Overexpression of PD-L1 causes germ cell failure and infertility via CRISP1/PD-L1 interaction in mouse epididymis.

Spermatogenesis is a highly complex process through which mature sperms are produced, and it requires three important stages; mitosis, meiosis and sperm formation. The expression of genes regulated by transcription factors at specific stages exerts important regulatory effects on the development process of germ cells. Male mice with overexpressed programmed death ligand 1 (PD-L1) (B7 homolog1) in the testis have infertility and abnormal sperm development, thereby exhibiting severe malformation and sloughing throughout spermatid maturation and collapsed and disorganized seminiferous epithelium structure. Furthermore, PD-L1 overexpression causes overexpression of cysteine-rich secretory protein 1 (CRISP1) in the epididymis and adversely affects or precludes sperm energization, sperm-pellucida binding and sperm-oocyte fusion. These findings suggest that CRISP1 and PD-L1 can interact with each other to induce male infertility and germ-cell dissociation.

Overexpression of PD-L1 causes germ cells to slough from mouse seminiferous tubules via the PD-L1/PD-L1 interaction.

Spermatogenesis is a cyclical process in which different generations of spermatids undergo a series of developmental steps at a fixed time and finally produce spermatids. Here, we report that overexpression of PD-L1 (B7 homolog1) in the testis causes sperm developmental disorders and infertility in male mice, with severe malformation and sloughing during spermatid development, characterized by disorganized and collapsed seminiferous epithelium structure. PD-L1 needs to be simultaneously expressed on Sertoli cells and spermatogonia to cause spermatogenesis failure. After that, we excluded the influence of factors such as the PD-L1 receptor and humoral regulation, confirming that PD-L1 has an intrinsic function to interact with PD-L1. Studies have shown that PD-L1 not only serves as a ligand but also plays a receptor-like role in signal transduction. PD-L1 interacts with PD-L1 to affect the adhesive function of germ cells, causing malformation and spermatid sloughing. Taken together, these results indicate that PD-L1 can interact with PD-L1 to cause germ cell detachment and male infertility.

Exhausted Cr(VI) Sensing/Removal Aerogels Are Recycled for Water Purification and Solar-Thermal Energy Generation.

Heavy metal pollution has resulted in numerous environmental challenges. However, classic approaches, involving the use of solid adsorbents are subject to limitations, including the high energy consumption required for processing before and after use. Accordingly, strategies that facilitate the use of metal capture media that extends beyond waste remediation are attractive. Herein, a porous fluorescent aerogel (CPC aerogel) is constructed by immersing amino-based carbon dots (CDs-NH2 ) into a polyethyleneimine (PEI)/carboxymethylated cellulose (CMC) aerogel network for the simultaneous detection and adsorption of Cr(VI). Adsorption experiments confirm that the CMC/PEI containing CDs-NH2 aerogel (CPC aerogel) exhibits good Cr(VI) extraction capacity, and can reach a level that conforms with industrial water safety standards. In addition, the CPC aerogel can continuously detect and remove Cr(VI) at high flux. Following Cr(VI) absorption, the CPC aerogel may be vulcanized (MSx -CPC gel) and used for solar thermoelectric generation resulting in power generation. Additionally, the MSx -CPC gel can be used for solar steam generation and exhibits excellent evaporation rates of ≈1.31 kg m-2 h-1 under one sun irradiation. The results serve to underscore how materials designed for metal ion recognition and adsorption once exhausted can be exploited to provide materials for solar thermoelectric power generation and seawater desalination.

Reclaimable MoS2 Sponge Absorbent for Drinking Water Purification Driven by Solar Energy.

With the fast development of modern industries, scarcity of freshwater resources caused by heavy metal pollution (i.e., Hg2+) has become a severe issue for human beings. Herein, a 3D-MoS2 sponge as an excellent absorbent is fabricated for mercury removal due to its multidimensional adsorption pathways, which decreases the biomagnification effect of methylmercury in water bodies. Furthermore, a secondary water purification strategy is employed to harvest drinkable water with the exhausted adsorbents, thus alleviating the crisis of drinking water shortage. Compared to the conventional landfill treatment, the exhausted MoS2 sponge absorbents are further functionalized with a poly(ethylene glycol) (PEG) layer to prevent the heavy metals from leaking and enhance the hydrophilicity for photothermal conversion. The fabricated evaporator displays excellent evaporation rates of ∼1.45 kg m-2 h-1 under sunlight irradiation and produces freshwater with Hg2+ under the WHO drinking water standard at 0.001 mg L-1. These results not only assist in avoiding the biodeposition effect of mercury in water but also provide an environment-friendly strategy to recycle hazardous adsorbents for water purification.

MiR-671-5p plays a promising role in restraining osteosarcoma cell characteristics through targeting TUFT1.

The aim of our study was to explore the roles of miR-671-5p in mediating biological processes of osteosarcoma (OS) cells and clinical implications. On the basis of the OS samples acquired from the GEO database, the expression difference and overall survival analyses of miR-671-5p and TUFT1 were determined. The expression of MiR-671-5p was verified using OS cell lines. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound-healing, and Transwell assays were respectively carried out to probe whether miR-671-5p regulated OS cell vitality, migration, and invasion. The expression of miR-671-5p was downregulated in OS tissues and cell lines. High expression of MiR-671-5p blocked OS cell growth, migration, and invasion. TUFT1 was predicted and validated as the target of miR-671-5p in OS cells using in silico analysis and luciferase reporter assays. Forced expression of TUFT1 reversed the suppressive influence of miR-671-5p on cell viability, migration, and invasion of OS cells. Moreover, the low expression of miR-671-5p and the high expression of TUFT1 led to poor prognosis. Taken together, targeting miR-671-5p/TUFT1 may be a promising strategy for treating OS.

MiR-320a was highly expressed in postmenopausal osteoporosis and acts as a negative regulator in MC3T3E1 cells by reducing MAP9 and inhibiting PI3K/AKT signaling pathway.

BACKGROUND: Postmenopausal osteoporosis (PMO), as a frequent disease in postmenopausal women, is mainly caused by the lack of estrogen. MiR-320a has been found to abate osteoblast function and induce oxidative stress before osteoporosis. However, studies on the downstream target gene and related signaling pathway of miR-320a in PMO are still obscure. This study aims to deal with these problems. METHODS: The expression levels of miR-320a and microtubule-associated protein 9 (MAP9) in patients with osteoporosis were analyzed on the basis of the GEO database. The cells viability was determined by methylthiazolyl tetrazolium bromide (MTT). Flow cytometry and western blot were used to detect the cells apoptosis and the expression of apoptosis-related proteins, respectively. The cells differentiation-related proteins were detected by qRT-PCR and western blot. The interaction between miR-320a and MAP9 was predicted by biological software and verified by dual luciferase reporter assay and rescue assay. The expression levels of PI3K, p-PI3K, AKT and p-AKT in MC3T3-E1 cells were assessed by western blot. RESULTS: We observed that miR-320a was over-expressed in PMO patients and exhibited inhibitory effects on MC3T3-E1 cells activity and differentiation, as well as promoting effects on MC3T3-E1 cells apoptosis. MAP9 was verified as a target gene of miR-320a and was negatively regulated by miR-320a. Based on the GEO database, MAP9 was found to be lower expressed in PMO patients. Rescue assay demonstrated that down-regulation of MAP9 could alleviate the promoting effects of miR-320a inhibitor on MC3T3-E1 cells activity and differentiation and the inhibitory effects of miR-320a inhibitor on MC3T3-E1 cells apoptosis. Mechanically, miR-320a/MAP9 possibly took part in MC3T3-E1 cells viability, differentiation and apoptosis via mediating PI3K/AKT signaling pathway. CONCLUSIONS: Our outcomes demonstrated that miR-320a promoted MC3T3-E1 cells apoptosis, suppressed MC3T3-E1 cells viability and differentiation through targeting MAP9 and modulating PI3K/AKT signaling pathway, which provided theoretical support for miR-320a/MAP9 as promising targets for the treatment and prevention of PMO.

Cyclane-aminol 10-hydroxycamptothecin analogs as novel DNA topoisomerase I inhibitors induce apoptosis selectively in tumor cells.

A novel series of cyclane-aminol 10-hydroxycamptothecin (HCPT) analogs was designed and synthesized through the Mannich reaction using HCPT as the lead compound, such as 10-hydroxyl-9-L-prolinol (+) methylcamptothecin (PRPT), 10-hydroxyl-9-(4'-hydroxy) piperidinylmethylcamptothecin (PPPT), and 10-hydroxy-9-(4'-hydroxyethyl)-piperazinylmethycamptothecin (QPPT). Three kinds of new cyclane-aminols were introduced into the structure of HCPT, which modified strong cytotoxic HCPT into cyclane-aminol HCPT analogs with moderate cytotoxicity and improved selectivity toward DNA topoisomerase I inhibition in tumor cells. Special metabolic pathways for cyclane-aminol HCPT analogs in rats were discovered, which differed from other HCPT analogs. Cyclane-aminol HCPT analogs can capture O2 and cause an increase in intracellular hydrogen peroxide levels with selective induction of apoptosis in tumor cells rather than in normal peripheral blood mononuclear cells. Among them, PPPT has a much better druggability than topotecan (TPT) and has the potential to be developed into an antitumor agent.

Surface engineering of pure magnesium in medical implant applications.

This review comprehensively surveys the latest advancements in surface modification of pure magnesium (Mg) in recent years, with a focus on various cost-effective procedures, comparative analyses, and assessments of outcomes, addressing the merits and drawbacks of pure Mg and its alloys. Diverse economically feasible methods for surface modification, such as hydrothermal processes and ultrasonic micro-arc oxidation (UMAO), are discussed, emphasizing their exceptional performance in enhancing surface properties. The attention is directed towards the biocompatibility and corrosion resistance of pure Mg, underscoring the remarkable efficacy of techniques such as Ca-deficientca-deficient hydroxyapatite (CDHA)/MgF2 bi-layer coating and UMAO coating in electrochemical processes. These methods open up novel avenues for the application of pure Mg in medical implants. Emphasis is placed on the significance of adhering to the principles of reinforcing the foundation and addressing the source. The advocacy is for a judicious approach to corrosion protection on high-purity Mg surfaces, aiming to optimize the overall mechanical performance. Lastly, a call is made for future in-depth investigations into areas such as composite coatings and the biodegradation mechanisms of pure Mg surfaces, aiming to propel the field towards more sustainable and innovative developments.

Revisiting the intersection of microglial activation and neuroinflammation in Alzheimer's disease from the perspective of ferroptosis.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic neuroinflammation with amyloid beta-protein deposition and hyperphosphorylated tau protein. The typical clinical manifestation of AD is progressive memory impairment, and AD is considered a multifactorial disease with various etiologies (genetic factors, aging, lifestyle, etc.) and complicated pathophysiological processes. Previous research identified that neuroinflammation and typical microglial activation are significant mechanisms underlying AD, resulting in dysfunction of the nervous system and progression of the disease. Ferroptosis is a novel modality involved in this process. As an iron-dependent form of cell death, ferroptosis, characterized by iron accumulation, lipid peroxidation, and irreversible plasma membrane disruption, promotes AD by accelerating neuronal dysfunction and abnormal microglial activation. In this case, disturbances in brain iron homeostasis and neuronal ferroptosis aggravate neuroinflammation and lead to the abnormal activation of microglia. Abnormally activated microglia release various pro-inflammatory factors that aggravate the dysregulation of iron homeostasis and neuroinflammation, forming a vicious cycle. In this review, we first introduce ferroptosis, microglia, AD, and their relationship. Second, we discuss the nonnegligible role of ferroptosis in the abnormal microglial activation involved in the chronic neuroinflammation of AD to provide new ideas for the identification of potential therapeutic targets for AD.

Triptolide enhances carboplatin-induced apoptosis by inhibiting nucleotide excision repair (NER) activity in melanoma.

Introduction: Carboplatin (CBP) is a DNA damaging drug used to treat various cancers, including advanced melanoma. Yet we still face low response rates and short survival due to resistance. Triptolide (TPL) is considered to have multifunctional antitumor effects and has been confirmed to enhance the cytotoxic effects of chemotherapeutic drugs. Herein, we aimed to investigate the knowledge about the effects and mechanisms for the combined application of TPL and CBP against melanoma. Methods: Melanoma cell lines and xenograft mouse model were used to uncover the antitumor effects and the underlying molecular mechanisms of the alone or combined treatment of TPL and CBP in melanoma. Cell viability, migration, invasion, apoptosis, and DNA damage were detected by conventional methods. The rate-limiting proteins of the NER pathway were quantitated using PCR and Western blot. Fluorescent reporter plasmids were used to test the NER repair capacity. Results: Our results showed that the presence of TPL in CBP treatment could selectively inhibit NER pathway activity, and TPL exerts a synergistic effect with CBP to inhibit viability, migration, invasion, and induce apoptosis of A375 and B16 cells. Moreover, combined treatment with TPL and CBP significantly inhibited tumor progression in nude mice by suppressing cell proliferation and inducing apoptosis. Discussion: This study reveals the NER inhibitor TPL which has great potential in treating melanoma, either alone or in combination with CBP.

Schisandrin B Alleviates Diabetic Cardiac Autonomic neuropathy Induced by P2X7 Receptor in Superior Cervical Ganglion via NLRP3.

Diabetic cardiovascular autonomic neuropathy (DCAN) is a common complication of diabetes mellitus which brings about high mortality, high morbidity, and large economic burden to the society. Compensatory tachycardia after myocardial ischemia caused by DCAN can increase myocardial injury and result in more damage to the cardiac function. The inflammation induced by hyperglycemia can increase P2X7 receptor expression in the superior cervical ganglion (SCG), resulting in nerve damage. It is proved that inhibiting the expression of P2X7 receptor at the superior cervical ganglion can ameliorate the nociceptive signaling dysregulation induced by DCAN. However, the effective drug used for decreasing P2X7 receptor expression has not been found. Schisandrin B is a traditional Chinese medicine, which has anti-inflammatory and antioxidant effects. Whether Schisandrin B can decrease the expression of P2X7 receptor in diabetic rats to protect the cardiovascular system was investigated in this study. After diabetic model rats were made, Schisandrin B and shRNA of P2X7 receptor were given to different groups to verify the impact of Schisandrin B on the expression of P2X7 receptor. Pathological blood pressure, heart rate, heart rate variability, and sympathetic nerve discharge were ameliorated after administration of Schisandrin B. Moreover, the upregulated protein level of P2X7 receptor, NLRP3 inflammasomes, and interleukin-1ß in diabetic rats were decreased after treatment, which indicates that Schisandrin B can alleviate the chronic inflammation caused by diabetes and decrease the expression levels of P2X7 via NLRP3. These findings suggest that Schisandrin B can be a potential therapeutical agent for DCAN.

Analysis of the Molecular Mechanism of Punicalagin in the Treatment of Alzheimer's Disease by Computer-Aided Drug Research Technology.

The objective of this work is to explore the effect and potential mechanism of Punicalagin (Pun) in managing Alzheimer's disease (AD) based on computer-aided drug technology. The following methods were used: the intersection genes of Pun and AD were retrieved from the database and subjected to PPI analysis, GO, and KEGG enrichment analyses. Preliminary verification was performed by molecular docking, molecular dynamics (MD) simulation, and combined free energy calculation. The motor coordination and balance ability, anxiety degree, spatial learning, and memory ability of mice were measured by a rotating rod fatigue instrument, elevated cross maze, and Y maze, respectively. The amyloid ß protein (Aß) in the hippocampus was examined by immunohistochemistry, and the phosphorylation of serine at position 404 of the tau protein (Tau-pS404) was examined by western blot in the mouse brain. The PPI network of Pun showed that the intersection genes were closely related and enriched in muscle cell proliferation and the response to lipopolysaccharide. Results of molecular docking, MD simulations, and MM-GBSA demonstrated that Pun was closely bound to the target protein. Pun could improve the cognitive function of AD mice, as well as reduce Aß1-42 deposition and Tau phosphorylation in the brain (P < 0.05, P < 0.01). It can be concluded that Pun holds great promise in improving the cognitive function of AD mice. Mechanistically, Pun potentially acts on ALB, AKT1, SRC, EGFR, CASP3, and IGF-1 targets and mediates proteoglycan, lipid, and atherosclerosis in cancer, so as to reduce the accumulation of neurotoxic proteins in the brain.

Naringin Relieves Diabetic Cardiac Autonomic Neuropathy Mediated by P2Y14 Receptor in Superior Cervical Ganglion.

Diabetes mellitus (DM), an emerging chronic epidemic, contributes to mortality and morbidity around the world. Diabetic cardiac autonomic neuropathy (DCAN) is one of the most common complications associated with DM. Previous studies have shown that satellite glial cells (SGCs) in the superior cervical ganglia (SCG) play an indispensable role in DCAN progression. In addition, it has been shown that purinergic neurotransmitters, as well as metabotropic GPCRs, are involved in the pathophysiological process of DCAN. Furthermore, one traditional Chinese medicine, naringin may potently alleviate the effects of DCAN. Ferroptosis may be involved in DCAN progression. However, the role of naringin in DCAN as well as its detailed mechanism requires further investigation. In this research, we attempted to identify the effect and relevant mechanism of naringin in DCAN mitigation. We observed that compared with those of normal subjects, there were significantly elevated expression levels of P2Y14 and IL-1ß in diabetic rats, both of which were remarkably diminished by treatment with either P2Y14 shRNA or naringin. In addition, abnormalities in blood pressure (BP), heart rate (HR), heart rate variability (HRV), sympathetic nerve discharge (SND), and cardiac structure in the diabetic model can also be partially returned to normal through the use of those treatments. Furthermore, a reduced expression of NRF2 and GPX4, as well as an elevated level of ROS, were detected in diabetic cases, which can also be improved with those treatments. Our results showed that naringin can effectively relieve DCAN mediated by the P2Y14 receptor of SGCs in the SCG. Moreover, the NRF2/GPX4 pathway involved in ferroptosis may become one of the principal mechanisms participating in DCAN progression, which can be modulated by P2Y14-targeted naringin and thus relieve DCAN. Hopefully, our research can supply one novel therapeutic target and provide a brilliant perspective for the treatment of DCAN.

LncRNA-UC.25 + shRNA Alleviates P2Y14 Receptor-Mediated Diabetic Neuropathic Pain via STAT1.

Diabetic neuropathic pain (DNP) is a common complication of diabetes, and its complicated pathogenesis, as well as clinical manifestations, has brought great trouble to clinical treatment. The spinal cord is an important part of regulating the occurrence and development of DNP. Spinal microglia can regulate the activity of spinal cord neurons and have a regulatory effect on chronic pain. P2Y12 receptor is involved in DNP. P2Y14 and P2Y12 receptors belong to the Gi subtype of P2Y receptors, but there is no report that the P2Y14 receptor is involved in DNP. Closely related to many human diseases, the dysregulation of long noncoding RNA (lncRNA) has the effect of promoting or inhibiting the occurrence and development of diseases. The aim of this research is to investigate the function of the spinal cord P2Y14 receptor in type 2 DNP and to understand the function as well as the possible mechanism of lncRNA-UC.25 + (UC.25 +) in rat spinal cord P2Y14 receptor-mediated DNP. Our results showed that P2Y14 shRNA can reduce the expression of P2Y14 in DNP rats, thereby restraining the activation of microglia, decreasing the expression of inflammatory factors and the level of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation. At the same time, UC.25 + shRNA can downregulate the expression of the P2Y14 receptor, reduce the release of inflammatory factors, and diminish the p38 MAPK phosphorylation, indicating that UC.25 + can alleviate spinal cord P2Y14 receptor-mediated DNP. The RNA immunoprecipitation result showed that UC.25 + enriched signal transducers and activators of transcription1 (STAT1) and positively regulated its expression. The chromatin immunoprecipitation result indicated that STAT1 combined with the promoter region of the P2Y14 receptor and positively regulated the expression of the P2Y14 receptor. Therefore, we infer that UC.25 + may alleviate DNP in rats by regulating the expression of the P2Y14 receptor in spinal microglia via STAT1.

LncRNA HOTAIRM1, miR-433-5p and PIK3CD function as a ceRNA network to exacerbate the development of PCOS.

BACKGROUND: Currently, several non-coding RNAs (ncRNAs) were distinguished in polycystic ovarian syndrome (PCOS). This present study aims to explore the potential function of lncRNA HOTAIRM1/miR-433-5p/PIK3CD in ovarian granulosa cells. METHODS: We analyzed the expression profiles of HOTAIRM1, miR-433-5p and PIK3CD in PCOS samples by enquiring GEO database. GSEA was applied to enrich the pathways related to PCOS. The target association between HOTAIRM1 and miR-433-5p or the binding association between miR-433-5p and PIK3CD were assessed by online prediction tools and a dual luciferase reporter assay. qPCR and western blotting assays were used to detect PIK3CD expression after HOTAIRM1 and miR-433-5p treatment. The proliferation and apoptosis of ovarian granulosa cells were estimated by cell counting kit-8 and flow cytometry assays, respectively. RESULTS: The expression profiles of HOTAIRM1 and PIK3CD were increased, whereas miR-433-5p was decreased in PCOS tissues. PIK3CD expression was positively regulated by HOTAIRM1 and negatively modulated by miR-433-5p. Overexpression of HOTAIRM1 reduced the proliferative ability and increased the apoptotic ability of granulosa cells, whereas upregulation of miR-433-5p or downregulation of PIK3CD reversed the effects of HOTAIRM1 on granulosa cells. Moreover, overexpression of miR-433-5 displayed a results with increasing proliferative ability and decreasing apoptotic ability, but upregulation of PIK3CD eliminated the function of miR-433-5p on granulosa cells. CONCLUSIONS: Our findings illustrated that HOTAIRM1 could sponge miR-433-5p to promote PIK3CD expression, thereby regulating the growth and apoptosis of granulose cells in PCOS.

Neferine alleviates P2X3 receptor in rat dorsal root ganglia mediated neuropathic pain.

Chronic neuropathic pain is caused by tissue damage or nervous system inflammation and is characterized by sensitivity to painful stimuli. P2X3 receptors play an important role in facilitating pain transmission. Neferine is a bisbenzylisoquinline alkaloid isolated from seed embryos of lotus, which has anti-inflammatory and anti-oxidation pharmacological functions. The present research investigated whether neferine relieves neuropathic pain related to the P2X3 receptor in rat dorsal root ganglia (DRGs). Chronic contraction injury (CCI) in rats was used as a model for neuropathic pain. The results indicated that the expression of P2X3 receptor was significantly increased in the DRGs of CCI rats and that mechanical allodynia and thermal hyperalgesia were also enhanced in CCI rats. Neferine markedly lowered the upregulated P2X3 receptor and interleukin-1beta, inhibited the phosphorylation and activation of ERK1/2 in the DRGs of CCI rats, and relieved neuropathic pain. Therefore, neferine alleviates neuropathic pain by downregulating the expression of P2X3 receptor.

LncRNA SNHG6/miR-125b-5p/BMPR1B Axis: A New Therapeutic Target for Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a significant cause of patient morbidity. The exactly pathobiological features of this condition has yet to be completely elucidated. METHODS: Breast cancer data obtained from The Cancer Genome Atlas (TCGA) database were evaluated for lncRNA SNHG6 expression. Normal human breast epithelial cell line (MCF-10A) and other breast cancer cell lines (BT-549, MDA-MB-231, Hs 578t, ZR-75-30, SK-BR-3, MCF-7) were also assessed for lncRNA SNHG6 expressions. Cellular proliferative ability was evaluated with colony formation and CCK-8 assays. The ability of cells to migrate was scrutinized with the wound healing and Boyden chamber cell migration assays. qRT-PCR enabled for detection of lncRNA SNHG6, miR-125b-5p and BMPR1B mRNA expressions. Protein BMPR1B expressions were further assessed using Western Blotting. Direct binding sites between transcripts were determined using dual-luciferase reporter assays. We also constructed a xenograft mouse model to further dissect the vivo implications of lncRNA SNHG6. Ki-67 and c-Caspase-3 expressions were detected using immunohistochemistry staining. RESULTS: Breast cancer cell lines demonstrated higher lncRNA SNHG6 expressions, particularly TNBC cell lines, in contrast to normal breast epithelial cell lines. This finding coincided with those noted on analysis of TCGA breast cancer data. lncRNA SNHG6 knockdown inhibited TNBC cell proliferation, migration, while promoted cell apoptosis. Furthermore, suppressed lncRNA SNHG6 expressions resulted in lower tumor weights and volumes in a xenograft mouse model, as evidenced by Ki-67 and c-Caspase-3 expression profiles in tumor tissues. miR-125b-5p and lncRNA SNHG6/BMPR1B both possessed direct binding sites for each other which was validated utilizing a dual-luciferase reporter assay. Decreasing lncRNA SNHG6 expression in TNBC cells upregulated miR-125b-5p expression. Another side, inhibiting miR-125b-5p upregulated BMPR1B expression in these cells. Moreover, knocking down lncRNA SNHG6 downregulated BMPR1B expression in TNBC cells, and the finding was rescued in cells which were exposed to miR-125b-5p inhibitor. Downregulating miR-125b-5p mitigated the effect of suppressing lncRNA SNHG6 on TNBC cell proliferation, migration, and apoptosis. CONCLUSION: Downregulation of lncRNA SNHG6 could inhibit TNBC cell proliferative, migratory capabilities and promote apoptosis capability, likely through modulation of the miR-125b-5p/BMPR1B axis. This axis may be targeted in formulating new therapies for TNBC.

LINK-A lncRNA is upregulated in osteosarcoma and regulates migration, invasion and stemness of osteosarcoma cells.

The present study aimed to investigate the involvement of long intergenic non-coding RNA for kinase activation (LINK-A) long non-coding RNA (lncRNA) in osteosarcoma. Plasma levels of LINK-A lncRNA and transforming growth factor ß1 (TGF-ß1) were measured by reverse transcription-quantitative polymerase chain reaction and ELISA, respectively. Correlation between LINK-A lncRNA and TGF-ß1 was analyzed by Pearson correlation coefficient. LINK-A lncRNA and TGF-ß1 were upregulated in patients with osteosarcoma compared with healthy controls. LINK-A lncRNA and TGF-ß1 were positively correlated in the two groups. LINK-A lncRNA short hairpin RNAs (shRNAs) were transfected into osteosarcoma cell lines and Transwell migration assay, Matrigel invasion assay and flow cytometry were used to evaluate cell migration, invasion and stemness, respectively. Effects of LINK-A lncRNA silencing and overexpression on TGF-ß1 expression were analyzed by western blotting. LINK-A lncRNA shRNA silencing inhibited, whereas TGF-ß1 treatment promoted cell migration, invasion and stemness. LINK-A lncRNA silencing inhibited TGF-ß1 expression, whereas TGF-ß1 treatment had no effects on LINK-A lncRNA expression. TGF-ß1 reduced the inhibitory effects of LINK-A lncRNA knockdown on cancer cell migration, invasion and stemness. These data indicated that LINK-A lncRNA is upregulated in osteosarcoma and may regulate migration, invasion and stemness of osteosarcoma cells through TGF-ß1.

Astragaloside IV ameliorates high glucose-induced HK-2 cell apoptosis and oxidative stress by regulating the Nrf2/ARE signaling pathway.

Diabetic nephropathy (DN) has become the major cause of end-stage renal disease increasing the mortality risk of diabetes. Research has demonstrated that the oxidative damage and apoptosis of renal tubular cells is present during DN. Astragaloside IV (AS-IV) has been widely used for the treatment of many diseases, however, the role and mechanism by which AS-IV may ameliorate high glucose-induced apoptosis and oxidative stress of the human proximal tubular cell line HK-2 remains largely unknown. The present study investigated the effect of AS-IV on high glucose-induced apoptosis and oxidative stress in HK-2 cells. Cell viability, apoptosis and protein expression were detected by Trypan blue staining, Cell Counting Kit-8 assay, terminal deoxynucleotidyl transferase 2'-deoxyuridine-5'-triphosphate nick-end labelling, flow cytometry and western blot analyses. In addition, enzymatic activities, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and lipid peroxide (LPO), were measured with the corresponding detection kits. DCFH-DA assay and flow cytometry were performed to detect the production of reactive oxygen species (ROS). Western blot analysis and reverse transcription-quantitative polymerase chain reaction were conducted to evaluate protein and mRNA expressions of the nuclear factor erythroid 2 like 2 (Nrf2)/antioxidant response element (ARE) signaling pathway. The results demonstrated that AS-IV significantly enhanced HK-2 cell viability induced by high glucose in a dose-dependent manner. In addition, AS-IV notably inhibited HK-2 cell apoptosis stimulated by high glucose, which may be associated with inhibition of BCL2 associated X protein, Cleaved-caspase-3 and Cleaved-caspase-9, expression and the promotion of Bcl-2. AS-IV significantly increased the activities of antioxidant enzymes SOD, GSH-Px and CAT, and decreased the high-glucose-induced ROS production in HK-2 cells, in a dose-dependent manner. Finally, it was determined that AS-IV regulated the Nrf2/ARE signaling pathway and inhibited the expression of liver-type fatty acid binding protein. In conclusion, these findings may provide evidence that AS-IV has a potential role for the treatment of DN.

Characteristics of gut microbiota and its response to a Chinese Herbal Formula in elder patients with metabolic syndrome.

Alterations in gut microbiota have been known to play a critical role in metabolic syndrome. However, the microbial features in elderly patients with metabolic syndrome remain unclear. A traditional Chinese Herbal Formula, Yangyin Tiluo Decoction (YTD), can alleviate metabolic syndrome and cardiovascular disease. To characterize gut microbiota in elder patients and effects of YTD on gut microbiota during treatment of metabolic syndrome, 11 healthy elderly persons and 12 elderly persons (aged 60-90 years) with metabolic syndrome were enrolled. The patients were randomly assigned to receive YTD for 4 weeks (200 mL of the decoction two times daily). The microbial composition in healthy control, pre- and post- YTD treatment group were analyzed by 16S rRNA sequencing of fecal DNAs. Biochemical measurements were conducted for elderly patients. The results showed a high inter-individual variation of gut microbiota in elderly persons. The gut microbiota was dominated by phylum Firmicutes and Actinobacteria, which was distinct from the previously defined microbiota in Irish elderly persons. The elderly patients with metabolic syndrome had higher proportions of Lactobacillus and Bifidobacterium, and lower proportions of Anaerostipes, Coprococcus, Ruminococcus than healthy controls. YTD treatment reduced the abundance of genus Bacteroidales Incertae Sedis and species Enterobacteriaceae Incertae Sedis. The concentration of plasma lipoprotein (a) was also reduced, which was negatively correlated with the abundance of an Acinetobacter species. These results reveal a remarkable dominance of Firmicutes and Actinobacteria, and highlight the distinct gut microbiota in elderly patients with metabolic syndrome, which may be involved in pathogenesis. Furthermore, the benefits of YTD treatment were observed, providing an approach to improve metabolic syndrome in elderly patients.