepatic injury, tumor necrosis factor-like-weak inducer of apoptosis (TWEAK) and TWEAK blocking antibody were used to manipulate the proliferation of HPCs in wild-type and IL-33-/- mice infected with S. japonicum. RESULTS: We found that the proliferation of HPCs was accompanied by inflammatory granulomas and fibrosis formation. HPCs expansion promoted liver regeneration and inhibited inflammatory egg granulomas, as well as the deposition of fibrotic collagen. Interestingly, the expression of IL-33 was negatively associated with HPCs' expansion. There were no obvious differences of liver injury caused by infection between wild-type and IL-33-/- mice with HPCs' expansion. However, liver injury was more attenuated in IL-33-/- mice than wild-type mice when the proliferation of HPCs was inhibited by anti-TWEAK. CONCLUSIONS: Our data uncovered a protective role of HPCs in hepatic schistosomiasis in an IL-33-dependent manner, which might provide a promising progenitor cell therapy for hepatic schistosomiasis.


Assuntos
Interleucina-33 , Cirrose Hepática/parasitologia , Esquistossomose Japônica , Células-Tronco , Animais , Interleucina-33/genética , Fígado/patologia , Cirrose Hepática/patologia , Camundongos , Schistosoma japonicum , Esquistossomose Japônica/patologia
13.
Inorg Chem ; 60(21): 16834-16839, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34693707

RESUMO

A novel Co/Ni bimetallic nanoparticle supported by nitrogen-doped porous carbon (NPC), Co5/Ni@NPC-700, exhibits high conversion, chemoselectivity, and recyclability in the hydrogenation of 16 different nitro compounds into desired amines with hydrazine hydrate under mild conditions. The synergistic effects of Co/Ni bimetal nanoparticles and the NPC-supported porous honeycomb structure with more accessible active sites may be responsible for the high catalytic hydrogenation performance.

14.
Artigo em Inglês | MEDLINE | ID: mdl-34639531

RESUMO

Haze has been a severe problem in China for some time, jeopardizing air quality, public health and sustainable growth. This paper examines the direct effect and spatial spillover effect of policy uncertainty on haze pollution with a spatial panel model, using prefecture-level data from 2004 to 2016. This study shows that: (1) policy uncertainty has increased the level of local haze pollution and has a significant spatial spillover effect on surrounding areas; (2) although local policy uncertainty has increased the haze pollution in geographically adjacent cities, it only affects the cities within the province with similar economic distances; and (3) the policy at the central level can effectively alleviate the impact of policy uncertainty at the local level on haze pollution, especially in relation to the spatial spillover effect, but still has limitations in eliminating the direct effect, which is due to the ineradicable nature of policy uncertainty.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , China/epidemiologia , Cidades , Monitoramento Ambiental , Poluição Ambiental/análise , Material Particulado/análise , Políticas , Incerteza
15.
Bioinorg Chem Appl ; 2021: 4763944, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691164

RESUMO

Development of multiple agents has a significant impact on the cancer diagnosis and therapy. Several fluorescent dyes including near-infrared (NIR) fluorescent agents have been already well studied in the field of photodynamic therapy (PDT). In the present study, we reported a novel fluorescent dye could obviously inhibit cancer cell proliferation with slight toxic effects on the biological organism. Furthermore, it displayed selective staining on cancer cells, particularly on cancer stem cells (CSCs), rather than normal cells. Mechanically, this dye preferred to invading mitochondria of cancer cells and inducing overwhelming reactive oxygen species (ROS) production. The in vivo experiments further demonstrated that this dye could image cancer cells and even CSCs in a short-time intratumor injection manner using a zebrafish model and subsequently inhibit cancer cell proliferation after a relatively long-time drug exposure. Taken together, the future development of this agent will promise to make an essential contribution to the cancer diagnosis and therapeutics.

16.
Front Cell Infect Microbiol ; 11: 759965, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660351

RESUMO

Salmonella has been known as an important zoonotic pathogen that can cause a variety of diseases in both animals and humans. Poultry are the main reservoir for the Salmonella serovars Salmonella Pullorum (S. Pullorum), Salmonella Gallinarum (S. Gallinarum), Salmonella Enteritidis (S. Enteritidis), and Salmonella Typhimurium (S. Typhimurium). The conventional serotyping methods for differentiating Salmonella serovars are complicated, time-consuming, laborious, and expensive; therefore, rapid and accurate molecular diagnostic methods are needed for effective detection and prevention of contamination. This study developed and evaluated a TaqMan multiplex real-time PCR assay for simultaneous detection and differentiation of the S. Pullorum, S. Gallinarum, S. Enteritidis, and S. Typhimurium. In results, the optimized multiplex real-time PCR assay was highly specific and reliable for all four target genes. The analytical sensitivity corresponded to three colony-forming units (CFUs) for these four Salmonella serovars, respectively. The detection limit for the multiplex real-time PCR assay in artificially contaminated samples was 500 CFU/g without enrichment, while 10 CFU/g after pre-enrichment. Moreover, the multiplex real-time PCR was applied to the poultry clinical samples, which achieved comparable results to the traditional bacteriological examination. Taken together, these results indicated that the optimized TaqMan multiplex real-time PCR assay will be a promising tool for clinical diagnostics and epidemiologic study of Salmonella in chicken farm and poultry products.


Assuntos
Galinhas , Salmonella enteritidis , Animais , Fazendas , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Salmonella enteritidis/genética , Sensibilidade e Especificidade , Sorogrupo
17.
Org Lett ; 23(21): 8262-8266, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34636566

RESUMO

Enamides are versatile precursors for synthesizing bioactive compounds. As their alkylations often require perstoichiometric amounts of oxidants, transition metals, or photocatalysts, we herein report a simple alternative for their alkylations by just using visible light to irradiate the mixture of the readily available N-hydroxyphthalimide esters and enamides without an additive. The reaction involves the photoactivation of a π-π stacking EDA complex between the substrates.

18.
Front Endocrinol (Lausanne) ; 12: 711991, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34589056

RESUMO

Purpose: Congenital growth hormone deficiency (GHD) is a rare and etiologically heterogeneous disease. We aim to screen disease-causing mutations of GHD in a relatively sizable cohort and discover underlying mechanisms via a candidate gene-based mutational burden analysis. Methods: We retrospectively analyzed 109 short stature patients associated with hormone deficiency. All patients were classified into two groups: Group I (n=45) with definitive GHD and Group II (n=64) with possible GHD. We analyzed correlation consistency between clinical criteria and molecular findings by whole exome sequencing (WES) in two groups. The patients without a molecular diagnosis (n=90) were compared with 942 in-house controls for the mutational burden of rare mutations in 259 genes biologically related with the GH axis. Results: In 19 patients with molecular diagnosis, we found 5 possible GHD patients received known molecular diagnosis associated with GHD (NF1 [c.2329T>A, c.7131C>G], GHRHR [c.731G>A], STAT5B [c.1102delC], HRAS [c.187_207dup]). By mutational burden analysis of predicted deleterious variants in 90 patients without molecular diagnosis, we found that POLR3A (p = 0.005), SUFU (p = 0.006), LHX3 (p = 0.021) and CREB3L4 (p = 0.040) represented top genes enriched in GHD patients. Conclusion: Our study revealed the discrepancies between the laboratory testing and molecular diagnosis of GHD. These differences should be considered when for an accurate diagnosis of GHD. We also identified four candidate genes that might be associated with GHD.

19.
Clin Genet ; 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34494659

RESUMO

The treatment of recessive dystrophic epidermolysis bullosa (RDEB) remains challenging. Elevated IgE levels have previously been reported in several RDEB patients. In this prospective, single-centre, open intervention study, elevated IgE levels were seen in 11 out of 12 patients with intense pruritus, and the patients with elevated IgE levels received anti-IgE therapy every 4 weeks for at least three cycles. Compared with the baseline, 10 patients with RDEB had good clinical outcomes with enhanced wound healing, a reduction in Birmingham (epidermolysis bullosa) EB severity score by 15%, a reduction in affected body surface area by 23.3%, amelioration of skin inflammation, and an increase in type VII collagen deposition by 13.1-fold. All the patients had a good tolerance to anti-IgE therapy. Furthermore, patients with higher IgE levels tended to have higher disease severity and more favorable clinical outcomes. Our report also suggested the potential role of IgE in the pathogenesis of inflammatory conditions associated with RDEB. (ChiCTR1900021437).

20.
Reprod Biomed Online ; 43(5): 913-919, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34493464

RESUMO

RESEARCH QUESTION: Male infertility is a global issue worldwide and multiple morphological abnormalities of the sperm flagella (MMAF) is one of the most severe forms of the qualitative sperm defects with a heterogeneous genetic cause that has not been completely understood. Can whole-exome sequencing (WES) reveal novel genetic causes contributing to MMAF in a consanguineous Pakistani family, comprising three infertile brothers? DESIGN: WES and bioinformatic analysis were conducted to screen potential pathogenic variants. The identified variant was validated by Sanger sequencing in all available family members Transmission electron microscopy analyses was carried out to examine the flagella ultrastructure of spermatozoa from patient. RESULTS: WES and Sanger sequencing identified a novel homozygous stop-gain mutation (ENST00000392644.4, c.182C>G, p.S61X) in ARMC2, which is expected to lead to loss of protein functions. Transmission electron microscopy analyses revealed that the flagellar ultrastructure of the patient's spermatozoa was disorganized along with a complete absence of central pair complex (CPC), suggesting that ARMC2 is involved in the assembly, stability of the axonemal complex, or both, particularly the CPC. CONCLUSION: We report that a familial stop-gain mutation in ARMC2 is associated with male infertility in humans caused by MMAF accompanied with loss of CPCs and axonemal disorganization. We provide genetic evidence that ARMC2 is essential for human spermatogenesis and its mutation may be pathogenic for MMAF. These findings will improve the knowledge about the genetic basis of MMAF and provide information for genetic counselling of this disease.

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