The high expression of ADRM1 in hepatocellular carcinoma is closely related to tumor immune infiltration and is regulated by miR-891a-5p.

Liver cancer is one of the most common malignant tumors worldwide. Although some progress has been made in the diagnosis and treatment of Hepatocellular carcinoma (HCC), the diagnosis and treatment of HCC is still facing great challenges because of the high mortality rate and poor prognosis of HCC. The purpose of this study was to explore the relationship between adhesion-regulating molecule1 (ADRM1), and liver cancer, and the relationship between prognoses. ADRM1 is highly expressed in tumors and is closely associated with the prognosis of patients with liver cancer. In our previous study, we found that ADRM1 was highly expressed in HCC and was closely related to tumor immune and immune checkpoint levels in HCC. We validated the immune expression of ADRM1 in liver cancer cells using flow cytometry. In hepatocellular carcinoma tissues, miR-891a-5p regulates ADRM1. Upregulation of miR-891a-5p upregulates ADRM1, and downregulation of miR-891a-5p downregulates ADRM1. It is suggested that ADRM1 plays a key role in the occurrence and development of hepatocellular carcinoma. This study is expected to provide new ideas for the research and development of anti-HCC drugs targeting miR-891a-5p/ADRM1. However, further trials are needed to confirm these results and explore the actual results in patients with HCC.

CYP2E1 mediated advanced oxidation protein products exacerbate acetaminophen induced drug-derived liver injury in vitro and in vivo.

Drug-induced liver injury (DILI) is prevalent in the treatment of chronic kidney disease (CKD). Advanced oxidation protein products (AOPPs) are markers of CKD progression and participate in the occurrence and development of liver diseases. However, the mechanisms underlying the regulation of DILI in CKD have not been established. Herein, we demonstrate the involvement of Cytochrome p450 2E1 (CYP2E1) in DILI induced by AOPPs is exacerbated by exposure to acetaminophen (APAP). We used a adenine-induced CKD model, a model of DILI induced by APAP, and the AOPPs model was generated by intraperitoneal injection. The decline in renal function was associated with a significantly increased concentration of Scr, BUN and AOPPs, and renal tissue fibrosis. The ALT, AST, and AOPPs levels and liver tissue necrosis increased significantly in CKD model group compared with the sodium carboxymethyl cellulose (CMCNa) group. In the AOPPs model, compared to the PBS controls, ALT, AST, and AOPP levels, and liver tissue necrosis increased significantly. In HepG2 or L0-2 cell lines, cell survival was significantly reduced in the AOPP + APAP treatment and CYP2E1 protein expression was increased. FPS-ZM1 or NAC attenuated the hepatocyte toxicity induced by AOPP + APAP and suppression of CYP2E1 expression. AOPPs exacerbated APAP-induced DILI through CYP2E1 signaling pathways. Protein uremic toxins, such as AOPPs, can modify drug toxicity in patients with CKD. This study provides new a rationale to reduce the generation of DILIs in clinical treatment in patients with CKD. AOPPs targeting may present a novel approach to reduce the occurrence of DILI.

Huang Gan Formula Alleviates Systemic Inflammation and Uremia in Adenine-Induced Chronic Kidney Disease Rats May Associate with Modification of Gut Microbiota and Colonic Microenvironment.

Purpose: This study aims to investigate the effects of Huang Gan formula (HGF), a Chinese herbal prescription used for chronic kidney disease (CKD), on the regulation of the gut microbiota and colonic microenvironment of CKD. Methods: CKD rats were induced by 150 mg/kg adenine gavage for 4 weeks, then orally treated with or without 3.6 g/kg or 7.2 g/kg of HGF for 8 weeks. The renal function and structure were analyzed by biochemical detection, hematoxylin and eosin, Masson's trichrome, Sirius red and immunochemical staining. Average fecal weight and number in the colon were recorded to assess colonic motility. Further, the changes in the gut microbiota and colonic microenvironment were evaluated by 16S rRNA sequencing, RT-PCR or immunofluorescence. The levels of inflammatory cytokines, uremic toxins, and NF-κB signaling pathway were detected by RT-PCR, ELISA, chloramine-T method or Western blotting. Redundancy analysis biplot and Spearman's rank correlation coefficient were used for correlation analysis. Results: HGF significantly improved renal function and pathological injuries of CKD. HGF could improve gut microbial dysbiosis, protect colonic barrier and promote motility of colonic lumens. Further, HGF inhibited systemic inflammation through a reduction of TNF-α, IL-6, IL-1ß, TGF-ß1, and a suppression of NF-κB signaling pathway. The serum levels of the selected uremic toxins were also reduced by HGF treatment. Spearman correlation analysis suggested that high-dose HGF inhibited the overgrowth of bacteria that were positively correlated with inflammatory factors (eg, TNF-α) and uremic toxins (eg, indoxyl sulfate), whereas it promoted the proliferation of bacteria belonging to beneficial microbial groups and was positively correlated with the level of IL-10. Conclusion: Our results suggest that HGF can improve adenine-induced CKD via suppressing systemic inflammation and uremia, which may associate with the regulations of the gut microbiota and colonic microenvironment.

A Theoretical Analysis of Density Peaks Clustering and the Component-Wise Peak-Finding Algorithm.

Density peaks clustering detects modes as points with high density and large distance to points of higher density. Each non-mode point is assigned to the same cluster as its nearest neighbor of higher density. Density peaks clustering has proved capable in applications, yet little work has been done to understand its theoretical properties or the characteristics of the clusterings it produces. Here, we prove that it consistently estimates the modes of the underlying density and correctly clusters the data with high probability. However, noise in the density estimates can lead to erroneous modes and incoherent cluster assignments. A novel clustering algorithm, Component-wise Peak-Finding (CPF), is proposed to remedy these issues. The improvements are twofold: 1) the assignment methodology is improved by applying the density peaks methodology within level sets of the estimated density; 2) the algorithm is not affected by spurious maxima of the density and hence is competent at automatically deciding the correct number of clusters. We present novel theoretical results, proving the consistency of CPF, as well as extensive experimental results demonstrating its exceptional performance. Finally, a semi-supervised version of CPF is presented, integrating clustering constraints to achieve excellent performance for an important problem in computer vision.

Paenibacillus spongiae sp. nov. isolated from deep-water marine sponge Theonella swinhoei.

A novel bacterial strain, designated as PHS-Z3T, was isolated from a marine sponge belonging to the genus Theonella on the Puerto Galera Deep Monkey, Philippines. Cells of PHS-Z3T were Gram-stain-positive, motile, oxidase- and catalase-positive, white-pigmented, spore-forming, short rods that could grow at 10-40 °C (optimum, 20 °C), pH 6.0-9.5 (optimum, pH 7.5) and with 2-16 % (w/v) NaCl (optimum, 7 %). The 16S rRNA gene sequence of PHS-Z3T showed 97.9 %, 96.7 %, and 96.2 % identities to Paenibacillus mendelii C/2T, Paenibacillus oenotherae DT7-4T and Paenibacillus aurantiacus RC11T, respectively. The results of phylogenetic analysis based on 16S rRNA gene sequences indicated that PHS-Z3T formed an independent cluster with Paenibacillus mendelii C/2T. The total genome of PHS-Z3T was approximately 7 613 364 bp in size with a DNA G+C content of 51.6 %. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between PHS-Z3T and other type strains of species of the genus Paenibacillus were 68.0-81.4 % [ANI by blast (ANIb)], 83.0-88.0 % [ANI by MUMmer (ANIm)] and 12.7-32.1 % (dDDH). The dDDH and ANI values were below the standard cut-off criteria for delineation of bacterial species. The percentage of conserved proteins (POCP) values between the genome of PHS-Z3T and those of members of the genus Paenibacillus were 39.7-75.7 %, while the average amino acid identity (AAI) values were 55.9-83.7 %. The sole respiratory quinone in the strain was MK-7, and the predominant fatty acids were anteiso-C15 : 0 and C16 : 0. The major polar lipids of PHS-Z3T consisted of diphosphatidylglycerol, phospholipid and phosphatidylglycerol. The characteristic amino acid in the cell wall of PHS-Z3T was diamino heptanoic acid (meso-DAP). On the basis of the molecular, physiological, biochemical and chemotaxonomic features, strain PHS-Z3T represents a novel species of the genus Paenibacillus, for which the name Paenibacillus spongiae sp. nov. is proposed, with the type strain PHS-Z3T (=MCCC 1K07848T=KCTC 43443T).

Non-canonical pathway for Rb inactivation and external signaling coordinate cell-cycle entry without CDK4/6 activity.

Cyclin-dependent kinases 4 and 6 (CDK4/6) are critical for initiating cell proliferation by inactivating the retinoblastoma (Rb) protein. However, mammalian cells can bypass CDK4/6 for Rb inactivation. Here we show a non-canonical pathway for Rb inactivation and its interplay with external signals. We find that the non-phosphorylated Rb protein in quiescent cells is intrinsically unstable, offering an alternative mechanism for initiating E2F activity. Nevertheless, this pathway incompletely induces Rb-protein loss, resulting in minimal E2F activity. To trigger cell proliferation, upregulation of mitogenic signaling is required for stabilizing c-Myc, thereby augmenting E2F activity. Concurrently, stress signaling promotes Cip/Kip levels, competitively regulating cell proliferation with mitogenic signaling. In cancer, driver mutations elevate c-Myc levels, facilitating adaptation to CDK4/6 inhibitors. Differentiated cells, despite Rb-protein loss, maintain quiescence through the modulation of c-Myc and Cip/Kip levels. Our findings provide mechanistic insights into an alternative model of cell-cycle entry and the maintenance of quiescence.

Sequential activation of E2F via Rb degradation and c-Myc drives resistance to CDK4/6 inhibitors in breast cancer.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are key therapeutic agents in the management of metastatic hormone-receptor-positive breast cancer. However, the emergence of drug resistance limits their long-term efficacy. Here, we show that breast cancer cells develop CDK4/6i resistance via a sequential two-step process of E2F activation. This process entails retinoblastoma (Rb)-protein degradation, followed by c-Myc-mediated amplification of E2F transcriptional activity. CDK4/6i treatment halts cell proliferation in an Rb-dependent manner but dramatically reduces Rb-protein levels. However, this reduction in Rb levels insufficiently induces E2F activity. To develop CDK4/6i resistance, upregulation or activating mutations in mitogenic or hormone signaling are required to stabilize c-Myc levels, thereby augmenting E2F activity. Our analysis of pre-treatment tumor samples reveals a strong correlation between c-Myc levels, rather than Rb levels, and poor therapeutic outcomes after CDK4/6i treatment. Moreover, we propose that proteasome inhibitors can potentially reverse CDK4/6i resistance by restoring Rb levels.

Exploring the possible mechanism(s) underlying the nephroprotective effect of Zhenwu Decoction in diabetic kidney disease: An integrated analysis.

BACKGROUND: Diabetic kidney disease (DKD) is one of the major chronic microvascular complications of diabetes and the main cause of end-stage renal failure. Zhenwu Decoction (ZWD), an ancient classic herbal formula in Chinese medicine, has been clinically used for the treatment of kidney disease in China for many years. However, there is currently limited research investigating the application of ZWD in the treatment of DKD and the underlying chemical and biochemical mechanisms involved. Therefore, in the present study, we aimed to identify active components in ZWD and unravel the possible mechanism(s) of action for ZWD in treating DKD. METHODS: The protective effect of ZWD against DKD was evaluated utilizing an in vitro model of diabetic renal proximal tubulopathy. The major chemical components from ZWD were identified by LC-MS/MS. Drug targets were predicted by submitting the SMILES (Simplified Molecular Input Line Entry System) of the compounds to SEA (Similarity Ensemble Approach) search server and SwissTargetPrediction. The differentially expressed genes (DEGs) of the disease were collected and integrated from GeneCards. The constructions of "Compounds-potential targets interaction" (CTI) network and Protein-Protein Interaction (PPI) network, as well as topology analysis were conducted by Cytoscape. Gene Ontology (GO) enrichment and Metacore pathway enrichment analysis were also performed. Lastly, molecular docking and experimental studies were adopted to validate the core target and identify an active component(s) of ZWD. RESULTS: We demonstrated that the ZWD extract could significantly rescue the palmitic acid (PA) and high glucose-induced apoptotic cell death in HK-2 cells, and the cytoprotection was accompanied by decreases in the extent of reactive oxygen species (ROS) production, mitochondrial membrane depolarization and ATP depletion. Fifty-seven compounds in the aqueous extract of ZWD were identified by LC-MS. The results of PPI analysis showed that top hub genes involved epidermal growth factor receptor (EGFR), Signal Transducer and Activator of Transcription 3 (STAT3), Serine/Threonine Kinase 1 (AKT1), Vascular Endothelial Growth Factor A (VEGFA) and Fibroblast Growth Factor 2 (FGF2). Pathway enrichment analysis revealed the involvement of S1P1 receptor signaling and EGFR pathways. The results of molecular docking analysis showed that albiflorin has a high binding affinity to EGFR. Albiflorin could also exert protective effects in an HK-2 cell model of DKD, which may be related to the inhibition of the high glucose/high lipid-induced EGFR and Akt phosphorylation. CONCLUSION: ZWD has been shown to be effective in ameliorating cell death in an experimental model of DKD. The beneficial effect of ZWD against DKD was associated with the interactions between the active ingredients and the hub genes, such as EGFR, STAT3, AKT1, and VEGF-A. Albiflorin may be one of the active components responsible for the nephroprotective effect in ZWD.

Brevibacterium spongiae sp. nov., isolated from marine sponge Hymeniacidon sp.

A novel bacterial strain, designated as WHS-Z9T, was isolated from marine sponge Hymeniacidon sp. collected from Weihai (37° 25' N, 121° 58' E), Shandong Province, PR China. Cells of strain WHS-Z9T were Gram-stain-positive, non-spore-forming, non-motile, short-rod-shaped and light yellow-pigmented. The strain could grow at 10-40 °C (optimum, 20 °C), pH 4.5-9.5 (optimum, pH 8.5) and 2-14 % (w/v) NaCl (optimum, 4 %). The 16S rRNA gene sequence of strain WHS-Z9T showed 98.7  % similarity to that of Brevibacterium epidermidis NBRC 14811T, 98.5  % to Brevibacterium sediminis FXJ8.269T and 98.4 % to Brevibacterium oceani BBH7T. The phylogenetic tree based on 16S rRNA gene sequences revealed that strain WHS-Z9T was clustered with Brevibacterium limosum o2T. The whole genome of WHS-Z9T was approximately 4 217 721 bp in size with a G+C content of 65.2  %. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values among WHS-Z9T and other Brevibacterium type strains were 83.3-85.5 % (ANI based on blast), 86.4-87.9  % (ANI based on MUMmer) and 41.9-57.5 % (dDDH). Percentage of conserved protein values between the genomes of strain WHS-Z9T and members of genera Brevibacterium were 76.8-82.9 %, while the average amino acid identity (AAI) values were 83.7-87.0  %. The dDDH, ANI, AAI and POCP values were below the standard cut-off criteria for the delineation of bacterial species. The sole respiratory quinone in strain WHS-Z9T was MK-8(H2), and the predominant fatty acids were anteiso-C15 : 0 and anteiso-C17 : 0. The major polar lipids of WHS-Z9T consisted of diphosphatidylglycerol and glycolipid. The diagnostic cell-wall diamino acid of strain WHS-Z9T was meso-diaminopimelic acid. Based on the data obtained in this study, strain WHS-Z9T (=MCCC 1K07845T=KCTC 49848T) should be classified as the type strain of a novel species of the genus Brevibacterium, for which the name Brevibacterium spongiae sp. nov. is proposed.

Qipengyuania spongiae sp. nov., isolated from marine sponge Cinachyrella kuekenthali.

A novel bacterial strain, designated as PHS-Z21T, was isolated from the marine sponge Cinachyrella kuekenthali collected from PG Dave's Rock, Philippines. Cells of PHS-Z21T are Gram-stain-negative, non-motile, pale-yellow-pigmented, short rods. PHS-Z21T is able to grow at 10-40 ℃ (optimum, 30 ℃), pH 5.5-9.0 (optimum, pH 8.5) and with 3-9 % (w/v) NaCl (optimum, 4 %). Its 16S rRNA gene sequence shows 98.6 % similarity to Qipengyuania nanhaisediminis CGMCC 1.7715T, 98.5 % similarity to Qipengyuania vulgaris 022-2-10T and 98.4 % similarity to Qipengyuania flava SW-46T, respectively. The phylogenetic tree based on 16S rRNA gene sequences reveals that PHS-Z21T is clustered with Q. flava SW-46T. The total genome of PHS-Z21T is approximately 2 932 896 bp in size with a DNA G+C content of 64.7 %. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values among PHS-Z21T and other type strains are 70.0-77.3 % (ANIb), 83.3-86.8 % (ANIm) and 13.0-26.9 % (dDDH), respectively. The dDDH and ANI values are below the standard cutoff criteria for delineating bacterial species. Percentage of conserved proteins (POCP) values between the genome of strain PHS-Z21T and those of members of the genera Qipengyuania, Erythrobacter, Altererythrobacter and Alteriqipengyuania were 62.0-74.5 %, 55.8-63.2 %, 60.7-66.9 % and 63.9-66.8%, respectively, while the AAI values were 68.4-74.3 %, 63.8-65.9 %, 66.3-68.3 % and 64.7-66.9%, respectively. The major fatty acids of PHS-Z21T are composed of summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c), C18 : 1ω7c 11-methyl, C16 : 0 and summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c). The polar lipids of PHS-Z21T mainly consist of diphosphatidylglycerol, glycolipid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and glycophospholipid. The respiratory lipoquinone was identified as Q-10. On the basis of the phenotypic and phylogenetic data, strain PHS-Z21T represents a novel species of the genus Qipengyuania, for which the name Qipengyuania spongiae sp. nov. is proposed. The type strain is PHS-Z21T (=MCCC 1K07849T=KCTC 92590T).

MicroRNA-211-5p in extracellular vesicles derived from BMSCs facilitates the repair of rat frozen shoulder via regulating KDM2B/LACC1 axis.

OBJECTIVE: This study aims to explore the mechanism of miR-211-5p in extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (BMSCs) in improving frozen shoulder (FS) in rat models. METHODS: Rat BMSCs and EVs derived from rat BMSCs were isolated, identified, and then injected into rats to assess the expression of TGF-ß, MMP1, MMP3, MMP12, GAP43, and PGP9.5 in shoulder capsule tissues. The range of motion of bilateral glenohumeral joints was assessed and pathological changes of shoulder capsule tissues were observed after hematoxylin-eosin staining. The binding sites of miR-211-5p to KDM2B and LACC1 to H3K4me3 were measured. FS rat models with LACC1 highly expressed were established to assess the motion of bilateral glenohumeral joints and expression of arthritis related factors in rats. RESULTS: EVs were successfully extracted from BMSCs. Injection of BMSCs-EVs could improve the activity of bilateral glenohumeral joints and the pathological condition of joint capsule in rats. Elevated expression of miR-211-5p was found in rats injected with BMSCs-EVs. Dual luciferase assay showed that miR-211-5p had a binding site with KDM2B. ChIP, qRT-PCR, and western blot experiments showed BMSCs-EVs injection resulted in elevated enrichment of LACC1 promoter in shoulder capsule tissues of FS rats, and decreased mRNA and protein expression of KDM2B and increased H3K4me3 methylation. Overexpression of LACC1 could also improve the pathological condition of joint capsule tissue. CONCLUSION: miR-211-5p in EVs derived from BMSCs increased H3K4me3 methylation in shoulder capsule tissue of rats by binding KDM2B, resulting in up-regulated transcription level of LACC1 and improving FS. AVAILABILITY OF DATA AND MATERIALS: The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Chemokine CCL14 affected the clinical outcome and correlated with immune infiltrates in thyroid carcinoma.

BACKGROUND: As an important member of the chemokines, CCL14 plays a vital role in cancer progression. However, the role of CCL14 in THCA has not been investigated. This study aimed to reveal the clinical significance of CCL14 in THCA. MATERIAL AND METHODS: This study evaluated the expression and prognostic value of CCL14 in THCA. Also, the correlation between CCL14 and immune infiltrates was assessed. Enrichment analysis was finally performed to predict CCL14-associated pathways involved in THCA. RESULTS: The mRNA and protein expressions of CCL14 in THCA tissues were down-regulated compared with normal tissues. CCL14 high expression predicted favorable DFI and PFI but did not influence the DSS and OS. Further, CCL14 showed a good prediction performance on the PFI of patients. Enrichment analysis found that CCL14 was negatively correlated with migration-related pathways such as Notch signaling, ECM-receptor interaction, and cell adhesion molecules. Further, we found that CCL14 was negatively related to immune infiltrates and their gene markers. A negative relationship was also observed between CCL14 and immune checkpoint genes. These results implied the potential effect of CCL14 on the immune response and immune therapy in THCA. CONCLUSIONS: CCL14 high expression prolonged the DFI and PFI of THCA patients. It was negatively correlated with the migration-related pathways, suggesting that CCL14 might participate in the recurrence of THCA. Further, CCL14 was also shown to be important in immune response and immune therapy in THCA.

Non-invasive classification of macrophage polarisation by 2P-FLIM and machine learning.

In this study, we utilise fluorescence lifetime imaging of NAD(P)H-based cellular autofluorescence as a non-invasive modality to classify two contrasting states of human macrophages by proxy of their governing metabolic state. Macrophages derived from human blood-circulating monocytes were polarised using established protocols and metabolically challenged using small molecules to validate their responding metabolic actions in extracellular acidification and oxygen consumption. Large field-of-view images of individual polarised macrophages were obtained using fluorescence lifetime imaging microscopy (FLIM). These were challenged in real time with small-molecule perturbations of metabolism during imaging. We uncovered FLIM parameters that are pronounced under the action of carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), which strongly stratifies the phenotype of polarised human macrophages; however, this performance is impacted by donor variability when analysing the data at a single-cell level. The stratification and parameters emanating from a full field-of-view and single-cell FLIM approach serve as the basis for machine learning models. Applying a random forests model, we identify three strongly governing FLIM parameters, achieving an area under the receiver operating characteristics curve (ROC-AUC) value of 0.944 and out-of-bag (OBB) error rate of 16.67% when classifying human macrophages in a full field-of-view image. To conclude, 2P-FLIM with the integration of machine learning models is showed to be a powerful technique for analysis of both human macrophage metabolism and polarisation at full FoV and single-cell level.

A comprehensive evaluation of pre- and post-processing sperm parameters for predicting successful pregnancy rate following intrauterine insemination with the husband's sperms.

BACKGROUND: To determine the predictive values of sperm parameters pre- and post-processing by density gradient centrifugation for clinical pregnancy rates (CPRs) following artificial insemination by husband (AIH) in infertile Chinese couples. METHODS: A total of 3,522 AIH cycles from 1,918 couples were retrospectively analyzed. The parameters were compared between the pregnant and non-pregnant groups and further between different etiological groups (Male-factor, Both-male-and-female-factor, and Other-factor). Multivariate logistic regression analysis was performed to create models for predicting the CPRs of each etiological group. RESULTS: The overall CPR was 13.3%. There were significant improvements for most sperm parameters after DGC. Multivariate logistic regression analysis indicated that, in overall AIH cases, the top parameters significantly influencing the CPR of AIH were pre-STR (OR = 1.037; P = 0.048) and post-VSL (OR = 1.036; P = 0.011). In the Male-factor Group, the top influencing parameters were pre-VCL (OR = 2.096; P = 0.008), pre-LIN (OR = 1.930; P = 0.002) and post-VSL (OR = 1.316; P = 0.023). In the Both-factor Group, the top influencing parameters were pre-VCL (OR = 1.451; P = 0.008) and post-motility (OR = 1.218; P = 0.049). In the Other-factor Group, the top influencing parameters were pre-VAP (OR = 1.715; P = 0.024), pre-STR (OR = 1.20; P = 0.011) and post-VSL (OR = 1.04; P = 0.017). Moreover, receiver operating characteristic analysis showed that the logistic regression models of the Male- and Both-factor Groups had greater powers for prognostic classification than those of other groups. CONCLUSIONS: This study demonstrated that some sperm parameters have a collinearity relationship in predicting the CPR following AIH. Moreover, the predictive capacity of a multivariate logistic regression model is better than those of individual parameters, especially for the Male- and Both-factor Groups. In these cases, pre-VCL is the common top influencing factor.

The gene regulatory role of non-coding RNAs in non-obstructive azoospermia.

Non-coding RNAs are classified as small non-coding RNAs, long non-coding RNAs and circular RNAs, which are involved in a variety of biological processes, including cell differentiation, proliferation, apoptosis and pathological conditions of various diseases. Many studies have shown that non-coding RNAs are related to spermatogenesis, maturation, apoptosis, function, etc. In addition, the expression of non-coding RNAs in testicular tissue and semen of patients with non-obstructive azoospermia was different. However, the role of non-coding RNAs in the pathogenesis of non-obstructive azoospermia has not been fully elucidated, and the role of non-coding RNAs in non-obstructive azoospermia is rarely reviewed. Here we summarize the research progress of non-coding RNAs in the pathogenesis of non-obstructive azoospermia.

Chronic vitamin D3 supplementation alleviates cognition impairment via inhibition of oxidative stress regulated by PI3K/AKT/Nrf2 in APP/PS1 transgenic mice.

Oxidative stress plays essential role in the pathogenesis of Alzheimer's disease, and vitamin D3 (VD3) is a nutrient with neuroprotective and antioxidant activities. The present study aimed to confirm the neuroprotective effect and the ameliorative effect of cortical oxidative stress of VD3 in APP/PS1 transgenic mice. APP/PS1 mice were treated with VD3 for 20 weeks. After treatment, Morris Water Maze test was used to evaluate cognitive level. Western blotting was used to determine APP, p-tau, tau and PI3K/AKT/Nrf2 pathway-related protein expression levels. Immunohistochemical staining was performed to determine the levels of ß amyloid peptide (Aß) deposition. Enzyme linked immunosorbent assay was used to determine the 25(OH)D3 levels and oxidative stress status. Our results showed that treatment with VD3 ameliorated behavioral deficits of APP/PS1 mice. In addition, the administration of VD3 significantly increased the cortical 25(OH)D3 levels, while reducing the levels of cortical Aß deposition and decreasing the expression levels of cortical APP, tau and p-tau in APP/PS1 mice. Moreover, VD3 protected the cortex against oxidative stress by enhancing the levels of superoxide dismutase, glutathione and total antioxidant capacity, and downregulating the malondialdehyde levels. Furthermore, VD3 clearly activated the PI3K/AKT/Nrf2 pathway, thereby elevating the expression levels of HO1 and NQO1. We concluded that VD3 improved cognitive function and cortical Alzheimer-like pathology of APP/PS1 mice, which may be related to the inhibition of oxidative stress via activation the PI3K/AKT/Nrf2 pathway.

Advanced oxidation protein products upregulate ABCB1 expression and activity via HDAC2-Foxo3α-mediated signaling in vitro and in vivo.

The unpredictable pharmacokinetics of non-renal cleared drugs in chronic kidney disease (CKD) patients is associated with the activity of drug transporters. However, the mechanisms underlying regulation of drug transporters are yet to be established. In this study, we demonstrated the involvement of a HDAC2-Foxo3α pathway in advanced oxidation protein products (AOPPs)-induced ATP-binding cassette subfamily B member 1 (ABCB1) expression and activity. The correlation of AOPPs accumulation with concentration of cyclosporine in plasma was evaluated in 194 patients with transplantation. Molecular changes in acetylation of various histones and related regulatory molecules were examined in HepG2 cell cultures treated with AOPPs. Accumulation of AOPPs in serum in relation to molecular changes in HDAC2-Foxo3α in vivo were evaluated in 5/6 nephrectomy (5/6 nx) and oral adenine (Adenine) CKD rat models. Interestingly, the cyclosporine level was negatively correlated with AOPPs in plasma. In addition, AOPPs markedly suppressed the expression of histone deacetylase 2 (HDAC2), inducing ABCB1 expression and activity in vitro and in vivo. Importantly, AOPPs modulated phosphorylation of Foxo3α and the upstream Akt protein. Our findings indicate that AOPPs regulate the expression and activity of ABCB1 via reducing HDAC2 expression and activating Foxo3α-dependent signaling. The collective results support the utility of AOPPs as a potential target for drug and/or dosage adjustment in CKD patients. Targeting of AOPPs presents a novel approach to regulate non-renal clearance.

Application of Induced Pluripotent Stem Cell-Derived Models for Investigating microRNA Regulation in Developmental Processes.

Advances in induced pluripotent stem cell (iPSC) techniques have opened up new perspectives in research on developmental biology. Compared with other sources of human cellular models, iPSCs present a great advantage in hosting the unique genotype background of donors without ethical concerns. A wide spectrum of cellular and organoid models can be generated from iPSCs under appropriate in vitro conditions. The pluripotency of iPSCs is orchestrated by external signalling and regulated at the epigenetic, transcriptional and posttranscriptional levels. Recent decades have witnessed the progress of studying tissue-specific expressions and functions of microRNAs (miRNAs) using iPSC-derived models. MiRNAs are a class of short non-coding RNAs with regulatory functions in various biological processes during development, including cell migration, proliferation and apoptosis. MiRNAs are key modulators of gene expression and promising candidates for biomarker in development; hence, research on the regulation of human development by miRNAs is expanding. In this review, we summarize the current progress in the application of iPSC-derived models to studies of the regulatory roles of miRNAs in developmental processes.

Sperm DNA integrity is critically impacted by male age but does not influence outcomes of artificial insemination by husband in the Chinese infertile couples.

The sperm chromatin structure assay (SCSA) is crucial for assessing male fertility. However, the predictive value of the SCSA parameters, including the DNA fragment indices (DFI) and the percentages of high DNA stainability (HDS), for outcomes of artificial insemination by husband (AIH) remains controversial. This study aims to evaluate the correlations between SCSA parameters and male aging as well as other routine semen parameters, and explore their prognostic powers on AIH outcomes of the Chinese infertile couples. A total of 809 AIH cycles were retrospectively analyzed. The results showed that DFI in the age groups < 35 years were significantly lower than that in the age groups ≥ 35 years (P < 0.001). Meanwhile, there was no statistical difference in HDS between the age groups (P = 0.063). DFI and HDS are negatively correlated with most routine semen parameters (all P < 0.05). The chi-square and generalized linear model tests indicated that neither DFI nor HDS influenced the clinical pregnancy rate of AIH. In summary, this study found that aging is a critical factor leading to increased sperm DFI but not HDS. DFI and HDS are negatively correlated with most semen parameters but do not significantly influence AIH outcomes.

The Relationship of 25(OH)D3 with Diabetes Mellitus and the Mediation Effect of Lipid Profile in Chinese Rural Population of Henan Province.

Background and Objectives: Studies suggest that vitamin D is involved in the development of type 2 diabetes mellitus (T2DM) and influences serum lipids levels, while lipid disorders are also closely related to T2DM. This study attempts to explore the complex relationship of serum 25(OH)D3, serum lipids, and T2DM among Chinese population. Materials and Methods: A cross-sectional study was carried out among 2326 subjects. The chi-square (χ2) test was applied to compare the prevalence of T2DM or dyslipidemia between two serum 25(OH)D3 levels. Linear regression was applied to analyze the correlation between serum lipids and 25(OH)D3 contents. Univariate and logistic analysis were used to explore the relationship between two lipid levels and T2DM. Mediation analysis was used to explore whether serum lipids mediate the relationship between two serum 25(OH)D3 levels and T2DM. Results: Compared to subjects with 25(OH)D3 ≥ 30 ng/mL, subjects with 25(OH)D3 < 30 ng/mL were higher in the prevalence of T2DM. The occurrences of high TG and low HDL-C were significantly higher in vitamin D deficiency and insufficiency than those in vitamin D sufficiency. Serum 25(OH)D3 content showed a reverse correlation with TC, TG, and LDL-C, but positive correlation with HDL-C. The odds ratios (ORs) (95% confidence intervals, 95%CI) of T2DM by comparing TG ≥ 2.26 mmol/L vs. TG < 2.26 mmol/L and HDL-C < 1.04 mmol/L vs. HDL-C ≥ 1.04 mmol/L in all participants were 2.48 (1.94-3.18) and 1.37 (1.07-1.75), respectively. Serum TG or HDL-C level partially mediated the relationship between two 25(OH)D3 level and T2DM. Conclusions: Serum 25(OH)D3 < 30 ng/mL seems to be associated with T2DM or dyslipidemia (high TG and low HDL-C) in our study, but there is still no proof of a cause-effect relationship. Moreover, serum TG or HDL-C level partially mediated the relationship between 25(OH)D3 levels and T2DM.