Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis.

Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.

Curcumin nicotinate increases LDL cholesterol uptake in hepatocytes through IDOL/LDL-R pathway regulation.

BACKGROUND: Curcumin nicotinate (Curtn), derived from curcumin and niacin, reduces serum LDL-C levels, partly due to its influence on PCSK9. This study investigates IDOL's role in Curtn's lipid-lowering effects. OBJECTIVE: To elucidate Curtn's regulation of the IDOL/LDLR pathway and potential molecular mechanisms in hepatocytes. METHODS: Differential metabolites in Curtn-treated HepG2 cells were identified via LC-MS. Molecular docking assessed Curtn's affinity with IDOL. Cholesterol content and LDLR expression effects were studied in high-fat diet Wistar rats. In vitro evaluations determined Curtn's influence on IDOL overexpression's LDL-C uptake and LDLR expression in hepatocytes. RESULTS: Lipids were the main differential metabolites in Curtn-treated HepG2 cells. Docking showed Curtn's higher affinity to IDOL's FERM domain compared to curcumin, suggesting potential competitive inhibition of IDOL's binding to LDLR. Curtn decreased liver cholesterol in Wistar rats and elevated LDLR expression. During in vitro experiments, Curtn significantly enhanced the effects of IDOL overexpression in HepG2 cells, leading to increased LDL-C uptake and elevated expression of LDL receptors. CONCLUSION: Curtn modulates the IDOL/LDLR pathway, enhancing LDL cholesterol uptake in hepatocytes. Combined with its PCSK9 influence, Curtn emerges as a potential hyperlipidemia therapy.

Research progress on the mechanism of glycolysis in ovarian cancer.

Glycolysis is the preferred energy metabolism pathway in cancer cells even when the oxygen content is sufficient. Through glycolysis, cancer cells convert glucose into pyruvic acid and then lactate to rapidly produce energy and promote cancer progression. Changes in glycolysis activity play a crucial role in the biosynthesis and energy requirements of cancer cells needed to maintain growth and metastasis. This review focuses on ovarian cancer and the significance of key rate-limiting enzymes (hexokinase, phosphofructokinase, and pyruvate kinase, related signaling pathways (PI3K-AKT, Wnt, MAPK, AMPK), transcription regulators (HIF-1a), and non-coding RNA in the glycolytic pathway. Understanding the relationship between glycolysis and these different mechanisms may provide new opportunities for the future treatment of ovarian cancer.

MicroRNA-148a-3p in pericyte-derived extracellular vesicles improves erectile function in diabetic mice by promoting cavernous neurovascular regeneration.

BACKGROUND: To investigate the regulatory role of microRNA (miR)-148a-3p in mouse corpus cavernous pericyte (MCPs)-derived extracellular vesicles (EVs) in the treatment of diabetes-induced erectile dysfunction (ED). METHODS: Mouse corpus cavernous tissue was used for MCP primary culture and EV isolation. Small-RNA sequencing analysis was performed to assess the type and content of miRs in MCPs-EVs. Four groups of mice were used: control nondiabetic mice and streptozotocin-induced diabetic mice receiving two intracavernous injections (days - 3 and 0) of phosphate buffered saline, MCPs-EVs transfected with reagent control, or MCPs-EVs transfected with a miR-148a-3p inhibitor. miR-148a-3p function in MCPs-EVs was evaluated by tube-formation assay, migration assay, TUNEL assay, intracavernous pressure, immunofluorescence staining, and Western blotting. RESULTS: We extracted EVs from MCPs, and small-RNA sequencing analysis showed miR-148a-3p enrichment in MCPs-EVs. Exogenous MCPs-EV administration effectively promoted mouse cavernous endothelial cell (MCECs) tube formation, migration, and proliferation, and reduced MCECs apoptosis under high-glucose conditions. These effects were significantly attenuated in miR-148a-3p-depleted MCPs-EVs, which were extracted after inhibiting miR-148a-3p expression in MCPs. Repetitive intracavernous injections of MCPs-EVs improved erectile function by inducing cavernous neurovascular regeneration in diabetic mice. Using online bioinformatics databases and luciferase report assays, we predicted that pyruvate dehydrogenase kinase-4 (PDK4) is a potential target gene of miR-148a-3p. CONCLUSIONS: Our findings provide new and reliable evidence that miR-148a-3p in MCPs-EVs significantly enhances cavernous neurovascular regeneration by inhibiting PDK4 expression in diabetic mice.

A diagnosis model of parental care: How parents optimize their provisioning strategy in brood reduction?

Altricial birds often display biased preferences in providing parental care for their dependent offspring, especially during food shortages. During this process, such inflexible rules may result in provisioning errors. To demonstrate how parents optimize their provisioning strategies, we proposed a "diagnosis model" of parental care to posit that parents will undergo a diagnosis procedure to test whether selecting against some particular offspring based on phenotype is an optimal strategy. We tested this model in an asynchronous hatching bird, the Azure-winged Magpie Cyanopica cyanus, based on 10 years of data about demography and parental provisioning behaviors. Given their higher daily survival rates, core offspring (those hatched on the first day) merits an investment priority compared with their marginal brood mates (those hatched on later days). However, a marginal offspring also merited a priority if it displayed greater weight gain than the expected value at the early post-hatching days. Parents could detect such a marginal offspring via a diagnosis strategy, in which they provisioned the brood at the diagnosis stage by delivering food to every nestling that begged, then biased food toward high-value nestlings at the subsequent decision stage by making a negative response to the begging of low-value nestlings. In this provisioning strategy, the growth performance of a nestling became a more reliable indicator of its investment value than its hatching order or competitive ability. Our findings provide evidence for this "diagnosis model of parental care" wherein parents use a diagnosis method to optimize their provisioning strategy in brood reduction.

Icariin as a potential anticancer agent: a review of its biological effects on various cancers.

Numerous chemical compounds used in cancer treatment have been isolated from natural herbs to address the ever-increasing cancer incidence worldwide. Therein is icariin, which has been extensively studied for its therapeutic potential due to its anti-inflammatory, antioxidant, antidepressant, and aphrodisiac properties. However, there is a lack of comprehensive and detailed review of studies on icariin in cancer treatment. Given this, this study reviews and examines the relevant literature on the chemopreventive and therapeutic potentials of icariin in cancer treatment and describes its mechanism of action. The review shows that icariin has the property of inhibiting cancer progression and reversing drug resistance. Therefore, icariin may be a valuable potential agent for the prevention and treatment of various cancers due to its natural origin, safety, and low cost compared to conventional anticancer drugs, while further research on this natural agent is needed.

Heme-binding protein 1 delivered via pericyte-derived extracellular vesicles improves neurovascular regeneration in a mouse model of cavernous nerve injury.

As a peripheral nerve injury disease, cavernous nerve injury (CNI) caused by prostate cancer surgery and other pelvic surgery causes organic damage to cavernous blood vessels and nerves, thereby significantly attenuating the response to phosphodiesterase-5 inhibitors. Here, we investigated the role of heme-binding protein 1 (Hebp1) in erectile function using a mouse model of bilateral CNI, which is known to promote angiogenesis and improve erection in diabetic mice. We found a potent neurovascular regenerative effect of Hebp1 in CNI mice, demonstrating that exogenously delivered Hebp1 improved erectile function by promoting the survival of cavernous endothelial-mural cells and neurons. We further found that endogenous Hebp1 delivered by mouse cavernous pericyte (MCP)-derived extracellular vesicles promoted neurovascular regeneration in CNI mice. Moreover, Hebp1 achieved these effects by reducing vascular permeability through regulation of claudin family proteins. Our findings provide new insights into Hebp1 as a neurovascular regeneration factor and demonstrate its potential therapeutic application to various peripheral nerve injuries.

Therapeutic effects of shikonin on adjuvant-induced arthritis in rats and cellular inflammation, migration and invasion of rheumatoid fibroblast-like synoviocytes via blocking the activation of Wnt/ß-catenin pathway.

BACKGROUND: Shikonin (SKN), the main bioactive component isolated from Lithospermum erythrorhizon Sieb et Zucc, has multiple activities including anti-rheumatic effect, but its specific roles and the precise mechanisms in regulating biological properties of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) are unclear and need further clarification. PURPOSE: This study explored the therapeutic roles of SKN on rat adjuvant-induced arthritis (AIA) and cellular inflammation, migration and invasion of TNF-α-induced RA FLS (MH7A cells), and further demonstrated the involved mechanisms. METHODS: SKN was intraperitoneally given to AIA rats and its therapeutic role was valued. The effects of SKN in vivo and in vitro on the production of pro-inflammatory factors were examined by ELISA and western blot. Wound-healing, transwell and phalloidin staining assay were carried out to evaluate the effects of SKN on TNF-α-induced migration and invasion in RA FLS. The involvement of Wnt/ß-catenin pathway was checked by immunohistochemistry or immunofluorescence assay for ß-catenin and western blot for pathway-related proteins. RESULTS: SKN treatment in AIA rats reduced paw swelling, arthritis index and pathological damage of ankle joints, indicating its anti-arthritic effect in vivo. SKN had anti-inflammatory roles in vivo and in vitro, evidenced by inhibiting the production of pro-inflammatory factors (like IL-1ß, IL-6, IL-8, TNF-α, MMP-2 and MMP-9) in sera and synovium of AIA rats, and in TNF-α-induced MH7A cells. Gelatin zymography result revealed the suppression of SKN on TNF-α-induced MMP-2 activity in vitro. Moreover, SKN inhibited TNF-α-induced migration, invasion and cytoskeletal reorganization in MH7A cells. Mechanistically, SKN suppressed the activation of Wnt/ß-catenin signaling in AIA rat synovium and in TNF-α-induced MH7A cells, indicated by the reduced protein levels of Wnt1, p-GSK-3ß (Ser9) and ß-catenin, the raised protein level of GSK-3ß and the decreased nuclear translocation of ß-catenin. Interestingly, the combination of LiCl (Wnt/ß-catenin agonist) canceled the therapeutic functions of SKN on cellular inflammation, migration and invasion in TNF-α-induced MH7A cells, whereas XAV939 (Wnt/ß-catenin inhibitor) enhanced the therapeutic roles of SKN. CONCLUSION: SKN showed therapeutic effects on rat AIA and cellular inflammation, migration and invasion of TNF-α-stimulated RA FLS via interrupting Wnt/ß-catenin pathway.

The activities and mechanisms of intestinal microbiota metabolites of TCM herbal ingredients could be illustrated by a strategy integrating spectrum-effects, network pharmacology, metabolomics and molecular docking analysis: Platycodin D as an example.

BACKGROUND: The intestinal microbiota plays a key role in understanding the mechanism of traditional Chinese medicine (TCM), as it could transform the herbal ingredients to metabolites with higher bioavailability and activity comparing to their prototypes. Nevertheless, the study of the activity and mechanism of microbiota metabolites reported by the published literature still lacks viable ways. Hence a new strategy is proposed to solve this issue. PURPOSE: A new strategy to study the activity and mechanism of intestinal microbiota metabolites of TCM herbal ingredients by integrating spectrum-effect relationship, network pharmacology, metabolomics analysis and molecular docking together was developed and proposed. METHOD: Platycodin D (PD) and its microbiota metabolites with antitussive and expectorant effect were selected as an example for demonstration. First, the PD and its microbiota metabolites with important contribution to antitussive and/or expectorant effects were screened through spectrum-effect relationship analysis. Second, network pharmacology and metabolomics analysis were integrated to identify the upstream key targets of PD and its microbiota metabolites as well as the downstream endogenous metabolites. Finally, the active forms of PD were further confirmed by molecular docking. RESULTS: Results showed that PD was an active ingredient with antitussive and/or expectorant effects, and the active forms of PD were its microbiota metabolites: 3-O-ß-d-glucopyranosyl platycodigenin, 3-O-ß-d-glucopyranosyl isoplatycodigenin, 7­hydroxyl-3-O-ß-d-glucopyranosyl platycodigenin, platycodigenin and isoplatycodigenin. In addition, those microbiota metabolites could bind the key targets of PAH, PLA2G2A, ALOX5, CYP2C9 and CYP2D6 to exert antitussive effects by regulating four metabolic pathways of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, glycerophospholipid metabolism and linoleic acid metabolism. Similarly, they could also bind the key targets of PLA2G1B, ALOX5, CYP2C9 and CYP2D6 to exert expectorant effect by regulating two pathways of glycerophospholipid metabolism and linoleic acid metabolism. CONCLUSION: The proposed strategy paves a new way for the illustration of the activities and mechanisms of TCM herbal ingredients, which is very important to reconcile the conundrums of TCM herbal ingredients with low oral bioavailability but high activity.

Argonaute 2 Restores Erectile Function by Enhancing Angiogenesis and Reducing Reactive Oxygen Species Production in Streptozotocin (STZ)-Induced Type-1 Diabetic Mice.

Severe vascular and nerve damage from diabetes is a leading cause of erectile dysfunction (ED) and poor response to oral phosphodiesterase 5 inhibitors. Argonaute 2 (Ago2), a catalytic engine in mammalian RNA interference, is involved in neurovascular regeneration under inflammatory conditions. In the present study, we report that Ago2 administration can effectively improve penile erection by enhancing cavernous endothelial cell angiogenesis and survival under diabetic conditions. We found that although Ago2 is highly expressed around blood vessels and nerves, it is significantly reduced in the penis tissue of diabetic mice. Exogenous administration of the Ago2 protein restored erectile function in diabetic mice by reducing reactive oxygen species production-signaling pathways (inducing eNOS Ser1177/NF-κB Ser536 signaling) and improving cavernous endothelial angiogenesis, migration, and cell survival. Our study provides new evidence that Ago2 mediation may be a promising therapeutic strategy and a new approach for diabetic ED treatment.

Salidroside ameliorates pathological cardiac hypertrophy via TLR4-TAK1-dependent signaling.

Salidroside, a prominent active ingredient in traditional Chinese medicines, is garnering increased attention because of its unique pharmacological effects against ischemic heart disease via MAPK signaling, which plays a critical role in regulating the evolution of ventricular hypertrophy. However, the function of Salidroside on myocardial hypertrophy has not yet been elucidated. C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with Salidroside (100 mg kg-1  day-1 ) by oral gavage for 3 weeks starting 1 week after surgery. Four weeks after TAC surgery, the mice were subjected to echocardiography and then sacrificed to harvest the hearts for analysis. For in vitro study, neonatal rat cardiomyocytes were used to validate the protective effects of Salidroside in response to Angiotensin II (Ang II, 1 µM) stimulation. Here, we proved that Salidroside dramatically inhibited hypertrophic reactions generated by pressure overload and isoproterenol (ISO) injection. Salidroside prevented the activation of the TAK1-JNK/p38 axis. Salidroside pretreatment of TAK1-inhibited cardiomyocytes shows no additional attenuation of Ang II-induced cardiomyocytes hypertrophy and signaling pathway activation. The overexpression of constitutively active TAK1 removed the protective effects of Salidroside on myocardial hypertrophy. TAC-induced increase of TLR4 protein expression was reduced considerably in the Salidroside treated mice. Transient transfection of small interfering RNA targeting TLR4 (siTLR4) in cardiomyocytes did not further decrease the activation of the TAK1/JNK-p38 axis. In conclusion, Salidroside functioned as a TLR4 inhibitor and displayed anti-hypertrophic action via the TAK1/JNK-p38 pathway.

Tuning oxygen vacancy in Bi2WO6 by heteroatom doping for enhanced photooxidation-reduction properties.

Heteroatom doping was recently regarded as an effective method to tune the band gap and improve the separation and transfer of photogenerated electron-hole pairs in semiconductor photocatalysts. Herein, a novel S,F-codoped Bi2WO6 (S,F-Bi2WO6) with suitable oxygen vacancies was synthesized via the hydrothermal-calcination and post-sulfurization, for efficient Cr(VI) reduction and methyl orange (MO) degradation under visible light. The amount of surface oxygen vacancies could be controlled by adjusting the S/F ratio during the doping process, which modulated the band structure and photogenerated charge behavior of Bi2WO6. The optimal S0.10F-Bi2WO6 exhibited an excellent photooxidation-reduction performance, which Cr(VI) reduction and MO degradation efficiencies were 1.6 and 2.6 times than those of the pristine Bi2WO6 without oxygen vacancy under visible-light, respectively. The enhanced photooxidation-reduction performance was because the right amount of oxygen vacancies could effectively narrow the bandgap and improve the separation efficiency of electron-hole pairs. Thus, this work offered a mild and simply approach for preparing heteroatom doped Bi2WO6 and a potential to be extended to the synthesis of other doped materials for environmental remediation.

[Advances in mechanism of traditional Chinese medicine in inhibiting angiogenesis in ovarian cancer].

Ovarian cancer is one of the three major cancers in gynecology. Ovarian cancer has insidious symptoms in its early stages and mostly has progressed to advanced stages when detected. Surgical treatment combined with chemotherapy is currently the main treatment, but the 5-year survival rate is still less than 45%. Angiogenesis is a key step in the growth and metastasis of ovarian cancer. The inhibition of ovarian cancer angiogenesis has become a new hotspot in anti-tumor targeted therapy, which has many advantages such as less drug resistance, high specificity, few side effects, and broad anti-tumor spectrum. Modern research has confirmed that traditional Chinese medicine(TCM) can inhibit tumor angiogenesis by inhibiting the expression of pro-angiogenic factors, up-regulating the expression of anti-angiogenic factors, inhibiting the proliferation of vascular endothelial cells, reducing the density of tumor microvessels, and regulating related signaling pathways, with unique advantages in the treatment of ovarian cancer. This paper presented a review of the role of TCM in inhibiting ovarian cancer angiogenesis in order to provide references for the optimization of clinical ovarian cancer treatment strategies.

[Activity of Codonopsis canescens against rheumatoid arthritis based on TLRs/MAPKs/NF-κB signaling pathways and its mechanism].

This paper aims to explore the activity of Codonopsis canescens extract against rheumatoid arthritis(RA) based on the Toll-like receptors(TLRs)/mitogen-activated protein kinases(MAPKs)/nuclear factor kappa B(NF-κB) signaling pathways and its mechanism. The ultra-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry(UPLC-Q-TOF-MS) was used to identify the components of C. canescens extract. Forty-eight male SD rats were randomly divided into six groups, namely the normal group, the model group, the methotrexate(MTX) tablet group, and the low, medium, and high-dose C. canescens extract(ZDS-L, ZDS-M, and ZDS-H) groups, with 8 rats in each group. The model of collagen-induced arthritis in rats was induced by injection of bovine type Ⅱ collagen emulsion. MTX(2.5 mg·kg~(-1)), ZDS-L, ZDS-M, and ZDS-H(0.3 g·kg~(-1), 0.6 g·kg~(-1), and 1.2 g·kg~(-1)) were administrated by gavage. Rats in the normal group and the model group received distilled water. MTX was given once every three days for 28 days, and the rest medicines were given once daily for 28 days. Body weight, degree of foot swelling, arthritis index, immune organ index, synovial histopathological changes, and serum levels of tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), and interleukin-6(IL-6) were observed. Protein expressions of TLR2, TLR4, NF-κB p65, p38 MAPK, and p-p38 MAPK in rats were determined by Western blot. Thirty-four main components were identified by UPLC-Q-TOF-MS, including 15 flavonoids, 7 phenylpropanoids, 4 terpenoids, 4 organic acids, 2 esters, and 2 polyalkynes. As compared with the normal group, the body weight of the model group was significantly decreased(P<0.01), and foot swelling(P<0.05, P<0.01), arthritis index(P<0.01), and the immune organ index(P<0.01) were significantly increased. The synovial histopathological injury was obviously observed in the model group. The serum levels of inflammatory factors TNF-α, IL-1ß, and IL-6 were significantly increased(P<0.01), and the protein expression levels of TLR2, TLR4, NF-κB p65, p-p38 MAPK/p38 MAPK in the synovial tissue were significantly increased(P<0.01) in the model group. As compared with the model group, the body weights of the ZDS dose groups were increased(P<0.01), and the degree of foot swelling(P<0.01) and the arthritis index were decreased(P<0.05, P<0.01). The immune organ index was decreased(P<0.01) in the ZDS dose groups, and the synovial tissue hyperplasia and inflammatory cell infiltration were alleviated. The serum levels of TNF-α, IL-1ß, and IL-6 were significantly decreased(P<0.05, P<0.01), and the protein expression levels of TLR2, TLR4, NF-κB p65, p-p38 MAPK/p38 MAPK were decreased(P<0.05, P<0.01) in the ZDS dose groups. C. canescens extract containing apigenin, tricin, chlorogenic acid, aesculin, ferulic acid, caffeic acid, and oleanolic acid has a good anti-RA effect, and the mechanism may be related to the inhibition of TLRs/MAPKs/NF-κB signaling pathways.

SENP1 Protects Against Pressure Overload-Induced Cardiac Remodeling and Dysfunction Via Inhibiting STAT3 Signaling.

Background SENP1 (sentrin/small ubiquitin-like modifier-specific protease 1) has emerged as a significant modulator involved in the pathogenesis of a variety of human diseases, especially cancer. However, the regulatory roles of SENP1 in cardiovascular biology and diseases remain controversial. Our current study aims to clarify the function and regulation of SENP1 in pressure overload-induced cardiac remodeling and dysfunction. Methods and Results We used a preclinical mouse model of transverse aortic constriction coupled with in vitro studies in neonatal rat cardiomyocytes to study the role of SENP1 in cardiac hypertrophy. Gene delivery system was used to knockdown or overexpress SENP1 in vivo. Here, we observed that SENP1 expression was significantly augmented in murine hearts following transverse aortic constriction as well as neonatal rat cardiomyocytes treated with phenylephrine or angiotensin II. Cardiac-specific SENP1 knockdown markedly exacerbated transverse aortic constriction-induced cardiac hypertrophy, systolic dysfunction, fibrotic response, and cellular apoptosis. In contrast, adenovirus-mediated SENP1 overexpression in murine myocardium significantly attenuated cardiac remodeling and dysfunction following chronic pressure overload. Mechanistically, JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3) acted as new interacting partners of SENP1 in this process. SENP1-JAK2/STAT3 interaction suppressed STAT3 nuclear translocation and activation, ultimately inhibiting the transcription of prohypertrophic genes and the initiation of hypertrophic response. Furthermore, cardiomyocyte-specific STAT3 knockout mice were generated to validate the underlying mechanisms, and the results showed that STAT3 ablation blunted the cardiac hypertrophy-promoting effects of SENP1 deficiency. Additionally, pharmacological inhibition of SENP1 by Momordin Ic amplified cardiac remodeling post-transverse aortic constriction. Conclusions Our study provided evidence that SENP1 protected against pressure overload-induced cardiac remodeling and dysfunction via inhibiting STAT3 signaling. SENP1 supplementation might constitute a new promising treatment against cardiac hypertrophy. Notably, cardiovascular side effects should be seriously considered while applying systemic SENP1 blockers to suppress tumors.

Functional and Immunofluorescence Evaluations of Vascular and Neural Integrities in Urinary Bladder of Streptozotocin-Induced Diabetic Mice.

PURPOSE: To assess functional and structural changes in vascular and neural structures associated with diabetic bladder dysfunction (DBD) in the bladders of streptozotocin (STZ)-induced diabetic mice. METHODS: Eight-week-old C57BL/6 mice were injected with STZ at 50 mg/kg daily for 5 consecutive days. Catheters were inserted 12 weeks later, and 5 days after catheter placement bladder functions were assessed by conscious cystometry. Neurovascular and extracellular matrix marker changes in harvested urinary bladders were investigated by immunofluorescent staining. Body weights and fasting and postprandial blood glucose levels were measured 12 weeks after STZ injection. RESULTS: STZ-induced diabetic mice had significantly lower body weights and significantly higher blood glucose levels. Assessment of bladder function in STZ-induced diabetic mice revealed a nearly 3-fold increase in bladder capacity and intercontractile interval compared to controls. However, basal pressure, maximal bladder pressure, and threshold pressure were not significantly different. Morphological and structural analysis showed that STZ-induced diabetic mice had significantly reduced microvascular density in lamina propria (33% of the nondiabetic control values), and severely decreased nerve contents in the detrusor region (42% of the nondiabetic control values). CONCLUSION: STZ-induced diabetic mice exhibit functional and structural derangements in urinary bladder. The present study provides a foundation and describes a useful means of evaluating the efficacies of therapeutic targets and exploring the detailed mechanism of DBD.

Umbelliferone Inhibits Migration, Invasion and Inflammation of Rheumatoid Arthritis Fibroblast-Like Synoviocytes and Relieves Adjuvant-Induced Arthritis in Rats by Blockade of Wnt/ß-Catenin Signaling Pathway.

Umbelliferone (UMB), a natural coumarin compound, has been reported to possess anti-rheumatic effects on rheumatoid arthritis (RA) experimental models, but its potential role of UMB in regulating migration, invasion and inflammation of RA fibroblast-like synoviocytes (FLS) remain unclear. Herein, MTT assay was performed to confirm the non-cytotoxic concentrations (10, 20, and 40[Formula: see text][Formula: see text]M) and the treatment time (24[Formula: see text]h) of UMB on TNF-[Formula: see text]-stimulated RA FLS (MH7A cells) in vitro. Results of wound-healing, transwell and phalloidin staining assays revealed that UMB inhibited TNF-[Formula: see text]-induced migration, invasion and F-actin cytoskeletal reorganization in MH7A. Results of ELISA, western blot and gelatin zymography indicated that UMB decreased the productions of pro-inflammatory factors, including IL-1[Formula: see text], IL-6, IL-8, MMP-2 and MMP-9, and inhibited MMP-2 activity in TNF-[Formula: see text]-stimulated MH7A cells. In vivo, UMB (25[Formula: see text]mg/kg and 50[Formula: see text]mg/kg) relieved the joint damage and synovial inflammation in rats with adjuvant-induced arthritis (AIA). Mechanistically, UMB could suppress Wnt/[Formula: see text]-catenin signaling both in TNF-[Formula: see text]-induced MH7A cells and in AIA rat synovium, evidenced by decreasing Wnt1 protein level, activating GSK-3[Formula: see text] kinase by blocking GSK-3[Formula: see text] (Ser9) phosphorylation, and reducing the protein level and nuclear translocation of [Formula: see text]-catenin. Importantly, combined use of lithium chloride (a Wnt/[Formula: see text]-catenin signaling agonist) eliminated the inhibitory effects of UMB on migration, invasion and inflammation in vitro and the anti-arthritic effects of UMB in vivo. We concluded that UMB inhibited TNF-[Formula: see text]-induced migration, invasion and inflammation of RA FLS and attenuated the severity of rat AIA through its ability to block Wnt/[Formula: see text]-catenin signaling pathway.

The role of vaginal microecology in the cervical cancer.

AIM: To explore the role of vaginal microecology in cervical cancer, so as to increase the understanding of cervical cancer and lay a foundation for future large-sample clinical trials. METHODS: We reviewed and summarized the literature comprehensively, and discussed the relationship between vaginal microecology and HPV infection, CIN progression and cervical cancer, as well as the potential molecular mechanism and the prospects of probiotics and prebiotics in future cancer treatments. RESULTS: With the popularization of high-throughput sequencing technology and the development of bioinformatics analysis technology, many evidences show that the increase in the diversity of the bacterial community in the vaginal microecological environment and the decrease in the number of Lactobacilli are associated with the continuous infection of HPV and the further development of CIN, cervical cancer-related. CONCLUSIONS: Vaginal microecological imbalance has an important impact on the occurrence and development of cervical cancer. However, the pathogenesis is not completely clear, and more high-level basic research and longitudinal clinical studies are needed to verify.

NEU1 Regulates Mitochondrial Energy Metabolism and Oxidative Stress Post-myocardial Infarction in Mice via the SIRT1/PGC-1 Alpha Axis.

Objective: Neuraminidase 1 (NEU1) participates in the response to multiple receptor signals and regulates various cellular metabolic behaviors. Importantly, it is closely related to the occurrence and progression of cardiovascular diseases. Because ischemic heart disease is often accompanied by impaired mitochondrial energy metabolism and oxidative stress. The purpose of this study was to investigate the functions and possible mechanisms of NEU1 in myocardial remodeling and mitochondrial metabolism induced by myocardial infarction (MI). Methods: In this study, the MI-induced mouse mode, hypoxia-treated H9C2 cells model, and hypoxia-treated neonatal rat cardiomyocytes (NRCMs) model were constructed. Echocardiography and histological analysis were adopted to evaluate the morphology and function of the heart at the whole heart level. Western blot was adopted to determine the related expression level of signaling pathway proteins and mitochondria. Mitochondrial energy metabolism and oxidative stress were detected by various testing kits. Results: Neuraminidase 1 was markedly upregulated in MI cardiac tissue. Cardiomyocyte-specific NEU1 deficiency restored cardiac function, cardiac hypertrophy, and myocardial interstitial fibrosis. What is more, cardiomyocyte-specific NEU1 deficiency inhibited mitochondrial dysfunction and oxidative stress induced by MI. Further experiments found that the sirtuin-1/peroxisome proliferator-activated receptor γ coactivator α (SIRT1/PGC-1α) protein level in MI myocardium was down-regulated, which was closely related to the above-mentioned mitochondrial changes. Cardiomyocyte-specific NEU1 deficiency increased the expression of SIRT1, PGC-1α, and mitochondrial transcription factor A (TFAM); which improved mitochondrial metabolism and oxidative stress. Inhibition of SIRT1 activity or PGC-1α activity eliminated the beneficial effects of cardiomyocyte-specific NEU1 deficiency. PGC-1α knockout mice experiments verified that NEU1 inhibition restored cardiac function induced by MI through SIRT1/PGC-1α signaling pathway. Conclusion: Cardiomyocyte-specific NEU1 deficiency can alleviate MI-induced myocardial remodeling, oxidative stress, and mitochondrial energy metabolism disorder. In terms of mechanism, the specific deletion of NEU1 may play a role by enhancing the SIRT1/PGC-1α signaling pathway. Therefore, cardiomyocyte-specific NEU1 may provide an alternative treatment strategy for heart failure post-MI.