The impact of diabetes on reproductive function is still not clearly defined. This study aimed to evaluate accelerated ovarian aging in women with type 2 diabetes mellitus (T2DM) and its association ...with adverse lipid profile.
Female patients with T2DM (n=964) and non-T2DM controls (n=263) aging from 18-80 years were included. Levels of circulating sex hormones were measured at the follicular phase in menstruating women. We analyzed the age-specific trends in the levels of sex hormones between T2DM and controls. The correlations of sex hormones with the lipid profile, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) and triglycerides (TG) were also evaluated.
In the temporal trends analysis, LH and FSH both started to increase obviously approximately from the age of 45 years among patients with T2DM, and displayed peaks of LH and FSH among patients with T2DM aged between 61 and 65, both of which were obviously earlier than that in non-T2DM controls and proved the accelerated ovarian aging among patients with T2DM. E2 of patients with T2DM was continuous lower than that of non-T2DM controls from approximately 45 years old, and LH and FSH of patients with T2DM were higher than those of non-T2DM controls between the age of 55 to 65 years. Multiple linear regression analyses revealed that LH was positively correlated with LDL-C (Coefficient=0.156, P=0.001) and TC (Coefficient=0.134, P=0.025), and was negatively correlated with HDL-C (Coefficient =-0.065, P=0.001) in patients with T2DM aged between 51 and 60, which was independent of age, T2DM duration, body mass index (BMI), glycosylated hemoglobin (HbA1c), FSH, E2 and other potential confounders. Higher E2 level was significantly and independently correlated with lower LDL-C (Coefficient= -0.064, P=0.033) in patients with T2DM aged between 51 and 60.
This study suggests that patients with T2DM have accelerated ovarian aging, and it is correlated with the occurrence of disturbed lipid profile in patients with T2DM. With an ever increasing number of female patients with T2DM diagnosed at younger ages, the accelerated ovarian aging and its adverse impacts in T2DM need to be carefully managed.
Oxygen evolution reaction (OER) is critical to renewable energy conversion technologies, but the structure-activity relationships and underlying catalytic mechanisms in catalysts are not fully ...understood. We herein demonstrate a strategy to promote OER with simultaneously achieved lattice oxygen activation and enhanced local electric field by dual doping of cations and anions. Rough arrays of Fe and F co-doped CoO nanoneedles are constructed, and a low overpotential of 277 mV at 500 mA cm
is achieved. The dually doped Fe and F could cooperatively tailor the electronic properties of CoO, leading to improved metal-oxygen covalency and stimulated lattice oxygen activation. Particularly, Fe doping induces a synergetic effect of tip enhancement and proximity effect, which effectively concentrates OH
ions, optimizes reaction energy barrier and promotes O
desorption. This work demonstrates a conceptual strategy to couple lattice oxygen and local electric field for effective electrocatalytic water oxidation.
Exenatide is a stable analogue of glucagon-like peptide 1 that can reduce postprandial hyperglycemia and has been utilized as adjunctive therapy for type 1 diabetes mellitus (T1DM). The human ...umbilical cord is a rich source of MSCs, and human umbilical cord mesenchymal stem cells (hUCMSCs) also show potential to enhance insulin secretion. Here, we aimed to explore the effects of hUCMSCs carrying exenatide in T1DM and further identify the possible mechanisms involved.
hUCMSCs were isolated from human umbilical cord tissues, identified, and transduced with recombinant lentivirus carrying exenatide to obtain exenatide-carrying hUCMSCs (hUCMSCs@Ex-4).
The results showed that hUCMSCs@Ex-4 restored the blood glucose levels and body weight of NOD mice, and repressed immune cell infiltration and islet tissue changes. Additionally, in T1DM mice, treatment with hUCMSCs@Ex-4 reduced the blood glucose levels and promoted repair of islet tissue damage. Moreover, hUCMSCs@Ex-4 attenuated renal tissue lesions in T1DM mice. Applying bioinformatic analysis, the effects of hUCMSCs@Ex-4 were suggested to correlate with decreased abundance of pro-inflammatory intestinal bacteria and increased abundance of anti-inflammatory intestinal bacteria.
Overall, the study indicated that hUCMSCs carrying exenatide might improve beneficial intestinal microflora abundance and promote islet tissue damage repair, thereby alleviating T1DM.
Zinc finger protein 143(ZNF143), a member of the Krüppel C2H2-type zinc finger protein family, is strongly associated with cell cycle regulation and cancer development. A recent study suggested that ...ZNF143 plays as a transcriptional activator that promotes hepatocellular cancer (HCC) cell proliferation and cell cycle transition. However, the exact biological role of ZNF143 in liver regeneration and normal liver cell proliferation has not yet been investigated. In our study, we constructed a stable rat liver cell line (BRL-3A) overexpressing ZNF143 and then integrated RNA-seq and Cleavage Under Targets and Tagmentation (CUT&Tag) data to identify the mechanism underlying differential gene expression. Our results show that ZNF143 expression is upregulated during the proliferation phase of liver regeneration after 2/3 partial hepatectomy (PH). The cell counting kit-8 (CCK-8) assay, EdU staining and RNA-seq data analyses revealed that ZNF143 overexpression (OE) significantly inhibited BRL-3A cell proliferation and cell cycle progression. We then performed CUT&Tag assays and found that approximately 10% of ZNF143-binding sites (BSs) were significantly changed genome-wide by ZNF143 OE. However, CCCTC-binding factor (CTCF) binding to chromatin was not affected. Interestingly, the integration analysis of RNA-seq and CUT&Tag data showed that some of genes affected by ZNF143 differential BSs are in the center of each gene regulation module. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that these genes are critical in the maintenance of cell identity. These results indicated that the expression level of ZNF143 in the liver is important for the maintenance of cell identity. ZNF143 plays different roles in HCC and normal liver cells and may be considered as a potential therapeutic target in liver disease.
The COVID-19 pandemic has resulted in great morbidity and mortality worldwide and human genetic factors have been implicated in the susceptibility and severity of COVID-19. However, few replicate ...researches have been performed, and studies on associated genes mainly focused on genic regions while regulatory regions were a lack of in-depth dissection. Here, based on previously reported associated variants and genes, we designed a capture panel covering 1,238 candidate variants and 25 regulatory regions of 19 candidate genes and targeted-sequenced 96 mild and 145 severe COVID-19 patients. Genetic association analysis was conducted between mild and severe COVID-19 patients, between all COVID-19 patients and general population, or between severe COVID-19 patients and general population. A total of 49 variants were confirmed to be associated with susceptibility or severity of COVID-19 (
< 0.05), corresponding to 18 independent loci. Specifically, rs1799964 in the promoter of inflammation-related gene
, rs9975538 in the intron of interferon receptor gene
, rs429358 in the exon of
, rs1886814 in the intron of
and a list of variants in the widely reported 3p21.31 and
gene were confirmed. It is worth noting that, for the confirmed variants, the phenotypes of the cases and controls were highly consistent between our study and previous reports, and the confirmed variants identified between mild and severe patients were quite different from those identified between patients and general population, suggesting the genetic basis of susceptibility and severity of SARS-CoV-2 infection might be quite different. Moreover, we newly identified 67 significant associated variants in the 12 regulatory regions of 11 candidate genes (
< 0.05). Further annotation by RegulomeDB database and GTEx eQTL data filtered out two variants (rs11246060 and rs28655829) in the enhancer of broad-spectrum antiviral gene
that might affect disease severity by regulating the gene expression. Collectively, we confirmed a list of previously reported variants and identified novel regulatory variants associated with susceptibility and severity of COVID-19, which might provide biological and clinical insights into COVID-19 pathogenesis and treatment.
Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a poorly characterized secreted protein of largely unknown physiological function. Here we demonstrate that scEMC10 ...is upregulated in people with obesity and is positively associated with insulin resistance. Consistent with a causal role for scEMC10 in obesity, Emc10
mice are resistant to diet-induced obesity due to an increase in energy expenditure, while scEMC10 overexpression decreases energy expenditure, thus promoting obesity in mouse. Furthermore, neutralization of circulating scEMC10 using a monoclonal antibody reduces body weight and enhances insulin sensitivity in obese mice. Mechanistically, we provide evidence that scEMC10 can be transported into cells where it binds to the catalytic subunit of PKA and inhibits its stimulatory action on CREB while ablation of EMC10 promotes thermogenesis in adipocytes via activation of the PKA signalling pathway and its downstream targets. Taken together, our data identify scEMC10 as a circulating inhibitor of thermogenesis and a potential therapeutic target for obesity and its cardiometabolic complications.
Endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is an evolutionarily conserved and multifunctional factor across species. We previously reported that Emc10 knockout (KO) leads to ...mouse male infertility. Emc10-null spermatozoa exhibit multiple aspects of dysfunction, including reduced sperm motility. Two subunits of a Na/K-ATPase, ATP1A4 and ATP1B3, are nearly absent in Emc10 KO spermatozoa. Here, two isoforms of EMC10 were characterized in the mouse testis and epididymis: the membrane-bound (mEMC10) and secreted (scEMC10) isoforms. We present evidence that mEMC10, rather than scEMC10, is required for cytoplasm sodium homeostasis by positively regulating ATP1B3 expression in germ cells. Intra-testis mEMC10 overexpression rescued the sperm motility defect caused by Emc10 KO, while exogenous recombinant scEMC10 protein could not improve the motility of spermatozoa from either Emc10 KO mouse or asthenospermic subjects. Clinically, there is a positive association between ATP1B3 and EMC10 protein levels in human spermatozoa, whereas no correlation was proven between seminal plasma scEMC10 levels and sperm motility. These results highlight the important role of the membrane-bound EMC10 isoform in maintaining cytoplasm sodium homeostasis and sperm motility. Based on the present results, the mEMC10-Na, K/ATPase α4β3 axis is proposed as a novel mechanism underlying the regulation of cytoplasmic sodium and sperm motility, and its components seem to have therapeutic potential for asthenospermia.
Aims/Introduction
To investigate the associations between parathyroid hormone (PTH) and non‐proliferative diabetic retinopathy (NPDR) in patients with type 2 diabetes mellitus.
Materials and Methods
...Data were collected from 2,322 patients with type 2 diabetes mellitus in hospital between 2017 and 2019. The odds ratio (OR) and the corresponding 95% confidence interval related to the quartiles of PTH were obtained by logistic regression analysis after adjusting the potential confounding variation.
Results
The patients were stratified into quartiles (Q1–Q4) based on the PTH levels, with the cut‐off limits of ≤23.74, 23.74–29.47, 29.47–37.30 and >37.30 pg/mL in men, and ≤24.47, 24.47–31.22, 31.22–39.49 and >39.49 pg/mL in women. The first quartile (Q1) represents the lowest quartile and the fourth quartile (Q4) is the highest. According to the quartiles (Q1–Q4), the prevalence rate of NPDR in patients showed a significantly decreasing trend (37.9%, 36.3%, 34.0% vs 24.0% in men; 43.2%, 40.5%, 31.1% vs 26.2% in women, both P < 0.05). Independent of age, diabetes duration and other metabolic factors, multivariate logistic regression showed that participants in Q4 had a lower OR of NPDR than those in Q1 (OR 0.443, 95% confidence interval 0.300–0.654, P < 0.001 for men; OR 0.428, 95% confidence interval 0.283–0.646, P < 0.001 for women).
Conclusions
Low serum PTH levels were significantly associated with complications of NPDR in inpatients. Its causality remains to be further studied.
Low serum parathyroid hormone levels were significantly associated with complications of non‐proliferative diabetic retinopathy in inpatients. Its causality remains to be further studied.
Aims/Introduction
The aim of this study was to investigate the relationship between serum progesterone (P) and retinopathy in male patients with type 2 diabetes mellitus, and to investigate whether P ...is associated with its progression.
Materials and methods
A total of 1,376 male participants with type 2 diabetes mellitus were recruited from Affiliated Hospital of Medical College Qingdao University (Qingdao, China). Through logistic regression analysis after adjusting the potential confounding variation, the odds ratio (OR) and the corresponding 95% confidence interval related to the quartiles of progesterone were obtained.
Results
According to the quartiles of P levels, the prevalence rate of diabetic retinopathy (DR) in the last quartile is obviously greater to other quartiles (52.5–34.9%, 31.9%, 37.5%, P < 0.001). Compared with those in the first quartile, the prevalence of DR for the last quartile had an OR of 1.85 in the non‐proliferative diabetic retinopathy group, while the OR was 8.35 in the proliferative diabetic retinopathy group (P < 0.001, unadjusted model). When adjusted for age, body mass index, duration of type 2 diabetes mellitus, glycated hemoglobin, blood pressure and other variables, the ORs for DR in the fourth quartile were 2.13 (95% confidence interval 1.49–3.06) in the non‐proliferative diabetic retinopathy group and 8.44 (95% confidence interval 2.69–26.43) in the proliferative diabetic retinopathy group (P < 0.001). The positive association between P and DR risk was independent in adjusted logistic regression.
Conclusions
High levels of serum progesterone are significantly associated with DR in male hospitalized patients. This could mean that a higher P level in men is a potential clinical factor to identify DR, and the causality remains to be further explored.
High levels of serum progesterone are significantly associated with diabetic retinopathy complications in male hospitalized patients. This could mean that a higher progesterone level in men is a predictor of diabetic retinopathy, and the causality remains to be further explored.
Our previous work have shown that certain subpopulations of
Klebsiella pneumoniae
exhibit significant phenotypic changes under simulated microgravity (SMG), including enhanced biofilm formation and ...cellulose synthesis, which may be evoked by changes in gene expression patterns. It is well known that prokaryotic cells genomic DNA can be hierarchically organized into different higher-order three-dimensional structures, which can highly influence gene expression. It is remain elusive whether phenotypic changes induced by SMG in the subpopulations of
K. pneumoniae
are driven by genome higher-order structural changes. Here, we investigated the above-mentioned issue using the wild-type (WT)
K. pneumoniae
(WT was used as a control strain and continuously cultivated for 2 weeks under standard culture conditions of normal gravity) and two previous identified subpopulations (M1 and M2) obtained after 2 weeks of continuous incubation in a SMG device. By the combination of genome-wide chromosome conformation capture (Hi-C), RNA-seq and whole-genome methylation (WGS) analyses, we found that the along with the global chromosome interactions change, the compacting extent of M1, M2 subpopulations were much looser under SMG and even with an increase in active, open chromosome regions. In addition, transcriptome data showed that most differentially expressed genes (DEGs) were upregulated, whereas a few DEGs were downregulated in M1 and M2. The functions of both types DEGs were mainly associated with membrane fractions. Additionally, WGS analysis revealed that methylation levels were lower in M1 and M2. Using combined analysis of multi-omics data, we discovered that most upregulated DEGs were significantly enriched in the boundary regions of the variable chromosomal interaction domains (CIDs), in which genes regulating biofilm formation were mainly located. These results suggest that
K. pneumoniae
may regulate gene expression patterns through DNA methylation and changes in genome structure, thus resulting in new phenotypes in response to altered gravity.
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