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Frontiers in Endocrinology 2021The CDK5 regulatory subunit-associated protein 1-like 1 () contributes to islet β-cell function and insulin secretion by inhibiting the activation of CDK5. The current... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
The CDK5 regulatory subunit-associated protein 1-like 1 () contributes to islet β-cell function and insulin secretion by inhibiting the activation of CDK5. The current studies on the relationship between polymorphisms rs7756992 A>G and rs7754840 C>G and the risk of gestational diabetes mellitus (GDM) have drawn contradictory conclusions.
MATERIALS AND METHODS
A meta-analysis with a fixed- or random-effects model was conducted to estimate the correlation between studied polymorphisms and GDM risk with the summary odds ratio (OR) and 95% confidence interval (CI). In addition, trial sequential analysis (TSA) and false-positive report probability (FPRP) analysis were performed to confirm the study findings.
RESULTS
A total of 13,306 subjects were included in the present study. Meta-analysis results showed that the variant heterozygous and homozygous genotypes of the two polymorphisms were associated with increased GDM risk in comparison with the wild-type AA genotype (AG AA: OR = 1.23, 95% CI = 1.08, 1.41, = 0.002; GG AA: OR = 1.47, 95% CI = 1.05, 2.05, = 0.024 for rs7756992; and CG GG: OR = 1.36, 95% CI = 1.13, 1.65, = 0.002; CC GG: OR = 1.76, 95% CI = 1.37, 2.26, < 0.001 for rs7754840). The TSA confirmed a significant association between rs7754840 and the susceptibility to GDM because the cumulative Z-curve crossed both the conventional cutoff value and the TSA boundaries under the heterozygote and homozygote models.
CONCLUSIONS
This study supported the finding that rs7756992 and rs7754840 are associated with susceptibility to GDM. However, further functional studies are warranted to clarify the mechanism.
Topics: Case-Control Studies; Cyclin-Dependent Kinase 5; Diabetes, Gestational; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Polymorphism, Single Nucleotide; Pregnancy; Risk Factors; tRNA Methyltransferases
PubMed: 34721291
DOI: 10.3389/fendo.2021.722674 -
Journal of Diabetes Research 2021Diabetes mellitus (DM) is a major chronic metabolic disease in the world, and the prevalence has been increasing rapidly in recent years. The channel of K plays an...
OBJECTIVES
Diabetes mellitus (DM) is a major chronic metabolic disease in the world, and the prevalence has been increasing rapidly in recent years. The channel of K plays an important role in the regulation of insulin secretion. The variants in gene encoding the SUR1 subunit of K could cause a variety of phenotypes, including neonatal diabetes mellitus (NDM) and -induced nonneonatal diabetes mellitus (-NNDM). Since the features of -NNDM have not been elucidated, this study is aimed at concluding the genetic features and clinical characteristics.
METHODS
We comprehensively reviewed the literature associated with -NNDM in the following databases: MEDLINE, PubMed, and Web of Science to investigate the features of -NNDM.
RESULTS
Based on a comprehensive literature search, we found that 87 probands with -NNDM carried 71 genetic variant alleles, 24% of whom carried inactivating variants, 24% carried activating variants, and the remaining 52% carried activating or inactivating variants. Nine of these variants were confirmed to be activating or inactivating through functional studies, while four variants (p.R370S, p.E1506K, p.R1418H, and p.R1420H) were confirmed to be inactivating. The phenotypes of -NNDM were variable and could also present with early hyperinsulinemia followed by reduced insulin secretion, progressing to diabetes later. They had a relatively high risk of microvascular complications and low prevalence of nervous disease, which is different from NDM.
CONCLUSIONS
Genetic testing is essential for proper diagnosis and appropriate treatment for patients with -NNDM. And further studies are required to determine the complex mechanism of the variants of -NNDM.
Topics: Animals; Blood Glucose; Diabetes Mellitus; Genetic Predisposition to Disease; Genetic Variation; Humans; Insulin; Phenotype; Sulfonylurea Receptors
PubMed: 34631896
DOI: 10.1155/2021/9479268 -
Arab Journal of Urology 2021: To provide a summary of the current evaluation of azoospermia and insights into future perspectives in the evaluation and counselling of men with azoospermia. : A...
: To provide a summary of the current evaluation of azoospermia and insights into future perspectives in the evaluation and counselling of men with azoospermia. : A search of PubMed, Cochrane Reviews and Web of Science databases was performed for full-text English-language articles published between 1943 and 2020 focussing on 'future perspectives', 'azoospermia' and 'evaluation'. : Azoospermia represents a severe form of male infertility characterised by sperm production so impaired that there are no sperm present in the ejaculate. The current evaluation of azoospermia focusses on patient history and physical examination with selected adjunctive laboratory investigations including serum hormones, a karyotype and screening for Y chromosome microdeletions. Future diagnostics are focussed on identifying the underlying genetic aetiologies for azoospermia, as well as a greater emphasis on screening for systemic illness that men with severe infertility may be predisposed to develop. : Azoospermia represents an extreme form of male infertility, and evaluation relies heavily on history and physical examination, as genetic evaluations for these individuals remain limited. Future evaluation will focus on next-generation sequencing and more rigorous evaluation for possible co-existing and future risk of systemic disease. : ADGRG2, adhesion G protein-coupled receptor G2; ASRM: American Society of Reproductive Medicine; AZF: azoospermia factor; CBAVD: congenital bilateral absence of the vas deferens; CFTR: cystic fibrosis transmembrane conductance regulator; CRKL: CRK-like proto-oncogene; E2F1: E2F transcription factor 1; HAUS7: HAUS augmin-like complex subunit 7; HR: hazard ratio; KS: Klinefelter syndrome; MAZ, MYC-associated zinc finger protein; NGS: next-generation sequencing; NOA: non-obstructive azoospermia; OA: obstructive azoospermia; RHOX: reproductive homeobox on the X chromosome; SH2: SRC homology 2; TAF7L: TATA-box binding protein associated factor 7-like; TEX11: testis-expressed 11; WES: whole-exome sequencing.
PubMed: 34552771
DOI: 10.1080/2090598X.2021.1954415 -
Traffic (Copenhagen, Denmark) Dec 2021Endoplasmic reticulum (ER)-to-Golgi trafficking is an essential and highly conserved cellular process. The coat protein complex-II (COPII) arm of the trafficking... (Review)
Review
Endoplasmic reticulum (ER)-to-Golgi trafficking is an essential and highly conserved cellular process. The coat protein complex-II (COPII) arm of the trafficking machinery incorporates a wide array of cargo proteins into vesicles through direct or indirect interactions with Sec24, the principal subunit of the COPII coat. Approximately one-third of all mammalian proteins rely on the COPII-mediated secretory pathway for membrane insertion or secretion. There are four mammalian Sec24 paralogs and three yeast Sec24 paralogs with emerging evidence of paralog-specific cargo interaction motifs. Furthermore, individual paralogs also differ in their affinity for a subset of sorting motifs present on cargo proteins. As with many aspects of protein trafficking, we lack a systematic and thorough understanding of the interaction of Sec24 with cargoes. This systematic review focuses on the current knowledge of cargo binding to both yeast and mammalian Sec24 paralogs and their ER export motifs. The analyses show that Sec24 paralog specificity of cargo (and cargo receptors) range from exclusive paralog dependence or preference to partial redundancy. We also discuss how the Sec24 secretion system is hijacked by viral (eg, VSV-G, Hepatitis B envelope protein) and bacterial (eg, the enteropathogenic Escherichia coli type III secretion system effector NleA/EspI) pathogens.
Topics: Animals; COP-Coated Vesicles; Endoplasmic Reticulum; Golgi Apparatus; Mammals; Membrane Proteins; Protein Transport; Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Secretory Pathway
PubMed: 34533884
DOI: 10.1111/tra.12817 -
Journal of Vascular Surgery. Venous and... Mar 2022PIK3CA (activating mutations of the p110α subunit of phosphatidylinositol 3-kinases)-related overgrowth spectrums (PROS) include a variety of clinical presentations...
BACKGROUND
PIK3CA (activating mutations of the p110α subunit of phosphatidylinositol 3-kinases)-related overgrowth spectrums (PROS) include a variety of clinical presentations that are associated with hypertrophy of different parts of the body. We performed a systematic literature review to assess the current treatment options and their efficacy and safety for PROS.
METHODS
A literature search was performed in Embase, MEDLINE (Ovid), Web of Science Core Collection, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Google Scholar to retrieve studies on the treatment of hypertrophy in PROS. Randomized controlled trials, cohort studies, and case series with ≥10 patients were included in the present review. The titles, abstracts, and full text were assessed by two reviewers independently. The risk of bias was assessed using the Newcastle-Ottawa scale.
RESULTS
We included 16 studies of the treatment of hypertrophy in PROS patients, 13 (81.3%) from clinical retrospective studies and 3 (13.7%) from prospective cohort studies. The risk of bias grade was low for 2, medium for 12, and high for 2 studies. Of the 16 studies, 13 reported on surgical treatment and 3 reported pharmacologic treatment using phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway inhibitors in PROS patients. In 3 studies, PROS was defined by a mutation in the PIK3CA gene, and 13 studies relied on a clinical definition of PROS. Surgical therapy was beneficial for a specific subgroup of PROS (macrodactyly). However, little has been reported concerning surgery and the potential benefits for other PROS entities. The reported side effects after surgical therapy were mostly prolonged wound healing or scarring. PI3K/mTOR pathway inhibition was beneficial in patients with PROS by reducing hypertrophy and systemic symptoms. The adverse effects reported included infection, changes in blood count, liver enzymes, and metabolic measures.
CONCLUSIONS
Surgery is a locally limited treatment option for specific types of PROS. A promising treatment option for PROS is pharmacologic PIK3CA inhibition. However, the level of evidence on the treatment of overgrowth in PROS patients is limited.
Topics: Class I Phosphatidylinositol 3-Kinases; Genetic Predisposition to Disease; Humans; Hypertrophy; MTOR Inhibitors; Molecular Targeted Therapy; Mutation; Phenotype; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction; Surgical Procedures, Operative; Syndrome; Treatment Outcome
PubMed: 34358672
DOI: 10.1016/j.jvsv.2021.07.008 -
BioMed Research International 2021Human Runt-associated transcription factor 3 (RUNX3) plays an important role in the development and progression of endometrial cancer (EC). However, the clinical and... (Meta-Analysis)
Meta-Analysis
Human Runt-associated transcription factor 3 (RUNX3) plays an important role in the development and progression of endometrial cancer (EC). However, the clinical and pathological significance of RUNX3 in EC needs to be further studied. In order to clarify the clinical and pathological significance of RUNX3, a systematic review and meta-analysis was conducted in EC patients. Keywords RUNX3, endometrial cancer, and uterine cancer were searched in Cochrane Library, Web of Knowledge, PubMed, CBM, MEDLINE, and Chinese CNKI database for data up to Dec 31, 2018. References, abstracts, and meeting proceedings were manually searched in supplementary. Outcomes were various clinical and pathological features. The two reviewers performed the literature searching, data extracting, and method assessing independently. Meta-analysis was performed by RevMan5.3.0. A total of 563 EC patients were enrolled from eight studies. Meta-analysis results showed that the expression of RUNX3 has significant differences in these comparisons: lymph node (LN) metastasis vs. non-LN metastasis ( = 0.26), EC tissues vs. normal tissues ( < 0.00001), clinical stages I/II vs. II/IV ( < 0.00001), muscular infiltration < 1/2 vs. muscular infiltration ≥ 1/2 ( < 0.00001), and G1 vs. G2/G3 ( < 0.00001). The decreasing expression of RUNX3 is associated with poor TNM stage and muscular infiltration. It is indicated that RUNX3 was involved in the suppression effect of EC. However, further multicenter randomized controlled trials are needed considering the small sample size of the included trials.
Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Core Binding Factor Alpha 3 Subunit; Endometrial Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Lymphatic Metastasis; Middle Aged; Muscles; Neoplasm Staging; Publication Bias
PubMed: 34337071
DOI: 10.1155/2021/9995384 -
Clinical Infectious Diseases : An... Mar 2022Recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants may pose a threat to immunity. A systematic landscape of neutralizing antibodies...
Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants Induced by Natural Infection or Vaccination: A Systematic Review and Pooled Analysis.
Recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants may pose a threat to immunity. A systematic landscape of neutralizing antibodies against emerging variants is needed. We systematically searched for studies that evaluated neutralizing antibody titers induced by previous infection or vaccination against SARS-CoV-2 variants and collected individual data. We identified 106 studies meeting the eligibility criteria. Lineage B.1.351 (beta), P.1 (gamma) and B.1.617.2 (delta) significantly escaped natural infection-mediated neutralization, with an average of 4.1-fold (95% confidence interval [CI]: 3.6-4.7-fold), 1.8-fold (1.4-2.4-fold), and 3.2-fold (2.4-4.1-fold) reduction in live virus neutralization assay, while neutralizing titers against B.1.1.7 (alpha) decreased slightly (1.4-fold [95% CI: 1.2-1.6-fold]). Serum from vaccinees also led to significant reductions in neutralization of B.1.351 across different platforms, with an average of 7.1-fold (95% CI: 5.5-9.0-fold) for nonreplicating vector platform, 4.1-fold (3.7-4.4-fold) for messenger RNA platform, and 2.5-fold (1.7-2.9-fold) for protein subunit platform. Neutralizing antibody levels induced by messenger RNA vaccines against SARS-CoV-2 variants were similar to, or higher, than that derived from naturally infected individuals.
Topics: Antibodies, Neutralizing; Antibodies, Viral; COVID-19; COVID-19 Vaccines; Humans; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Vaccination
PubMed: 34302458
DOI: 10.1093/cid/ciab646 -
Frontiers in Physiology 2021Cardiomyocyte death in the form of apoptosis and necrosis represents a major cellular mechanism underlying cardiac pathogenesis. Recent advances in cell death research...
Cardiomyocyte death in the form of apoptosis and necrosis represents a major cellular mechanism underlying cardiac pathogenesis. Recent advances in cell death research reveal that not all necrosis is accidental, but rather there are multiple forms of necrosis that are regulated. Necroptosis, the earliest identified regulated necrosis, is perhaps the most studied thus far, and potential links between necroptosis and Cullin-RING ligases (CRLs), the largest family of ubiquitin E3 ligases, have been postulated. Cullin neddylation activates the catalytic dynamic of CRLs; the reverse process, Cullin deneddylation, is performed by the COP9 signalosome holocomplex (CSN) that is formed by eight unique protein subunits, COPS1/CNS1 through COPS8/CNS8. As revealed by cardiomyocyte-restricted knockout of (Cops8-cko) in mice, perturbation of Cullin deneddylation in cardiomyocytes impairs not only the functioning of the ubiquitin-proteasome system (UPS) but also the autophagic-lysosomal pathway (ALP). Similar cardiac abnormalities are also observed in Cops6-cko mice; and importantly, loss of the desmosome targeting of COPS6 is recently implicated as a pathogenic factor in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Cops8-cko causes massive cardiomyocyte death in the form of necrosis rather than apoptosis and rapidly leads to a progressive dilated cardiomyopathy phenotype as well as drastically shortened lifespan in mice. Even a moderate downregulation of Cullin deneddylation as seen in mice with Cops8 hypomorphism exacerbates cardiac proteotoxicity induced by overexpression of misfolded proteins. More recently, it was further demonstrated that cardiomyocyte necrosis caused by Cops8-cko belongs to necroptosis and is mediated by the RIPK1-RIPK3 pathway. This article reviews these recent advances and discusses the potential links between Cullin deneddylation and the necroptotic pathways in hopes of identifying potentially new therapeutic targets for the prevention of cardiomyocyte death.
PubMed: 34262479
DOI: 10.3389/fphys.2021.690423 -
Asian Pacific Journal of Cancer... Jun 2021In this study, we aimed to detect Succinate Dehydrogenase Complex Iron Sulfur Subunit B (SDHB) frequency in paragangliomas and pheochromocytomas (PPGL) with...
Succinate Dehydrogenase Complex Iron Sulfur Subunit B (SDHB) Immunohistochemistry in Pheochromocytoma, Head and Neck Paraganglioma, Thoraco-Abdomino-Pelvic Paragangliomas: Is It a Good Idea to Use in Routine Work?
BACKGROUND
In this study, we aimed to detect Succinate Dehydrogenase Complex Iron Sulfur Subunit B (SDHB) frequency in paragangliomas and pheochromocytomas (PPGL) with immunohistochemistry; compare with Pheochromacytoma of the Adrenal Gland Scaled Score (PASS) classification and analyse the differences between pheochromocytoma (Pheo), head-neck paragangliomas (HNPGL) and thoraco-abdominal-pelvic paraganglioma (TAPPGL) sub-groups.
METHODS
A total 114 PPGL cases (73 HNPGL, 15 TAPPGL and 27 Pheo belonging to 112 cases) are included. Immunohistochemically, SDHB and Ki-67 are investigated and malignancy risks are determined by PASS classification. Results are assessed statistically with chi-square test and p <0,01 is considered significant.
RESULTS
SDHB mutations are observed in 20 of 114 (17.54 %) PPGL cases, 3 (11,12%) of which is Pheo, 12 (16,44) is HNPGL, and 5 (35,71%) is TAPPGL (P <0,02). While 15/82 (18,29%) cases with SDHB mutations do not have a malignancy potential according to PASS classification, 5/32 (15,63%) cases has (p=0,73). TAPPGL, HNPGL and Pheo sub-groups have a significant difference between SDHB expression (p <0,02), malignancy potential according to PASS classification (p <0,0001) and Ki-67 proliferation index (p <0,0001).
CONCLUSION
To identify patients for molecular pathological examination, routine application of SDHB immunohistochemistry to PPGL tumors are suggested especially in HNPGLs.
Topics: Head and Neck Neoplasms; Humans; Immunohistochemistry; Paraganglioma; Pheochromocytoma; Succinate Dehydrogenase; Thoracic Neoplasms
PubMed: 34181326
DOI: 10.31557/APJCP.2021.22.6.1721 -
BioMed Research International 2021Acute respiratory distress syndrome (ARDS) is defined as the acute onset of noncardiogenic edema and subsequent gas-exchange impairment due to a severe inflammatory... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Acute respiratory distress syndrome (ARDS) is defined as the acute onset of noncardiogenic edema and subsequent gas-exchange impairment due to a severe inflammatory process known as cytokine storm. Xuebijing injection (hereinafter referred to as Xuebijing) is a patent drug that was used to treat ARDS or severe pneumonia (SP) in China. However, its efficacy and mechanism of actions remain unclear. In this study, we used meta-analysis and network pharmacology to assess these traits of Xuebijing.
METHODS
We searched PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang databases for randomized controlled trials (RCTs) that evaluated Xuebijing therapy for ARDS or SP. The outcomes were total mortality, intensive care unit (ICU) stay time, and TNF- and IL-6 levels. We performed a meta-analysis using RevMan 5.3 software. The putative targets, top 10 proteins, and possible pathway of Xuebinjing on ARDS were analyzed by network pharmacology. TNF- and IL-6 were further docked with the six main active components of Xuebinjing using AutoDock 4.2.6 and PyMol 1.5.0.3 software.
RESULTS
Fifteen RCTs involving 2778 patients (13 ARDS and 2 SP) were included. Compared with the control, Xuebijing treatment significantly reduced the mortality rate (risk ratio, 0.64 (95% credible interval (CrI), 0.54-0.77)), reduced the ICU stay time (mean difference (MD), -4.51 (95% CrI, -4.97--4.06)), reduced the TNF- ((MD), -1.23 (95% CrI, -1.38--1.08)) and IL-6 ((MD), -1.15 (95% CrI, -1.52--0.78)) levels. The 56 putative targets, top 10 proteins (MAPK1 (mitogen-activated protein kinase 1), MAPK8 (mitogen-activated protein kinase 8), RELA (transcription factor p65), NFKB1 (nuclear factor NF-kappa-B p105 subunit), JUN (transcription factor AP-1), SRC (proto-oncogene tyrosine-protein kinase), TNF (tumor necrosis factor), HRAS (GTPase HRas), IL6 (interleukin-6), and APP (amyloid-beta A4 protein)), and possible pathways (Ret tyrosine kinase, IL2-mediated signaling events, CD4+/CD8+ T cell-related TCR signaling, p75(NTR)-mediated signaling, CXCR4-mediated signaling events, LPA receptor-mediated events, IL12-mediated signaling events, FAS (CD95) signaling pathway, and immune system) of Xuebinjing's action on ARDS were obtained. The molecular docking results showed that all the six components of Xuebinjing docked with TNF-, and two components docked with IL-6 got the binding energies lower than -5.
CONCLUSION
Our results recommended Xuebijing treatment for patients with ARDS. Xuebijing has therapeutic effects on ARDS patients partly by regulating the immune cell/cytokine pathways and thus inhibiting the cytokine storm. TNF- is the cytokine both directly and indirectly inhibited by Xuebijing, and IL-6 is the cytokine mainly indirectly inhibited by Xuebijing.
Topics: Drugs, Chinese Herbal; Gene Expression Regulation; Humans; Intensive Care Units; Proto-Oncogene Mas; Respiratory Distress Syndrome; Signal Transduction
PubMed: 34124260
DOI: 10.1155/2021/8824059