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Protecting Cerebral Blood Flow Autoregulation: A Frontier Study on Aripiprazoles Inhibition of the MAPK Signaling Pathway after Cerebral Ischemia
No full textBackground: Cerebral ischemia-reperfusion injury (CIRI) is a common severe complication following cerebrovascular diseases and poses significant challenges to human health and life. Aripiprazole, due to its unique pharmacological effects, is recognized to exert a protective effect against Ischemia/Reperfusion (I/R) injury. Therefore, this study aimed to explore the protective effect of Aripiprazole on CIRI by inhibiting the p38 mitogen-activated protein kinase (MAPK) signaling pathway and its impact on the function of cerebral blood flow autoregulation. Methods: We successfully developed the CIRI rat model and divided rats into different groups: the Sham group, the I/R+DMSO group, the I/R+Aripiprazole low-dose group (1 mg/kg), and the high-dose group (3 mg/kg). The neuroprotective effect of Aripiprazole, its impact on the p38 MAPK signaling pathway, cell apoptosis, inflammatory response, oxidative stress response, and improvement of cerebral blood flow autoregulation function were evaluated using Triphenyltetrazolium Chloride (TTC) staining, western blot, terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) staining, and Enzyme-Linked Immunosorbent Assay (ELISA). Results: Compared to the I/R+DMSO group, the I/R+Aripiprazole group exhibited a significant reduction in the volume of cerebral infarction, brain edema, neurological function injury scores, and the number of TUNEL-positive cells in brain tissue (p < 0.05, p < 0.01, and p < 0.001), indicating a significant neuroprotective effect of Aripiprazole. Western blot results revealed that Aripiprazole significantly inhibited the activation of the p38 MAPK signaling pathway induced by I/R (p < 0.05, p < 0.01, and p < 0.001). Additionally, Aripiprazole significantly reduced the expressions of pro-inflammatory cytokines (interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), IL-6), decreased malondialdehyde (MDA) levels, and elevated the levels of superoxide dismutase (SOD) and glutathione (GSH) (p < 0.05, p < 0.01, and p < 0.001). Conclusion: Aripiprazole effectively protects rats from CIRI by inhibiting the p38 MAPK signaling pathway, reducing cell apoptosis, suppressing inflammation and oxidative stress response, and improving cerebral blood flow autoregulation function. These findings provide an experimental basis for applying Aripiprazole in treating CIRI and lay the foundation for future clinical research
Short-chain Fatty Acids Inhibit NLRP3 Inflammasome to Alleviate Inflammation and Epithelial-mesenchymal Transition in Diabetic Nephropathy Rats via GPR41/43
Get PDFBackground: The role of Short-chain fatty acids (SCFAs) and their G-protein-coupled receptors (GPRs) in mitigating diabetic nephropathy (DN) has been recognized. This study aimed to investigate the impact of SCFAs on inflammation in DN via G-protein-coupled receptors 41 and 43 (GPR41/43). Methods: Human kidney tubular HK-2 cells were transfected to silence GPR41/43 and treated with sodium acetate (Ac, 48 mmol/L)/sodium propionate (Pr, 24 mmol/L)/sodium butyrate (But, 8 mmol/L) under high glucose (HG, 30 mM) or normal glucose conditions. Rats were administered lentivirus solution to silence GPR41/43 and streptozotocin (STZ, 60 mg/kg) to induce DN, followed by treatment with But (100 mmol/L). Diabetic symptoms and renal function were evaluated, kidney weight/body weight (KW/BW) was calculated, and renal histopathology was examined using hematoxylin-eosin, periodic acid-Schiff, and Masson staining. Quantitative real-time polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay, and immunohistochemistry were employed to assess epithelial-mesenchymal transition (EMT)-related proteins, GPR41, GPR43, NLR family pyrin domain containing 3 (NLRP3), and inflammatory factor levels in HK-2 cells and kidney tissues. Results: Ac/Pr/But reversed HG-induced downregulation in GPR41/GPR43 and upregulation of NLRP3/tumor necrosis factor-α (TNF-α)/interleukin-18 (IL-18)/IL-6/IL-1β in HK-2 cells (p< 0.001). But attenuated HG-induced decrease in epithelial cadherin (E-cadherin) (p < 0.001) and increase in alpha-smooth muscle actin (α-SMA) (p < 0.05) in HK-2 cells. Silencing GPR41/43 reversed the effects of But (p < 0.05). STZ induced diabetic symptoms, increased urine albumin level, serum creatinine/ blood urea nitrogen (BUN) level, KW/BW, α-SMA, NLRP3, and inflammatory factor levels in kidney tissues, exacerbated kidney morphology, and downregulated E-cadherin and GPR41/GPR43 in kidney tissues in rats (p < 0.001). But attenuated these effects of STZ, which were reversed by silencing GPR41/43 (p < 0.05). Conclusions: SCFAs inhibit NLRP3 inflammasome activation, thus alleviating inflammation and EMT in DN by upregulating GPR41/43
Overexpression of NPRL2 is Linked to Patients with Bladder Cancer and Promotes Bladder Cancer Cells Progression by Regulating ENO1-SMAD2/3 Axis
No full textBackground: Nitrogen permease regulator-like 2 (NPRL2) acts as an effective gene for diverse tumor suppression and its expression is up-regulated in castration-resistant prostate cancer (CRPC). However, potential mechanisms of NPRL2 in bladder cancer (BCa) progression remain to be discovered. To explore the function and molecular mechanism of NPRL2 in the development and progression of BCa, bioinformatics analysis and verification were performed. Methods: Extensive bioinformatic analysis explored NPRL2 expression associated with BCa using data from the Cancer Genome Atlas (TCGA) database. BCa cell lines (T24 and 5637 cells) were used to verify the function and molecular mechanism of NPRL2 in BCa, and they were divided into four groups: NC-CMV-NPRL2 (transfected with PDS237_pL-CMV-GFP vector), CMV-NPRL2 (transfected with PDS237_pL-CMV-GFP-TUSC4), NC-sh-NPRL2 (transfected with pl6.3-SHRNA-BSD vector), and sh-NPRL2 (transfected with pl6.3-SHRNA-GFP-NPRL2). The proliferation, invasion, migration, cell cycle and apoptosis of T24 and 5637 cells were further evaluated by Cell Counting Kit-8 (CCK-8), Transwell, flow cytometry and Western blot assays. Nude mice were used to establish xenotransplantation models, and three groups (control, sh1-NPRL2, sh2-NPRL2) were developed. The control group was subcutaneously injected with T24 cell suspension. The sh-NPRL2 groups were subcutaneously injected with two groups of T24 cells that had been stably transduced with NPRL2 knockout genes. Results: NPRL2 gene expression exhibited remarkable upregulation in BCa (p = 0.004). Overexpression of NPRL2 enhanced the proliferation and invasion of T24 and 5637 cells, while simultaneously inhibiting apoptosis. Furthermore, NPRL2 deficiency in the xenotransplantation model exhibited inhibition of tumorigenesis in vivo. Additionally, Immunoprecipitation and Shotgun Liquid Chromatography-Mass Spectrometry (LC-MS) analysis revealed a protein interaction between NPRL2 and alpha-enolase (ENO1) which was highly expressed in BCa. ENO1 had a noticeable effect on BCa stage and survival by promoting cell proliferation, epithelial-mesenchymal transition (EMT), small mothers against decapentaplegic (SMAD)2/3 phosphorylation, and ENO1s stability was enhanced by NPRL2. Conclusions: The present study reveals that NPRL2 is upregulated in BCa and can enhance SMAD2/3 phosphorylation by upregulating ENO1. NPRL2 is a potential biomarker for BCa diagnosis and prognosis
Ursolic Acid: A Novel PTP-oc Inhibitor that Suppresses Osteoclastogenesis and Root Resorption
No full textBackground: Root resorption, an unwanted side effect often seen in orthodontics, depends largely on osteoclasts. Osteoclastic protein tyrosine phosphatase (PTP-oc) plays a major role in controlling osteoclast activity. This study aimed to investigate the effects of Ursolic acid (UA), a novel PTP-oc inhibitor, on osteoclastogenesis and root resorption. Methods: UA was pinpointed using a PTP inhibition assay. Its inhibitory characteristics, inhibitor constant (Ki) against ∆PTP-oc, and selectivity were through an Inhibition Kinetics assay. The effects of UA on osteoclastogenesis were examined by treating human U937 histiocytic lymphoma cells with or without UA and then assessing osteoclastogenesis mediated by phorbol 12-myristate 13-acetate /1α, 25 di-hydroxy vitamin D3 (1,25(OH)2D3). The cell counting kit-8 (CCK-8) evaluated how a UA affects U937 cell proliferation in vitro. Osteoclast-like cell development was examined using tartrate-resistant acid phosphatase (TRAP) Staining, while Real-time-polymerase chain reaction (qPCR) was used to assess the expression of tartrate-resistant acid phosphatase (TRAP), receptor activator of nuclear factor-κB (RANK), matrix metalloproteinase-9 (MMP-9), cathepsin K (CK), and calcitonin receptor (CTR). Tyrosine kinase c-Src (c-Src) protein was measured using Western Blot. A rat model was used to study the levels of root resorption and tyrosine phosphorylation of c-Src (PY-527) by histology and immunohistochemistry. Results: UA displayed a strong and reversible inhibitory effect on PTP-oc in a competitive manner, showing selective in vitro (p < 0.001). The compound did not impact the viability of U937 cells at concentrations between 1–5 μM UA. UAs inhibition of osteoclastogenesis depends on its concentration, and the compound effectively suppresses the expression of osteoclast marker genes, TRAP, RANK, MMP-9, CK, and CTR. Additionally, the area of TRAP-positive cells was reduced. This effect is facilitated by inhibiting enzymatically active PTP-oc, which elevates the levels of c-Src tyrosine phosphorylation, thereby decreasing the activity of c-Src Protein Tyrosine Kinases (PTK). In animal studies, as UA concentration increased, there was a noticeable delay and weakening in root resorption. Finally, IHC staining results revealed that compared to the 0 μM UA (control) group, c-Src PY-527 in the model groups increased alongside the rise in UA concentration (p < 0.05). Conclusions: This study demonstrates that UA application effectively suppresses osteoclastogenesis and root resorption by inhibiting the enzymatic activity of PTP-oc. This effect is dose-dependent and may be mediated by the regulation of c-Src signaling pathway
Hepatoprotective-Like Efficacy of Pimenta dioica Berries against Paracetamol-Induced Hepatic Damage in an Experimental Rat Model
No full textBackground: Drug-induced acute liver damage is a contributing factor in nearly 50% of acute liver failures. Acute liver failure has been linked to pharmaceutical overdoses, particularly with paracetamol. Plant-based medication could be a possible agent for mitigating the effects of paracetamol overdose. The present study investigated Pimenta dioica (PD) berries extract for its hepatoprotective properties against paracetamol-induced liver toxicity in rats. Materials and Methods: Two chemicals, paracetamol and silymarin, were used in this study. Furthermore, fully mature berries of PD were used to extract the bioactive constituents in 90% ethanol. Moreover, male Wistar albino rats (n = 40) were used to assess the hepatoprotective activity. For this purpose, hepatotoxicity was induced by orally administering 2 g/kg body weight of paracetamol. The rats were divided into five groups. Group I (control group) received 1 mL/kg of 1% sodium carboxymethyl cellulose. Group II (hepatotoxic control group) received an oral dose of 2 g/kg of paracetamol. Group III was given silymarin at a dose of 100 mg/kg. Group IV and V received PD at 200 mg/kg and 400 mg/kg, respectively. The liver was surgically excised to calculate relative liver weight and histopathological examination in different rat groups. Blood samples were collected from the retro-orbital plexus on the 8th day of treatment and examined for serum alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TB) content, and gamma-glutamyl transferase (GGT) levels. The data were statistically analyzed using a one-way Analysis of Variance (ANOVA), with a p-value < 0.05 considered significant. Results: It was observed that paracetamol significantly increased (p < 0.001) relative liver weight as well as liver biomarker enzymes such as ALP, ALT, AST, TB, and GGT. Furthermore, paracetamol caused histological alterations in the hepatocytes. Moreover, Pimenta dioica (PD) significantly inhibited (p < 0.001) paracetamol-induced changes in relative liver weight, liver biomarkers levels, and hepatocyte histopathology in a dose-dependent manner. Conclusion: These findings suggest that PD possesses hepatoprotective properties against paracetamol-induced hepatocellular damage. Although, based on the current findings, it is difficult to speculate on the precise mechanism of action, attenuation of paracetamol-induced generation of free radicals could be one of the mechanisms. Therefore, further investigation to identify potentially active components and to establish the precise mechanism of action for its hepatoprotective effect could make PD a novel candidate for therapeutic use
Active Ingredient Irigenin from Belamcanda chinensis (L.) DC Alleviates IL-18-Mediated Pyroptosis of Corneal Epithelial Cells in Dry Eye Disease
No full textBackground: Dry eye disease (DED) is closely coupled with ocular surface inflammation. Irigenin, an active ingredient in traditional Chinese medicine Belamcanda chinensis (L.) DC, possesses various pharmacological effects including anti-inflammation. This study aims to reveal the impact of irigenin on DED. Methods: DED model cells in vitro were constructed by 24-h hyperosmolarity intervention (90 mM sodium chloride (NaCl)) and treated with different concentrations (10, 20 and 40 μM) of irigenin in the same time. Cell counting kit-8, 5-ethynyl-2′-deoxyuridine, Transwell, enzyme-linked immunosorbent assays, and flow cytometry, were used to determine the effect and mechanism of irigenin on DED. The expressions of pyroptosis-related proteins were measured by Western blot. Hyaluronan synthase 2 (HAS2) and HAS3 expressions were quantified by quantitative reverse transcription polymerase chain reaction. Results: Irigenin exerted no cytotoxicity on HCE-2 cells at concentrations of 10, 20 or 40 μM. Irigenin enhanced the viability, proliferation, migration, and inhibited the apoptosis of hyperosmolarity-induced HCE-2 cells, but these effects were reversed by interleukin 18 (IL-18) overexpression. Irigenin decreased the level of IL-1β, tumor necrosis factor alpha (TNF-α) as well as the expressions of Gasdermin-D (GSDMD), IL-18 and caspase-1, but increased the expressions of HAS2 and HAS3 in hyperosmolarity-induced HCE-2 cells. These effects of irigenin on inhibiting inflammation and pyroptosis as well as on promoting hyaluronic acid synthesis in hyperosmolarity-induced HCE-2 cells were reversed by IL-18 overexpression. Conclusion: Irigenin protected HCE-2 cells against hyperosmolarity-induced inflammation and dysfunction by reducing IL-18-mediated pyroptosis. Irigenin has potential in developing therapeutic agents for DED
Sodium Aescinate Alleviates Diabetic Retinopathy in Rats by Inhibiting the AGE-RAGE Signaling Pathway
No full textBackground: Diabetic retinopathy (DR) is a complication of diabetes that impacts the vision and quality of life of patients. Sodium aescinate (SA) has been widely used in resisting exudation and treating inflammation and vascular diseases, which is consistent with the disease symptoms of DR. However, the therapeutic effect and molecular mechanism of SA on DR are lacking. Therefore, this study is aimed at examining the palliative impact of SA on DR rats induced by streptozotocin (STZ). Methods: DR model was established by injecting STZ (80 mg/kg) into the Sprague Dawley (SD) rats (7-week-old). Later, SA was administered via the tail vein at a dosage of 1 mg/kg/per, 7 days/cycle, totaling 21 days. During this period, the changes in the rats body weight and blood sugar levels were observed, and their glucose tolerance was monitored. The fundus conditions of the rats were then examined using fundus photography, focusing on the diameter and permeability of blood vessels. Retinal pathology was assessed using hematoxylin-eosin (HE) staining, and the changes in DR-related markers vascular endothelial growth factor (VEGF) and tumor necrosis factor-α (TNF-α) in the retinas were assayed. The changes in reactive oxygen species (ROS), lipid peroxidation (Lip-ROS), malondialdehyde (MDA), glutathione (GSH), and insulin-like growth factor 1 (IGF1) in retinal protein, as well as the changes of IGF1 in the serum, were also evaluated. Additionally, the changes in the advanced glycation end products (AGE)-receptor for AGEs (RAGE) signaling pathway were investigated. Results: The treatment group with SA slowed down the diameter of fundus blood vessels and reduced angiogenesis in DR. It inhibited the expression of VEGF and TNF-α. At the same time, SA could also inhibit the activation of ROS, MDA, GSH, and IGF1, and reduce the protein content of IGF1. Additionally, the expression of AGE and RAGE in the advanced glycation end products (AGE)-receptor for AGEs (RAGE) signaling pathway was decreased, and the phosphorylated Janus kinase-signal transd ucer and activator of transcription 3 (JAK/STAT3) in its downstream pathway was also downregulated. Conclusions: SA has the capacity to diminish DR by inhibiting oxidative stress and AGE-RAGE signaling pathway
Efficacy and Adverse Effects of Oxycodone and Morphine in the Treatment of Cancer Pain
No full textBackground: Morphine and oxycodone are effective analgesics for treating both acute and chronic pain. However, previous studies have primarily focused on their oral efficacy and potential side effects. This study aims to assess the effectiveness and adverse reactions of oxycodone and morphine in the treatment of cancer-related pain. Methods: A total of 39 patients admitted to our hospital from April 5, 2022 to April 5, 2023 received oxycodone (n = 19) or morphine (n = 20). Their treatment data were retrospectively analyzed. These patients received either oxycodone or morphine orally for five consecutive days. Pain intensity was evaluated using the Numeric Rating Scale for Pain (NRS Pain) from day 0 to day 5. The study also recorded pain relief rates, incidence of adverse reactions, and treatment satisfaction. Results: After receiving treatment with either oxycodone or morphine, all subjects experienced a reduction in cancer pain grade from moderate or severe to mild. On the third day of drug administration, there was a statistically significant decrease in NRS Pain scores (p < 0.05). Furthermore, by the fifth day of treatment, although pain symptoms were notably alleviated in both groups, satisfaction was significantly higher in the morphine group (p < 0.05). Both groups exhibited adverse effects such as vomiting, nausea, and constipation. However, the incidence of adverse effects and the number of patients experiencing vomiting were significantly lower in the oxycodone group compared to the morphine group. The incidence of adverse effects increased after the administration of high doses of oxycodone or morphine but remained lower in the oxycodone group than in the morphine group. Conclusions: When compared to morphine, oxycodone exhibits a slightly shorter onset of action, a more potent short-term analgesic effect, and fewer adverse effects. This study provides clinical evidence to refine drug regimens in managing cancer pain. Further basic research is expected to elucidate the different mechanisms underlying the effects of oxycodone and morphine
Bioinformatics Analysis Reveals Esophageal Squamous Cell Carcinoma-Associated Lysine-Related Genes as Poor Prognostic Factors and Potential Therapeutic Targets
No full textBackground: Esophageal squamous cell carcinoma (ESCC) represents a prevalent malignancy within the digestive tract, often diagnosed at advanced stages, leading to treatment challenges and poor prognosis. Despite its essential roles in biosynthesis, antioxidation, and energy metabolism, the involvement of lysine in cancer pathogenesis remains poorly understood. This study aimed to elucidate the significance of lysine-associated genes in ESCC, potentially enhancing treatment outcomes. Methods: mRNA expression data for ESCC were retrieved from The Cancer Genome Atlas (TCGA) for limma differential expression analysis. Lysine-related genes were extracted from the GeneCards database and overlapped with differentially expressed genes. Lysine levels were quantified using single-sample Gene Set Enrichment Analysis (ssGSEA), followed by metabolic pathway analysis comparing high and low lysine levels. The random survival forest (RSF) algorithm identified lysine-related genetic signatures associated with poor prognosis of ESCC. Further analysis encompassed drug susceptibility profiling and assessment of immune cell infiltration. Subsequently, single-cell analysis was conducted using data from the Gene Expression Omnibus (GEO) database (GSE196756) to validate key lysine-related genes. Results: Ubiquitination Factor E4A (UBE4A) and Apolipoprotein C1 (APOC1) were identified as key lysine-associated genes in ESCC. Functional enrichment analysis revealed that the lysine-related genes remarkably enriched lysine-regulated pathways, including histone modification, histone lysine methylation, and lysine degradation pathways. Moreover, these lysine-related differentially expressed genes (DEGs) served as independent prognostic factors, and a nomogram incorporating these genes and clinical factors accurately predicted 1- and 2-year survival rates in ESCC patients. Drug databases highlighted AICAR, BI.D1870, MS.275, and lapatinib as potential therapeutic agents. Immunemicroenvironment infiltration analysis indicated that UBE4A was actively connected with T cells CD4 memory resting and passively connected with B cells memory. APOC1 was actively linked to macrophages M2, T cells CD4 memory activated, T cells CD8, and was passively linked to the activated Dendritic cells, T cells CD4 memory resting and Eosinophils. We further performed single-cell analysis, and 21 subtypes were obtained by t-Distributed Stochastic Neighbor Embedding (tSNE) algorithm. The total clusters were labeled to tissue stem cells, neurons, epithelial cells, B cells, neutrophils, monocytes, T cells, smooth muscle cells, NK cells, and endothelial cells. Conclusions: Our findings underscore the pivotal role of lysine-related gene regulation in ESCC. The identified lysine-related genes hold promise as prognostic indicators for ESCC patients, shedding light on potential mechanisms underlying poor prognosis and facilitating the search for targeted therapeutics to enhance the success rate of ESCC treatment
Human Extravillous Trophoblast Cell-Derived Follistatin Promotes the Viability and Proliferation of Human Umbilical Vein Endothelial Cells by Activating the AMPK Signaling Pathway
No full textBackground: Gestational diabetes mellitus (GDM) elevates the risk of complications in pregnant women and fetuses. The follistatin (FST) expression is decreased during GDM. However, its precise impact and the underlying mechanisms in human umbilical vein endothelial cell (HUVEC) are not fully understood. Therefore, this study aimed to delve into the impact of FST on HUVEC and to elucidate the underlying molecular mechanisms. Methods: FST level in GDM was bioinformatically analyzed using two datasets, GSE49524 and GSE87295. Human extravillous trophoblast cells (HTR-8/SVneo) were cultured in a high glucose (HG) medium and subsequently transfected with lentiviral vectors overexpressing FST or its negative control. Moreover, HUVEC was grown in HTR-8/SVneo cell culture media replete with Compound C (CC, an inhibitor of adenosine monophosphate (AMP)-activated protein kinase (AMPK)), and FST level was observed using enzyme linked immunosorbent assay (ELISA). Furthermore, the expression levels of FST, glucose-6-phosphatase (G6Pase), proliferating cell nuclear antigen (PCNA), marker of proliferation Ki-67 (Ki67), phosphorylated AMPK (pAMPK), AMPK, histone deacetylase 4 (HDAC4), and phosphorylated histone deacetylase 4 (pHDAC4) were assessed in the treated HUVECs utilizing quantitative real time polymerase chain reaction (qRT-PCR) and western blot analysis. Additionally, the viability and proliferation of HUVECs were determined through 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and 5-ethynyl-2′-deoxyuridine (EdU) staining assays. Results: HG treatment inhibited FST level in HTR-8/SVneo cells as well as in their cell culture medium (p < 0.01). Furthermore, overexpression of FST promoted the viability and proliferation of HUVECs, increased the levels of Ki67, PCNA, and pAMPK, and decreased G6Pase and pHDAC4 levels in HG-induced HUVECs (p < 0.05). Additionally, CC treatment further counteracted the influences of overexpressed FST on pAMPK/AMPK and pHDAC4/HDAC4 ratios, G6Pase, Ki67, and PCNA levels, and the viability and proliferation in HUVECs (p < 0.05). Conclusion: In summary, HTR-8/SVneo-derived FST promoted the viability and proliferation of HUVEC by activating the AMPK signaling pathway