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C14H20Cl2N4O4Zn, monoclinic, P21/n (no. 14), a = 8.562(2) Å, b = 27.953(8) Å, c = 8.804(2) Å, β = 117.092(4)°, V = 1875.9(9) Å3, Z = 4, R gt(F) = 0.0441, wR ref(F 2) = 0.1031, T = 296 K.

C6H6N2O2, monoclinic P21/c (no. 14), a = 6.7909(2) Å, b = 23.9261(7) Å, c = 7.5103(2) Å, β = 95.265(2)°, V = 1215.12(6) Å3, Z = 8, R gt(F) = 0.0574, wR ref(F 2) = 0.1439, T = 293.

Introduction: Diabetic peripheral neuropathy (DPN), a widely prevalent complication in patients with type 2 diabetes, exerts a significant influence on patients' overall health and financial circumstances. Photobiomodulation therapy is one of the means of physical therapy for DPN. Although preliminary findings suggest the efficacy of photobiomodulation therapy in alleviating peripheral neuropathy, the existing literature lacks substantial evidence regarding its safety and effectiveness specifically in the context of diabetes-related peripheral neuropathy. Therefore, we plan to arrive at more distinct findings through systematic evaluation and meta-analysis. Methods: We will conduct a comprehensive search for studies published from the beginning until October 1, 2023, using various databases including Web of Science, Embase, Cochrane Library, PubMed, AMED, Wanfang database, VIP database, China National Knowledge Infrastructure, and the Chinese Biomedical Literature database. Simultaneously, we will also search for the WHO International Clinical Trial Registration Platform, China Clinical Trial Registration Platform, and Clinical Trials.gov. Gray literature will be retrieved using Google Scholar and opengrey.edu. Only randomized controlled trials in Chinese and English were included, with no restrictions on publication status. The primary outcomes will include change of symptom scores, change of nerve conduction velocity. Additional outcomes will encompass quality of life, change in pain, blood glucose levels after fasting and 2 hours after eating, levels of glycosylated hemoglobin, and any adverse events associated with photobiomodulation therapy. Reman V.5.4 and R language will be used for the meta-analysis. Assessment of potential bias will be conducted through Cochrane risk of bias 2 tool (RoB 2.0) and Physiotherapy Evidence Database (PEDro) scale. Registration: PROSPERO (registration number: CRD42023466586). Discussion: This meta-analysis aims to assess the efficacy and safety of photobiomodulation therapy as a potential treatment for diabetic peripheral neuropathy (DPN), and providing a straightforward and convenient therapeutic for patients. Additionally, it expands the range of treatment alternatives available to healthcare professionals managing DPN. [ABSTRACT FROM AUTHOR]

C6H6N2O2, monoclinic P21/c (no. 14), a = 6.7909(2) Å, b = 23.9261(7) Å, c = 7.5103(2) Å, β = 95.265(2)°, V = 1215.12(6) Å3, Z = 8, Rgt(F) = 0.0574, wRref(F2) = 0.1439, T = 293. [ABSTRACT FROM AUTHOR]

C14H20Cl2N4O4Zn, monoclinic, P21/n (no. 14), a = 8.562(2) Å, b = 27.953(8) Å, c = 8.804(2) Å, β = 117.092(4)°, V = 1875.9(9) Å3, Z = 4, Rgt(F) = 0.0441, wRref(F2) = 0.1031, T = 296 K. [ABSTRACT FROM AUTHOR]

C6H6N2O2, monoclinic P21/c (no. 14), a = 6.7909(2) Å, b = 23.9261(7) Å, c = 7.5103(2) Å, β = 95.265(2)°, V = 1215.12(6) Å3, Z = 8, Rgt(F) = 0.0574, wRref(F2) = 0.1439, T = 293. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) is an endogenous incretin hormone. Liraglutide, a GLP-1 receptor agonist, can lower blood sugar by increasing insulin production and inhibiting the production of glucagon. This study researched the bioequivalence and safety of the test and reference drugs in healthy Chinese subjects. Subjects (N = 28) were randomly divided into group A and group B at a ratio of 1:1 for a two-cycle cross-over study. There was single dose per cycle with subcutaneous injection of the test and reference drugs, respectively. The washout was set at 14 days. Plasma drug concentrations were detected by specific liquid chromatography and tandem mass spectrometry (LC-MS/MS) assays. Statistical analysis of major pharmacokinetic (PK) parameters was conducted to assess drug bioequivalence. In addition, we evaluated the safety of the drugs throughout the trial. The geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ for the test and reference drugs were 107.11%, 106.56%, 106.09%, respectively. The 90% confidence intervals (CIs) were all within 80%-125%, meeting the bioequivalence standards. In addition, both had good safety in this study. The study shows that the two drugs had similar bioequivalence and safety. DCTR: CTR20190914; ClinicalTrials.gov: NCT05029076 [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) has become a global epidemic, and there is no specific treatment for anti‐COVID‐19 drugs. However, treatment of COVID‐19 using Chinese herbal medicine (CHM) has been widely practiced in China. PubMed, Embase, Cochrane Library, CNKI, Wanfang and VIP databases were searched to evaluate the efficacy and safety of CHM in the treatment of COVID‐19. Twenty‐six studies were included in this meta‐analysis. The included cases were all patients diagnosed with COVID‐19 according to the "New Coronary Virus Pneumonia Diagnosis and Treatment Program," with a total of 2,407 cases. Patients were treated with CHM, including 36 prescriptions, and 105 flavors of CHM were included. The results of the meta‐analysis showed that the CHM group improved in lung CT, clinical cure rate, clinical symptom score and time to negative for viral nucleic acid. However, this study still has many limitations due to the limited number of included studies. Therefore, high‐quality RCT studies are needed to provide more reliable evidence for CHM treatment of COVID‐19. In conclusion, CHM may significantly improve the clinical manifestations and laboratory indicators of patients with COVID‐19. In addition, no serious adverse reactions were found after CHM treatment. Therefore, CHM may be used as a potential candidate for COVID‐19. Highlights: COVID‐19 has become a global epidemic, and there is no specific treatment for anti‐COVID‐19 drugs.CHM has made a new breakthrough in the treatment of COVID‐19.CHM may relieve lung CT images of COVID‐19 patients.CHM may improve clinical symptoms of COVID‐19 patients.CHM may inhibit the expression of inflammatory factors in patients with COVID‐19. [ABSTRACT FROM AUTHOR]

Background. Diabetic osteoporosis (DOP) is a progressive osteoblast dysfunction induced by high glucose, which has negative impacts on bone homeostasis. Qizhi Kebitong formula (QKF) is a traditional Chinese medicine (TCM) formula for treating DOP. However, its role in the protection of DOP has not been clarified yet. Here, we aimed to explore the potential mechanisms of QKF on DOP development via in vivo experiment. Methods. Network pharmacology was used to detect the key targets and signaling pathways of QKF on DOP. The effects of QKF on DOP were examined by the phenotypic characteristics, micro-CT, and hematoxylin-eosin (H&E) staining. The predicted targets and pathways were validated by a streptozocin- (STZ-) induced mouse model. Subsequently, the levels of the selected genes and proteins were analyzed using qRT-PCR and Western blot. Finally, AutoDock and PyMOL were used for molecular docking. Results. In this study, 90 active compounds and 2970 related disease targets have been found through network pharmacology. And QKF could improve the microstructures of femur bone mass, reduce inflammatory cell infiltration, and downregulate the levels of TNF-α, IKBKB, IL-6, and IL-1β. Moreover, the underlying effect of PI3K/Akt/NF-κB pathways was also recommended in the treatment. Conclusion. Altogether, our findings suggested that QKF could markedly alleviate osteoblast dysfunction by modulating the key targets and PI3K/Akt/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Background. Long noncoding RNA (lncRNA) is involved in the occurrence and development of diabetic kidney disease (DKD). It is necessary to identify the expression of lncRNA from DKD patients through systematic reviews, and then carry out silico analyses to recognize the dysregulated lncRNA and their associated pathways. Methods. The study searched Pubmed, Embase, Cochrane Library, WanFang, VIP, CNKI, and CBM to find lncRNA studies on DKD published before March 1, 2021. Systematic review of the literature on this topic was conducted to determine the expression of lncRNA in DKD and non-DKD controls. For the dysregulated lncRNA in DKD patients, silico analysis was performed, and lncRNA2Target v2.0 and starBase were used to search for potential target genes of lncRNA. The Encyclopedia of Genomics (KEGG) pathway enrichment analysis was performed to better identify dysregulated lncRNAs in DKD and determine the associated signal pathways. Results. According to the inclusion and exclusion criteria, 28 publications meeting the eligibility criteria were included in the systematic evaluation. A total of 3,394 patients were enrolled in this study, including 1,238 patients in DKD group, and 1,223 diabetic patients, and 933 healthy adults in control group. Compared with the control, there were eight lncRNA disorders in DKD patients (MALAT1, GAS5, MIAT, CASC2, NEAT1, NR_033515, ARAP1-AS2, and ARAP1-AS1). In addition, five lncRNAs (MALAT1, GAS5, MIAT, CASC2, and NEAT1) participated in disease-related signal pathways, indicating their role in DKD. Discussion. This study showed that there were eight lncRNAs in DKD that were persistently dysregulated, especially five lncRNAs which were closely related to the disease. Although systematic review included 28 studies that analyzed the expression of lncRNA in DKD-related tissues, the potential of these dysregulated lncRNAs as biomarkers or therapeutic targets for DKD remains to be further explored. Trial registration. PROSPERO (CRD42021248634). [ABSTRACT FROM AUTHOR]

The final outcome of diabetes is chronic complications, of which vascular complications are the most serious, which is the main cause of death for diabetic patients and the direct cause of the increase in the cost of diabetes. Type 1 and type 2 diabetes are the main types of diabetes, and their pathogenesis is completely different. Type 1 diabetes is caused by genetics and immunity to destroy a large number of β cells, and insulin secretion is absolutely insufficient, which is more prone to microvascular complications. Type 2 diabetes is dominated by insulin resistance, leading to atherosclerosis, which is more likely to progress to macrovascular complications. This article explores the pathogenesis of two types of diabetes, analyzes the pathogenesis of different vascular complications, and tries to explain the different trends in the progression of different types of diabetes to vascular complications, in order to better prevent diabetes and its vascular complications. [ABSTRACT FROM AUTHOR]

C12H9BrClN3, monoclinic, P21/n (no. 14), a = 3.8743(5) Å, b = 22.229(2) Å, c = 13.631(1) Å, β = 98.103(6)°, V = 1162.2 Å3, Z = 4, Rgt(F) = 0.0287, wRref(F2) = 0.0831, T = 113 K.

Aims/Introduction: Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. At present, there is no comprehensive summary of the clinical trials related to DPN. In this article, we summarized the basic characteristics of the interventional clinical trials pertaining to DPN to determine the current status of research in this field and the existing issues. Materials and Methods: We searched the World Health Organization International Clinical Trial Registration Platform (ICTRP), PubMed and Web of Science for clinical trials from 2005 to April 2021 and extracted 149 registered and 459 published clinical trials on DPN. We summarized the characteristics of the clinical trials, including the source registration, recruitment status, stage, age group, allocation method, intervention, end point classification, funding source, and treatment. Results: After excluding noninterventional and nontreatment trials, 149 registered clinical trials out of 292 records from 12 registration centers and 459 published articles were included in this study. Among the registered trials, 43% had been completed, and 34.4% had been published in peer-reviewed journals. Among these trials, more than half used random allocation and blinded placebo-controlled methodologies. A total of 40.3% of the trials were multicenter studies, 63.8% of the treatments were drug therapies, and the endpoint classifications of 49% were efficacy and safety. Of the 459 published interventional clinical trials on DPN, 69.7% of the trials used drug treatments; more than half were randomized, double-blind, placebo-controlled clinical trials; 94.1% had positive outcomes; 46.4% had a target size of 50; and 22.9% were multicenter. Conclusion: This paper systematically summarizes the current status of interventional trials on DPN registered in the ICTRP and published clinical trials and provides a reference for the development of high-quality intervention strategies for DPN in the future. [ABSTRACT FROM AUTHOR]

Current understanding holds that Klinefelter syndrome (KS) is not inherited, but arises randomly during meiosis. Whether there is any genetic basis for the origin of KS is unknown. Here, guided by our identification of some USP26 variations apparently associated with KS, we found that knockout of Usp26 in male mice resulted in the production of 41, XXY offspring. USP26 protein is localized at the XY body, and the disruption of Usp26 causes incomplete sex chromosome pairing by destabilizing TEX11. The unpaired sex chromosomes then result in XY aneuploid spermatozoa. Consistent with our mouse results, a clinical study shows that some USP26 variations increase the proportion of XY aneuploid spermatozoa in fertile men, and we identified two families with KS offspring wherein the father of the KS patient harbored a USP26‐mutated haplotype, further supporting that paternal USP26 mutation can cause KS offspring production. Thus, some KS should originate from XY spermatozoa, and paternal USP26 mutations increase the risk of producing KS offspring. Synopsis: Klinefelter syndrome (KS) is believed to be not inherited, and whether there is a genetic basis for the origin of KS is unknown. Here, paternal USP26 mutations are found to produce XY spermatozoa, thus greatly increase the risk for producing KS offspring.Whole‐genome sequencing‐based mutational scanning in KS patients shows that USP26 variants are likely to affect the etiology of KS.Loss of Usp26 in male mice results in the production of 41, XXY offspring.The disruption of Usp26 causes incomplete sex chromosome pairing by destabilizing TEX11, thus producing XY aneuploid spermatozoa.Paternal USP26 mutations increase the proportion of XY aneuploid sperm and cause KS offspring production. [ABSTRACT FROM AUTHOR]

Domestication and subsequent selection of cattle to form breeds and biological types that can adapt to different environments partitioned ancestral genetic diversity into distinct modern lineages. Genome-wide selection particularly for adaptation to extreme environments left detectable signatures genome-wide. We used high-density genotype data for 42 cattle breeds and identified the influence of Bos grunniens and Bos javanicus on the formation of Chinese indicine breeds that led to their divergence from India-origin zebu. We also found evidence for introgression, admixture, and migration in most of the Chinese breeds. Selection signature analyses between high-altitude (≥1800 m) and low-altitude adapted breeds (<1500 m) revealed candidate genes (ACSS2 , ALDOC, EPAS1 , EGLN1, NUCB2) and pathways that are putatively involved in hypoxia adaptation. Immunohistochemical, real-time PCR and CRISPR/cas9 ACSS2 -knockout analyses suggest that the up-regulation of ACSS2 expression in the liver promotes the metabolic adaptation of cells to hypoxia via the hypoxia-inducible factor pathway. High altitude adaptation involved the introgression of alleles from high-altitude adapted yaks into Chinese Bos taurus taurus prior to their formation into recognized breeds and followed by selection. In addition to selection, adaptation to high altitude environments has been facilitated by admixture and introgression with locally adapted cattle populations. • 42 taurine and indicine breeds and 3 yak breeds were genotyped using 777KSNP assay. • Introgression, admixture and migration were found in most of Chinese cattle breeds. • B. grunniens and B. javanicus introgressions caused divergence of indicine breeds. • Selection signatures revealed candidate genes involved in hypoxia adaptation. • Introgressed ACSS2 promotes adaptation to hypoxia via HIF pathway. [ABSTRACT FROM AUTHOR]

Under extreme environmental conditions such as hypoxia, insufficient nutrition, and glucose deficiency, the acetyl-CoA synthetase 2 (ACSS2)-mediated acetyl-CoA synthesis pathway plays an alternative role to ensure the normal operation of metabolic activities. To investigate the potential effect of the ACSS2 gene on hypoxic adaptation and its regulatory mechanism of gene expression in high-altitude cattle breeds, we analyzed the genetic variations of the ACSS2 gene in five Bos taurus taurus , Bos taurus indicus , hybrid Bos taurus taurus × Bos taurus indicus Chinese cattle breeds, and two Bos grunniens (yak) breeds distributed at different altitudes (95-3850 m). A total of 58 SNPs was detected in seven populations, and abundant genetic variation was found in high-altitude breeds. We identified the bovine ACSS2 core promoter region between g.-682 and g.-264 by using the luciferase assay in FFB and HepG2 cells. We also identified that the high-altitude hypoxia-specific haplotype (CAGTCT) was composed of six highly linked SNPs. The tagSNP g.-473 T>C (rs23) is located in the core promoter of ACSS2 in the Bos taurus taurus and yak breeds. The recombinant plasmid containing rs23 and analyses of luciferase activity of different genotypes showed that the activity of ACSS2 promoter increased significantly when T was mutated to C. We also found a yak-specific SNP rs20 that consists of 12 base insertions (g.-562 ins GAAAGGACCCTA) in the promoter of yak breeds. Luciferase activity analysis showed that the insertion mutant significantly decreased the promoter activity of ACSS2. Hence, ACSS2 may play an important role in the adaptation to high-altitude hypoxia by generating adaptive alleles to influence gene transcription in cattle. These results signify that different genetic variants and haplotypes affect the activity of the core promoter to regulate ACSS2 gene expression and subsequently overcome and adapt to a high-altitude environment within different cattle breeds. Our findings may have important implications for understanding the mechanism of adaptation to high altitude and for application of molecular breeding in Bos species. [ABSTRACT FROM AUTHOR]

Spermatogenesis is a complex differentiating developmental process in which undifferentiated spermatogonial germ cells differentiate into spermatocytes, spermatids, and finally, to mature spermatozoa. This multistage developmental process of spermatogenesis involves the expression of many male germ cell-specific long noncoding RNAs (lncRNAs) and highly regulated and specific gene expression. LncRNAs are a recently discovered large class of noncoding cellular transcripts that are still relatively unexplored. Only a few of them have post-meiotic; however, lncRNAs are involved in many cellular biological processes. The expression of lncRNAs is biologically relevant in the highly dynamic and complex program of spermatogenesis and has become a research focus in recent genome studies. This review considers the important roles and novel regulatory functions whereby lncRNAs modulate mammalian spermatogenesis. [ABSTRACT FROM AUTHOR]

A series of hydrotalcite-like compounds were synthesized, and these compounds had different interlayer ions and various intercalations with different valence inorganic acid radicals and different chain-length organic acid radicals. The effect of the hydrotalcite-like compounds on the thermal stability of PVC were investigated by means of thermal aging oven method, Congo red method and torque rheometer. The results indicated that the thermal stability of PVC was improved by incorporating the rare-earth elements and increasing the quantity of ions in the interlay of the compounds. For the hydrotalcite-like compounds with different valence inorganic acid radicals and organic acid radicals, the compounds intercalated with bivalent acid radicals exhibited the best thermal stability. Moreover, the thermal stability showed an increasing trend at first and then tended to decrease with an increase of the carbon-chain length of organic acids in the hydrotalcite-like intercalation. [ABSTRACT FROM AUTHOR]

Copy number variations (CNVs) have been demonstrated as crucial substrates for evolution, adaptation and breed formation. Chinese indigenous cattle breeds exhibit a broad geographical distribution and diverse environmental adaptability. Here, we analyzed the population structure and adaptation to high altitude of Chinese indigenous cattle based on genome-wide CNVs derived from the high-density BovineHD SNP array. We successfully detected the genome-wide CNVs of 318 individuals from 24 Chinese indigenous cattle breeds and 37 yaks as outgroups. A total of 5,818 autosomal CNV regions (683 bp–4,477,860 bp in size), covering ~14.34% of the bovine genome (UMD3.1), were identified, showing abundant CNV resources. Neighbor-joining clustering, principal component analysis (PCA), and population admixture analysis based on these CNVs support that most Chinese cattle breeds are hybrids of Bos taurus taurus (hereinafter to be referred as Bos taurus) and Bos taurus indicus (Bos indicus). The distribution patterns of the CNVs could to some extent be related to the geographical backgrounds of the habitat of the breeds, and admixture among cattle breeds from different districts. We analyzed the selective signatures of CNVs positively involved in high-altitude adaptation using pairwise Fst analysis within breeds with a strong Bos taurus background (taurine-type breeds) and within Bos taurus × Bos indicus hybrids, respectively. CNV-overlapping genes with strong selection signatures (at top 0.5% of Fst value), including LETM1 (Fst = 0.490), TXNRD2 (Fst = 0.440), and STUB1 (Fst = 0.420) within taurine-type breeds, and NOXA1 (Fst = 0.233), RUVBL1 (Fst = 0.222), and SLC4A3 (Fst=0.154) within hybrids, were potentially involved in the adaptation to hypoxia. Thus, we provide a new profile of population structure from the CNV aspects of Chinese indigenous cattle and new insights into high-altitude adaptation in cattle. [ABSTRACT FROM AUTHOR]

Genetic mutations, including single nucleotide polymorphisms (SNPs), result in aberrant alternatively splicing of gene and involves in susceptibility of inflammatory diseases, including bovine mastitis. C-C motif chemokine ligand 5 (CCL5) is an immune-associated gene, but its alternative splicing (AS) mechanism of gene expression has not yet been understood. The present study identified the splice variant of CCL5 and the compared differential expression of various transcripts between healthy and mastitic mammary gland tissue from cows. A novel transcript lacking exon 2 with a deletion of 112 bp (referred to as CCL5-AS) was identified in the mammary gland. The expression of CCL5-AS was lower compared with CCL5-reference in the healthy and mastitic mammary tissues. A total of two novel SNPs (g.1647 C>T and g.1804 G>A) were identified in exon 2 of CCL5. Using the splicing mini-gene reporter assay in bovine mammary epithelial cells (MAC-T) and 293T cells, it was confirmed that the production of CCL5-AS was not caused by the two SNPs. The present findings suggested that alternative splicing is one of the mechanisms of CCL5 expression regulation and is involved in mastitis infection, but that genetic mutation was not responsible for the generation of the abnormal transcript of CCL5 in cows. [ABSTRACT FROM AUTHOR]

Background: Ophiocordyceps sinensis (OS), a medicinal fungus, has been made into OS preparations, which are frequently used as adjunctive therapy for patients with Diabetic Kidney Disease (DKD) in China. It is necessary to assess the efficacy and safety of OS preparations in the adjunctive treatment of DKD by conducting a systematic review and meta-analysis.Objective: Ophiocordyceps sinensis preparations were evaluated for their efficacy and safety as adjunctive therapy to conventional drugs (angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)) for DKD.Methods: We searched seven electronic literature databases for randomized controlled trials (RCTs) comparing ACEI/ARB and OS combined with ACEI/ARB from inception up to March 2022. Two reviewers extracted data and assessed the risk of bias independently. Evidence certainty was rated using the GRADE system. Standardized mean difference (SMD) or mean difference (MD) was pooled with random effects models and was reported with corresponding 95% confidence intervals (CIs). Meta-analysis, sensitivity analysis and Egger's test were performed using R software (version 14.2) (PROSPERO registration no. CRD42021248634).Results: Thirty eight RCTs involving 3167 patients met the inclusion criteria. No trials were reported with outcomes about kidney disease progression and cardiovascular events. In meta-analysis, compared with the control group of ACEI/ARB alone, OS combined with ACEI/ARB can achieve better effects in the treatment of DKD on reducing serum creatinine (Scr) [MDScr =-11.48 95% CI [-15.78, -7.18], p < 0.01], blood urea nitrogen (BUN) [MDBUN= -1.00, 95% CI [-1.44, -0.55], p < 0.01], β2-microglobulin (β2-MG) [SMDβ2-MG= -1.32, 95% CI [-2.27, -0.37], p < 0.01], cystatin C (CysC) [MDCysC=-0.64, 95% CI [-0.83, -0.45], p < 0.01], 24-h urine proteinuria (24hUP) [SMD24hUP= -1.99, 95% CI [-2.68; -1.31], p < 0.01], urine microalbumin (UALB) [MDUALB= -37.41, 95% CI [-44.76, -30.06], p < 0.01] and decreasing urinary albumin excretion rate (UAER) [MDUAER= -24.11, 95% CI [-30.54, -17.68], p < 0.01] and albumin creatinine ratio (ACR) [SMDACR = 1.01, 95% CI [-1.73, -0.29], p < 0.01]. The OS adjuvant treatment also improved outcomes of blood pressure, blood glucose, blood lipid, inflammation and oxidative stress. No significant change in fasting blood glucose (FPG), glycated hemoglobin (HbA1c), malondialdehyde (MDA), and transforming growth factor beta 1 (TGF-β1) was detected. Yet, no significant difference was found about the adverse events between the two groups.Conclusions: Ophiocordyceps sinensis preparation combined with ACEI/ARB has beneficial influence on renal function, decrease proteinuria, dyslipidemia, and even oxidative stress and inflammation in DKD patients. However, there is no trial that evaluated outcomes of kidney disease progression and cardiovascular events. Future study should move beyond surrogate endpoints to actual cardiovascular or renal outcome benefits with an aim to explore effects of OS preparation in the long-term. [ABSTRACT FROM AUTHOR]

Inner centromere protein (INCENP) plays an important role in mitosis and meiosis as the main member of chromosomal passenger protein complex (CPC). To investigate the functional markers of the INCENP gene associated with semen quality, the single nucleotide polymorphisms (SNPs) g.19970 A>G and g.34078 T>G were identified and analyzed. The new splice variant INCENP-TV is characterized by the deletion of exon 12. The g.19970 A>G in the exonic splicing enhancer (ESE) motif region results in an aberrant splice variant by constructing two minigene expression vectors using the pSPL3 exon capturing vector and transfecting vectors into MLTC-1 cells. INCENP-TV was more highly expressed than INCENP-reference in adult bull testes. The g.34078 T>G located in the binding region of bta-miR-378 could affect the expression of INCENP, which was verified by luciferase assay. To analyze comprehensively the correlation of SNPs with sperm quality, haplotype combinations constructed by g.19970 A>G and g.34078 T>G, as well as g.-692 C>T and g.-556 G>T reported in our previous studies, were analyzed. The bulls with H1H12 and H2H2 exhibited a higher ejaculate volume than those with H2H10 and H9H12, respectively (P < 0.05). Bulls with H11H11 and H2H10 exhibited higher initial sperm motility than those with H2H2 (P < 0.05). The expression levels of INCENP in bulls with H1H12 and H11H11 were significantly higher than those in bulls with H9H12 (P < 0.05), as determined by qRT-PCR. Findings suggest that g.19970 A>G and g.34078 T>G in INCENP both of which appear to change the molecular and biological characteristics of the mRNA transcribed from the locus may serve as a biomarkers of male bovine fertility by affecting alternative splicing mode and binding affinity with the target bta-miR-378. [ABSTRACT FROM AUTHOR]

Neutrophil cytosolic factor 4 (NCF4) is component of the nicotinamide dinucleotide phosphate oxidase complex, a key factor in biochemical pathways and innate immune responses. In this study, splice variants and functional single-nucleotide polymorphism (SNP) of NCF4 were identified to determine the variability and association of the gene with susceptibility to bovine mastitis characterized by inflammation. A novel splice variant, designated as NCF4-TV and characterized by the retention of a 48 bp sequence in intron 9, was detected in the mammary gland tissues of infected cows. The expression of the NCF4-reference main transcript in the mastitic mammary tissues was higher than that in normal tissues. A novel SNP, g.18174 A>G, was also found in the retained 48 bp region of intron 9. To determine whether NCF4-TV could be due to the g.18174 A>G mutation, we constructed two mini-gene expression vectors with the wild-type or mutant NCF4 g.18174 A>G fragment. The vectors were then transiently transfected into 293T cells, and alternative splicing of NCF4 was analyzed by reverse transcription-PCR and sequencing. Mini-gene splicing assay demonstrated that the aberrantly spliced NCF4-TV with 48 bp retained fragment in intron 9 could be due to g.18174 A>G, which was associated with milk somatic count score and increased risk of mastitis infection in cows. NCF4 expression was also regulated by alternative splicing. This study proposes that NCF4 splice variants generated by functional SNP are important risk factors for mastitis susceptibility in dairy cows. [ABSTRACT FROM AUTHOR]

The 3-hydroxyisobutyrate dehydrogenase (HIBADH) is regarded as a human sperm-motility marker. However, the molecular mechanisms involved in the regulation of expression of the HIBADH gene in bulls remain largely unknown. HIBADH was detected in the testis, epididymis, and sperm via reverse transcription polymerase chain reaction and Western blot analysis. It is also expressed in the seminiferous epithelium, spermatids, and the entire epididymis, as detected by immunohistochemistry. Furthermore, HIBADH was expressed in the neck-piece and mid-piece of bull spermatids, as shown in the immunofluorescence assay. Using serially truncated bovine HIBADH promoters and luciferase constructs, we discovered an 878 bp (-703 bp to +175 bp) fragment that constitutes the core promoter region. One SNP g.-165 T>C of HIBADH was identified and genotyped in 307 Chinese Holstein bulls. Correlation analysis revealed that bulls with the TT genotype had higher initial sperm motility than those with the CC genotype (P < 0.05). Furthermore, the T- or C-containing loci (designated as pGL3-T and pGL3-C) were transiently transfected into MLTC-1 to test the effect of SNP on HIBADH expression. The luciferase reporter assay showed that the pGL3-T genotype exhibited 58% higher transcriptional activity than the pGL3-C genotype (P < 0.05). The bisulfite sequencing analysis revealed that the methylation pattern of the core promoter presented hypomethylation in the ejaculated semen in high-motility and low-motility bulls. The results demonstrated for the first time that the g.-165 T>C rather than methylation in the 5'-flanking region could affect the bovine sperm motility through the regulation of HIBADH gene transcriptional activity. [ABSTRACT FROM AUTHOR]

Neutrophil cytosolic factor 1 ( NCF1 ) plays a crucial role in host defense against microbial pathogens. In this study, we investigated the potential alternative splicing patterns, expression and splice-relevant single nucleotide polymorphisms (SNPs) of the bovine NCF1 gene to increase insights into its potential role against bovine mastitis caused by Escherichia coli infection. Using RT-PCR and clone sequencing methods, we found two novel splice variants designed as NCF1-TV1 (retained intron 6) and NCF1-TV2 (retained part of intron 8), respectively, encoding two putative truncated proteins (239AA and 283AA). Two splice variants were drastically up-regulated in the mastitis-infected cows’ mammary tissues, blood and neutrophils compared with these of healthy cows using real-time RT-PCR. Genomic sequencing analysis identified four novel SNPs g.10112 G>A, g.10766 T>C, SNPs g.12085 G>A and g.12430 T>C at the ends of intron 6 and intron 8 of NCF1 . ESE motif predicted that the SNP (g.10766 T>C) might affect the binding with splicing-related factors and subsequently caused the production of aberrant splice variant NCF1-TV1 , which is one of the potential reasons that the functional SNP was associated with increased milk somatic cell score in cow. Our results would help in better understanding the NCF1 gene function in the process against pathogen infection, and the effect of splicing-related SNP on the production of aberrant splice variant and careful functional characterization in dairy cattle. [ABSTRACT FROM AUTHOR]

The increasing global incidence of type 2 diabetes mellitus(T2DM) requires new drug interventions. For more than two thousand years, the combination of Radix Bupleuri and Radix Paeoniae Alba couplet medicine (BPCM) has provided beneficial activities in the treatment of diabetes. The object of this network pharmacology study was explore their combined mechanisms with verification In vitro. The chemical compounds and potential targets of BPCM were analyzed through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Gene information related to T2DM was collected using GeneCards and OMIM database. The core targets were obtained through Venn Diagram, and the protein interaction network (PPI) was constructed using the STRING database. The networks of compound-target and drug-compound-common target-disease were constructed by Cytoscape. Gene ontology (GO) term enrichment analysis and biological pathway (KEGG) enrichment analysis were performed using R language. SYBYL docking for key compounds with targets were performed to explore their binding modes, which was further verified through cell experiments. The study identified 17 active ingredients in Radix Bupleuri and 13 active ingredients in Radix Paeoniae Alba. There were 23 targets related to type 2 diabetes, including caspase 3 (CASP3), peroxisome proliferation-activated receptor γ (PPARG) and intercellular adhesion molecule-1 (ICAM1). Further analysis identified 403 GO biological processes and 76 related signal pathways. It was found that CASP3-kaempferol, CASP3-quercetin, and ICAM1-stigmasterol had high binding activities. In the palmitic acid-induced HepG2 cells, BPCM improved lipid aggregation and up-regulated the levels of p-ACC and p-AMPK. Importantly, experimental verification results showed that BPCM increased the expression of PPARG and decreased the levels of CASP3 and ICAM1. Through network pharmacology, molecular docking and vitro experiments, the study found that BPCM may treat T2DM by promoting AMPK/ACC conduction and inhibiting lipid accumulation. [ABSTRACT FROM AUTHOR]

This paper preliminarily studied the post-transcription regulation mechanism of sperm flagella 2( SPEF2) gene through analyzing gene alternative splicing, and further single nucleotide polymorphism( SNP) was scanned and predicted whether it is the reason producing the SPEF2 gene splice variant or not. Meanwhile, the association between the SNP and semen quality traits was analysed. Using RT-PCR and clone sequencing, we investigated the potentiol splices variant of bovine SPEF2 gene.50 Chinese Holstein bulls were genotyped by the PCR-RFLP( PCR-restriction fragment length polymorphism). The results showed that a novel bovine SPEF2 splice variant(SPEF2-SV)was identified in testis tissues using RT-PCR and cloning sequence which deleted a 459 bp sequence and encoded a putative shorten isoform(1 618 aa);RT-PCR results showed that SPEF2-SV presented lower expression in testis when compared with the reference SPEF2-complete transcript. A SNP(g.11043C>T)near the splice sites around 140 bp was found in intron 1 of the bovine SPEF2 gene, which was located within a putative exonic splice enhancer( ESE). Using ESEfinder 3. 0 software, we predicted that the SNP changed the SC35 combination with the target sequence and it might be the reason for the generation of the aberrant SPEF2-SV transcript. Association between the genotypes of the SNP and sperm quality traits showed that the SNP had a significant effect on the semen deformity rate(P<0.05). However, no significant differences were found for the ejaculate volume, sperm density and sperm motility, of which, the additive, dominance and allele substitution effects of mutant allele on sperm deformity rate were -1. 24%, -2. 99% and -0. 76%,respectively. The result indicated that SPEF2 gene was regulated by alternative splicing mechanism and the SNP(g.11043C>T)can be used as a potential novel molecular marker for the selection of fineness semen quality traits in Chinese Holstein bulls. [ABSTRACT FROM AUTHOR]

C13H12BrN3O, monoclinic, P21/c (no. 14), a = 5.520(3) Å, b = 13.400(7) Å, c = 17.204(9) Å, β = 94.916(9)°, V = 1267.9 Å3, Z = 4, Rgt(F) = 0.0335, wRref(F2) = 0.0957, T = 296 K. [ABSTRACT FROM AUTHOR]