Pyrroloquinoline quinone inhibits PCSK9-NLRP3 mediated pyroptosis of Leydig cells in obese mice.

Abnormal lipid metabolism and chronic low-grade inflammation are the main traits of obesity. Especially, the molecular mechanism of concomitant deficiency in steroidogenesis-associated enzymes related to testosterone (T) synthesis of obesity dominated a decline in male fertility is still poorly understood. Here, we found that in vivo, supplementation of pyrroloquinoline quinone (PQQ) efficaciously ameliorated the abnormal lipid metabolism and testicular spermatogenic function from high-fat-diet (HFD)-induced obese mice. Moreover, the transcriptome analysis of the liver and testicular showed that PQQ supplementation not only inhibited the high expression of proprotein convertase subtilisin/Kexin type 9 (PCSK9) but also weakened the NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated pyroptosis, which both played a negative role in T synthesis of Leydig Cells (LCs). Eventually, the function and the pyroptosis of LCs cultured with palmitic acid in vitro were simultaneously benefited by suppressing the expression of NLRP3 or PCSK9 respectively, as well the parallel effects of PQQ were affirmed. Collectively, our data revealed that PQQ supplementation is a feasible approach to protect T synthesis from PCSK9-NLRP3 crosstalk-induced LCs' pyroptosis in obese men.

CircKDM5B sponges miR-128 to regulate porcine blastocyst development by modulating trophectoderm barrier function.

Circular RNAs (circRNAs), which exert critical functions in the regulation of transcriptional and post-transcriptional gene expression, are found in mammalian cells but their functions in mammalian preimplantation embryo development remain poorly understood. Here, we showed that circKDM5B mediated miRNA-128 (miR-128) to regulate porcine early embryo development. We screened circRNAs potentially expressed in porcine embryos through an integrated analysis of sequencing data from mouse and human embryos, as well as porcine oocytes. An authentic circRNA originating from histone demethylase KDM5B (referred to as circKDM5B) was abundantly expressed in porcine embryos. Functional studies revealed that circKDM5B knockdown not only significantly reduced blastocyst formation but also decreased the number of total cells and trophectoderm (TE) cells. Moreover, the knockdown of circKDM5B resulted in the disturbance of tight junction assembly and impaired paracellular sealing within the TE epithelium. Mechanistically, miR-128 inhibitor injection could rescue the early development of circKDM5B knockdown embryos. Taken together, the findings revealed that circKDM5B functions as a miR-128 sponge, thereby facilitating early embryonic development in pigs through the modulation of gene expression linked to tight junction assembly.

Icariin Ameliorates Spermatogenesis Disorder in Obese Mice Induced by High-Fat Diet through Regulating the Glycolytic Pathway.

SCOPE: Obesity is a global threat for male infertility, which can cause spermatogenic dysfunction. However, there are no available drugs for the treatment of obesity-induced spermatogenesis dysfunction. This study characterizes the protective effects of icariin (ICA) on spermatogenesis dysfunction in obese mice. METHODS AND RESULTS: Obese mice are induced by a high-fat diet to determine whether ICA has a protective effect. ICA treatment reduces body weight and the proportion of abnormal sperm, brings about a recovery of sperm count, and the number of spermatogenic cells. ICA treatment improves histopathological changes of the testes and inhibits testicular apoptosis, as evidenced by reduced the expression of Bax and increased the expression of Bcl-2, PCNA, WT1, GATA-4, vimentin, HK2, PKM2, and LDHA in the testes. In vitro, TM4 cells are treated with 0.4 mm palmitic acid (PA) to induce Sertoli cell injury, and are then utilized for ICA treatment. ICA improves PA-induced decreased TM4 cells viability, reduces the levels of lactate, and increases the levels of pyruvate and the expression of HK2, PKM2, and LDHA and restores the glycolytic process in vitro. CONCLUSION: ICA ameliorates spermatogenic dysfunction in obese mice by regulating glycolytic activity, providing effective strategies for obesity treatment.

CDT1 is the major functional regulatory subunit of the pre-replication complex in zygotes.

Pre-replication complex (pre-RC) is critical for DNA replication initiation. CDT1 and MCM2 are the subunits of pre-RC, and proper regulation of CDT1 and MCM2 are necessary for DNA replication and cell proliferation. The present study aimed to explore the role of CDT1 and MCM2 in oocyte meiotic maturation and early embryonic development. The depletion and overexpression of Cdt1 and Mcm2 in oocyte and zygote were achieved by microinjecting specific siRNA and mRNA to explored their functions in oocyte meiotic maturation and embryonic development. Then, we examined the effect of CDT1 and MCM2 on other signal pathways by immunostaining the expression of related maker genes. We showed that neither depletion nor overexpression of Cdt1 affected oocyte meiotic progressions. The CDT1 was degraded in S phase and remained at a low level in G2 phase of zygote. Exogenous expression of Cdt1 in G2 phase led to embryo attest at zygote stage. Mechanistically, CDT1 overexpression induced DNA re-replication and thus DNA damage check-point activation. Protein abundance of MCM2 was stable throughout the cell cycle, and embryos with overexpressed MCM2 could develop to blastocysts normally. Overexpression or depletion of Mcm2 also had no effect on oocyte meiotic maturation. Our results indicate that pre-RC subunits CDT1 and MCM2 are not involved in oocyte meiotic maturation. In zygote, CDT1 but not MCM2 is the major regulator of DNA replication in a cell cycle dependent manner. Furthermore, its' degradation is essential for zygotes to prevent from DNA re-replication in G2 stage.

Antioxidant for treatment of diabetic complications: A meta-analysis and systematic review.

Antioxidants may provide a complementary treatment for patients with chronic diseases. Nevertheless, studies that have measured the effects of antioxidant on diabetes complications have provided conflicting results. This study aimed to elucidate the association between antioxidant and diabetic complications and to develop robust evidence for clinical decisions by systematic reviews and meta-analysis. PubMed, Embase, The Cochrane Library, Web of Science, Scopus databases were searched to collect clinical studies related to the efficacy of antioxidants in the treatment of diabetes complications from inception to May 5, 2021. Statistical meta-analyses were performed using the RevMan 5.4 software. Stata16 software was used to detect publication bias. The data of diabetic nephropathy (DN), diabetic nonalcoholic fatty liver disease (NAFLD), and diabetic periodontitis were collected to analyze the effect of antioxidant on diabetes and the above three complications. The meta-analysis results showed that antioxidant treatment was associated with significantly changes in the fasting plasma glucose (FPG) (standardized mean difference [SMD]: - 0.21 [95% confidence interval [CI]: - 0.33, -0.10], p < 0.001), hemoglobin A1c (HbA1c) (MD: - 0.41 [95% CI: - 0.63, -0.18], p < 0.001), total antioxidant capacity (TAC) (SMD: 0.44 [95% CI: 0.24, 0.63], p < 0.001) and malondialdehyde (MDA) (SMD: - 0.82 [95% CI: - 1.24, -0.41], p < 0.001) than the control group. Antioxidant supplements have the potential to treat three complications of diabetes. In conclusion, the meta-analysis results indicate that antioxidant treatment is effective clinically for diabetes mellitus and its complications.

Effects of NAD+ precursor supplementation on glucose and lipid metabolism in humans: a meta-analysis.

BACKGROUND: This meta-analysis was performed to investigate the effects of nicotinamide adenine dinucleotide (NAD+) precursor supplementation on glucose and lipid metabolism in human body. METHODS: PubMed, Embase, CENTRAL, Web of Science, Scopus databases were searched to collect clinical studies related to the supplement of NAD+ precursor from inception to February 2021. Then the retrieved documents were screened, the content of the documents that met the requirements was extracted. Meta-analysis and quality evaluation was performed detection were performed using RevMan5.4 software. Stata16 software was used to detect publication bias, Egger and Begg methods were mainly used. The main research terms of NAD+ precursors were Nicotinamide Riboside (NR), Nicotinamide Mononucleotide (NMN), Nicotinic Acid (NA), Nicotinamide (NAM). The changes in the levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and fasting blood glucose were mainly concerned. RESULTS: A total of 40 articles were included in the meta-analysis, with a sample of 14,750 cases, including 7406 cases in the drug group and 7344 cases in the control group. The results of meta-analysis showed that: NAD+ precursor can significantly reduce TG level (SMD = - 0.35, 95% CI (- 0.52, - 0.18), P < 0.0001), and TC (SMD = - 0.33, 95% CI (- 0.51, - 0.14), P = 0.0005), and LDL (SMD = - 0.38, 95% CI (- 0.50, - 0.27), P < 0.00001), increase HDL level (SMD = 0.66, 95% CI (0.56, 0.76), P < 0.00001), and plasma glucose level in the patients (SMD = 0.27, 95% CI (0.12, 0.42), P = 0.0004). Subgroup analysis showed that supplementation of NA had the most significant effect on the levels of TG, TC, LDL, HDL and plasma glucose. CONCLUSIONS: In this study, a meta-analysis based on currently published clinical trials with NAD+ precursors showed that supplementation with NAD+ precursors improved TG, TC, LDL, and HDL levels in humans, but resulted in hyperglycemia, compared with placebo or no treatment. Among them, NA has the most significant effect on improving lipid metabolism. In addition, although NR and NAM supplementation had no significant effect on improving human lipid metabolism, the role of NR and NAM could not be directly denied due to the few relevant studies at present. Based on subgroup analysis, we found that the supplement of NAD+ precursors seems to have little effect on healthy people, but it has a significant beneficial effect on patients with cardiovascular disease and dyslipidemia. Due to the limitation of the number and quality of included studies, the above conclusions need to be verified by more high-quality studies.

Effect of spermidine on ameliorating spermatogenic disorders in diabetic mice via regulating glycolysis pathway.

Diabetes mellitus (DM), a high incidence metabolic disease, is related to the impairment of male spermatogenic function. Spermidine (SPM), one of the biogenic amines, was identified from human seminal plasma and believed to have multiple pharmacological functions. However, there exists little evidence that reported SPM's effects on moderating diabetic male spermatogenic function. Thus, the objective of this study was to investigate the SPM's protective effects on testicular spermatogenic function in streptozotocin (STZ)-induced type 1 diabetic mice. Therefore, 40 mature male C57BL/6 J mice were divided into four main groups: the control group (n = 10), the diabetic group (n = 10), the 2.5 mg/kg SPM-treated diabetic group (n = 10) and the 5 mg/kg SPM-treated diabetic group (n = 10), which was given intraperitoneally for 8 weeks. The type 1 diabetic mice model was established by a single intraperitoneal injection of STZ 120 mg/kg. The results showed that, compare to the control group, the body and testis weight, as well the number of sperm were decreased, while the rate of sperm malformation was significantly increased in STZ-induced diabetic mice. Then the testicular morphology was observed, which showed that seminiferous tubule of testis were arranged in mess, the area and diameter of which was decreased, along with downregulated anti-apoptotic factor (Bcl-2) expression, and upregulated pro-apoptotic factor (Bax) expression in the testes. Furthermore, testicular genetic expression levels of Sertoli cells (SCs) markers (WT1, GATA4 and Vimentin) detected that the pathological changes aggravated observably, such as the severity of tubule degeneration increased. Compared to the saline-treated DM mice, SPM treatment markedly improved testicular function, with an increment in the body and testis weight as well as sperm count. Pro-apoptotic factor (Bax) was down-regulated expression with the up-regulated expression of Bcl-2 and suppression of apoptosis in the testes. What's more, expression of WT1, GATA4, Vimentin and the expressions of glycolytic rate-limiting enzyme genes (HK2, PKM2, LDHA) in diabetic testes were also upregulated by SPM supplement. The evidence derived from this study indicated that the SMP's positive effect on moderating spermatogenic disorder in T1DM mice's testis. This positive effect is delivered via promoting spermatogenic cell proliferation and participating in the glycolytic pathway's activation.

Multishell Hollow Metal/Nitrogen/Carbon Dodecahedrons with Precisely Controlled Architectures and Synergistically Enhanced Catalytic Properties.

Multishell hollow nanoarchitectures are one of the most important branches in the nanomaterial field due to their enormous potential in many fields, but synthesizing them in a well-controlled manner remains challenging. Herein, we present a general strategy for the construction of multishell hollow metal/nitrogen/carbon dodecahedrons (metal@NC) with well-defined and precisely controlled architectures. This strategy is based on the pyrolysis of multilayer solid ZIFs prepared by a step-by-step crystal growth approach, which enables precise control over the shell number and composition of the resultant hollow metal@NC. Impressively, our strategy can be further extended to the synthesis of yolk@multishell hollow structures or multishell hollow structures that are assembled by carbon nanotubes. The multishell hollow structures can efficiently facilitate the mass diffusion, which together with the high dispersity and increased surface area are responsible for their significantly enhanced catalytic performances for the selective hydrogenation of biomass-derived furfural to cyclopentanol when compared with their solid and single-shell counterparts. We anticipate that our general strategy would shed light on the rational design and accurate construction of other complex multishell hollow materials for various important yet challenging applications.

MOF-Derived Isolated Fe Atoms Implanted in N-Doped 3D Hierarchical Carbon as an Efficient ORR Electrocatalyst in Both Alkaline and Acidic Media.

In order to improve the catalytic performance of oxygen reduction reaction (ORR), it is pivotal to increase the density and accessibility of the active sites. Herein, we have developed a template-free melamine-assisted cocalcined strategy to afford Fe-embedded and N-doped carbons (Fe-N-C) with not only high density of atomically dispersed Fe-Nx active sites but also abundant three-dimensional interconnected mesopores by directly pyrolyzing Fe-ZIF-8 covered with a controllable melamine layer. It is demonstrated that the introduction of melamine in the precursor plays a key role in constructing various carbonized products with controllable morphology, porosity, and components. With an optimal mass ratio 1:1 of melamine to Fe-ZIF-8, the resultant Fe@MNC-1 exhibits excellent ORR activity and stability, which exceeds 20 wt % commercial Pt/C catalyst (with a half-wave potential of 0.88 V vs 0.85 V) in an alkaline electrolyte and is even comparable to the commercial Pt/C catalyst (with a half-wave potential of 0.78 V vs 0.80 V) in an acidic electrolyte. To the best of our knowledge, Fe@MNC-1 can be ranked among the best nonprecious metal electrocatalysts for ORR in both alkaline and acidic media. The present synthetic strategy may provide a new opportunity for the design and construction of metal-organic framework-derived nanomaterials with rational composition and a desired porous structure to boost their electrocatalytic performance.