Journal of Physiology and Pharmacology最新文献

Multiple myeloma (MM) is a clonal B-cell malignancy arising from plasma cells in the bone marrow that can lead to various symptoms such as bone pain and fractures, anemia, renal failure and repeated infection. Treatment involves steroids, chemotherapy, targeted therapy and stem cell transplantation. On the other hand, resistance to these treatments often develops, particularly in relapsed/refractory MM, necessitating new strategies. This study examined the degradation of RAD51 recombinase (RAD51) in MM cell lines resistant to existing treatments using proteolysis targeting chimeras (PROTACs). Resistant cell lines were established by exposing human B lymphoblast cell lines, MM.1S and MM.1R, to increasing doses of lenalidomide or pomalidomide. Targeted RAD51 degradation (TRD) 2, a novel PROTAC targeting RAD51, reduced the RAD51 protein levels and cell proliferation. TRD2, combined with chemotherapy drug cisplatin, showed enhanced efficacy in cell proliferation compared to single-agent treatment. In vivo studies confirmed the synergistic effects of TRD2 and cisplatin in inhibiting tumor growth in lenalidomide-resistant MM.1R xenograft models without significant toxicity. MM cells exhibit increased RAD51 expression as they develop resistance to chemotherapy. This study shows that targeting RAD51 with TRD2 enhances the efficacy of DNA-damaging treatments, providing a promising approach for overcoming drug resistance in MM. The inhibition of RAD51 combined with cisplatin therapy can maximize the treatment efficacy of MM patients resistant to dexamethasone and lenalidomide. Nevertheless, further research will be needed to explore the clinical applications of these findings.

Subarachnoid hemorrhage (SAH) is a cerebral hemorrhagic disorder that can severely damage the brain and lead to cognitive impairment. Gastrodin (GAS) is the main bioactive ingredient extracted from Gastrodiae Rhizoma, which has neuroprotective effects against brain injury. The aim of this study was to investigate the potential treatment of cognitive dysfunction after SAH and to explore the mechanism of action of the multi-targeted drug Gastrodin to alleviate cognitive dysfunction after SAH. The SAH rat model was established by vascular puncture, and the target sequences were delivered to rats via adenoviral vectors. Dual luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay were used to verify the targeting relationship between microRNA-378e (miR-378e) and myocyte enhancer factor 2D (MEF2D). Neurologic scores of rats were evaluated according to the modified Garcia scoring system. Learning memory ability of rats was determined by Morris water maze assay and open field assay. Rat brain edema index was determined by wet/dry method. Blood-brain barrier (BBB) permeability was assessed by Evan's blue assay. The pathological changes in the tissues were analyzed using hematoxylin-eosin (HE) staining, and the apoptosis of neuronal cells was analyzed using TUNEL. Reactive oxygen species (ROS) generation was observed using fluorescence microscopy. Oxidative stress was assessed through the analysis of ROS, malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH). Tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) levels in hippocampal tissue were measured by ELISA. A direct targeting relationship existed between miR-378e and MEF2D. The number of TUNEL-positive neurons in the hippocampus was significantly reduced after Gastrodin treatment compared to SAH rats (P<0.05). This finding was associated with the observed decrease in the level of the apoptosis-related Bcl-2-associated X (Bax) protein, the rise in B-cell lymphoma 2 (Bcl-2) expression, and the inhibition of cleaved caspase-3 activation after SAH (P<0.05). GAS effectively alleviated SAH-induced brain edema and blood-brain barrier dysfunction and reduced brain water content and Evan's blue in brain tissue (P<0.05). GAS significantly improved the learning and memory abilities of rats as tested by Morris water maze and open field experiments. In addition, the up-regulation of both oxidative stress and inflammatory response-related factors in tissues after SAH were reversed by GAS administration (P<0.05). Summing up the results, GAS ameliorates SAH-induced cognitive deficits and brain damage by modulating the miR-378e/MEF2D axis, exerting a cerebroprotective effect. This may provide some new clues for future therapies to mitigate the damage after SAH.

Lung cancer remains a critical global health issue, with the molecular intricacies and specific role of phosphorylase kinase regulatory subunit alpha 1 (PHKA1) not well understood. This study aims to utilize an integrated bioinformatic analyses and experimental validations to investigate PHKA1 in lung cancer. Bioinformatic tools provided a pan-cancer perspective, emphasizing PHKA1's oncogenic potential such as GEPIA and UALCAN revealed significantly elevated mRNA expression of PHKA1 in lung adenocarcinoma (LUAD) across various stages, highlighting its diagnostic significance. The study also explored the impact of PHKA1 on immune cells in LUAD, finding strong correlations between high PHKA1 expression and increased presence of CD4+, CD8+ T cells, and macrophages using TIMER 2.0 database. Survival analysis using Kaplan-Meier (KM) plots showed that patients with elevated PHKA1 levels had poorer prognoses, reinforcing its potential as an oncogenic gene in non-small cell lung cancer (NSCLC) by KM plotter. Immunohistochemistry by HPA database supported these findings, demonstrating increased PHKA1 protein levels in lung cancer tissues. Protein-protein interaction analysis using STRING and cytoscape identified a network of genes linked to PHKA1 in NSCLC, offering insights into its functional interactions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis suggested that PHKA1 might be involved in the PI3K-AKT signaling pathway, known for its role in cell growth and survival, further supporting its oncogenic role. Experimental validation through RT-PCR and Western blot confirmed elevated PHKA1 expression in A549 and NCI-H460 lung cancer cells. Moreover, deletion of PHKA1 reduces cell growth and promotes apoptosis in A549 cells and confirmed by Western blot. In conclusion, this comprehensive study suggests that targeting PHKA1 in NSCLC could be a promising therapeutic strategy, highlighting its crucial role in the molecular landscape of lung cancer progression.

The neuregulin 1 (NRG1)-epidermal growth factor receptor 4 (ErbB4) signaling pathway is expressed in multiple systems of the body and has been shown to be involved in various life activities, with upregulation observed in some pathological processes. ErbB4 is a member of the receptor tyrosine kinase family, which, when activated by its ligand, NRG1, forms the NRG1-ErbB4 signaling pathway. Initially, this pathway garnered attention due to its high expression and relevance in cardiovascular system development and related diseases. However, little was known about its role in other systems in the past. In recent years, with the advancement of research in neuroscience, the role of the NRG1-ErbB4 signaling pathway in the nervous system has gradually been recognized. Increasing evidence suggests that upon activation, the NRG1-ErbB4 signaling pathway plays a crucial role in various neuronal activities such as proliferation, development, and differentiation, and is closely associated with a variety of physiological and pathological processes including schizophrenia, Alzheimer's disease, depression, epilepsy, among others. Moreover, based on extensive research data, mature clinical diagnostic and therapeutic approaches targeting the NRG1-ErbB4 signaling pathway have been proven effective. Additionally, a detailed information on the risk score based on the pathway's activity is included, highlighting its potential in predicting and managing neurological disorders. Therefore, it can be considered that the role and mechanism of the NRG1-ErbB4 signaling pathway in neurological diseases are valuable research topics in the field of neuroscience. This article reviews recent research on the role of the NRG1-ErbB4 signaling pathway in the nervous system.

The role of inflammation and oxidative stress (OS) is significant in the progression and development of diabetic nephropathy (DN). Resveratrol (Res) has various pharmacological effects including anti-inflammatory and anti-OS. Tumor necrosis factor receptor-related factor (TRAF3) has been shown to have anti-inflammatory and anti-OS effects in a variety of diseases. This study investigated the potential mechanisms underlying the renoprotective effects of Res, with a special focus on the regulation of TRAF3 in the Toll-like receptor 4 (TLR4)-mediated nuclear factor kappaB (NF-κB) inflammatory signaling pathway. A high-fat diet combined with intraperitoneal injection of streptozotocin (35 mg/kg) was used to induce type 2 diabetes mellitus (T2DM) in a rat model, and a high glucose (HG, 30 mmol/L)-treated glomerular thylakoid cell model was established in HBZY-1 rats. Res (40 mg/kg/day) was studied in vivo by gavage for 8 weeks and in vitro by treatment with Res (25, 50, and 100 μmol/L) for 48 hours. The degree of renal injury was evaluated by blood urea nitrogen (BUN), blood creatinine (Cr) and urine protein. Renal structure and glycogen changes were observed by hematoxylin and eosin and periodic acid Schiff staining (PAS). Inflammatory factors, including interleukin (IL)-1βt IL-6, monocyte chemotactic protein (MCP)-1, tumor necrosis factor-alpha (TNF-α), and oxidative stress markers, including superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA), were measured by enzyme-linked immunosorbent assay. Immunoblotting was performed to detect TRAF3, TLR4, MyD88, phosphorylated (p)-IκBβ, p-p65, and p65. Protein blotting was applied for final mechanistic validation using lentiviral transfection of diabetes mellitus (DM) rats and high glucose-induced cells against TRAF3. As a result Res effectively ameliorated renal loss and renal histopathologic changes in DM rats, as evidenced by decreased BUN (P<0.01), Cr (P<0.01), urine protein (P<0.01), and renal structural lesions and reduced basement membrane glycogen (P<0.015). In terms of molecular mechanisms, Res was able to significantly promote the expression of TRAF3, which in turn inhibited the activation of the TLR4/NF-κB signaling pathway and reduced the release of pro-inflammatory cytokines such as IL-1β, IL-6, MCP-1, and TNF-α (all P<0.01), thereby attenuating inflammatory responses in the kidney. In addition, Res significantly reduced OS in renal tissues and in the HG cell model, such as increasing SOD and CAT activities and decreasing MDA levels (all P<0.05). Silencing of TRAF3, on the other hand, partially reduced the anti-inflammatory and anti-OS effects of Res and activated the TLR4-mediated NF-κB signaling pathway. To sum up Res can alleviate DN by attenuating inflammation and OS, and the underlying mechanisms are related to TRAF3 in the TLR4/NF-κB-mediated anti-inflammatory pathway.

Gastrointestinal bleeding is a common clinical problem. In 5% of these cases, no source of bleeding can be found by gastroscopy or colonoscopy. The aim of this study was to investigate which of these patients benefit from capsule endoscopy (CE) and how it affects subsequent management. 305 patients who underwent CE for suspected obscure gastrointestinal bleeding at two German gastroenterological centers were analysed retrospectively. All patients had previously undergone gastroscopy and colonoscopy without evidence of a sufficient source of bleeding. The PillCam SB (Medtronic) was used for CE. A source of bleeding was identified in 63.9% (195/305) of cases with CE. A source of bleeding tented to be detected more frequently by CE in patients with melena only (72.4%, p=0.002) compared to patients with hematochezia with or without melena (55.6% and 45.9%). Furthermore, early CE (day 1: 73.3%, day 2: 61.5%, day 3: 53.8%; p=0.378) and complete CE (71.1% vs. 38.8%, p=2.56*10-6) were associated with a higher detection rate. Blood was detected in 31.5% (96/305) of all CEs. However, this tended to be observed more often in patients with a high need for red blood concentrates (0 RBC: 21.4%, 1-2 RBC: 34.9%, 3-4 RBC: 38.3%, ≥5 RBC: 45.7%; p=0.026), a derailed INR (<1.15: 32.6%, 1.16-2.0: 19.5%, 2.0-3.0: 32.0%, >3: 60.0%; p=0.023) and early CE (day 1: 46.7% (7/15), day 2: 41.0% (16/39), day 3: 25.0% (13/52); p=0.244). In 12.5% of the patients a double-ballon enteroscopy (DBE) was conducted. The detection of blood during CE increased the probability for a DBE (25.0% vs. 6.7%; OR: 4.61; p=2.061*10-5). Detection of a source of hemorrhage with CE increased the likelihood of detecting a source of hemorrhage with DBE (48.1% vs. 9.1%; OR: 8.83; p=0.030). Performing a DBE did not affect the length of hospitalisation (without DBE 10d, with DBE 9.1d, p=0.81) or the number of RBCs transfused after CE (without DBE 1.9 RBC, with DBE 2.4 RBC, p=0.67). In particular, patients with melena and an increased need for RBCs could benefit from an early and complete capsule endoscopy. If a source of bleeding was detected by CE, the probability of a finding in DBE could be increased.

Although cisplatin (CP) is a frequently prescribed medication for the treatment of malignant tumours, its clinical application is restricted by a variety of adverse effects, particularly acute kidney injury. Currently, there are only a limited number of effective pharmacological strategies that can be employed to prevent kidney injury caused by CP. Vindoline is a monoterpene indole alkaloid that functions as both the biosynthetic and synthetic precursor of the therapeutically significant anticancer medications. This study evaluates the effects of vindoline in a rodent model of CP-induced nephrotoxicity and elucidates the underlying mechanisms. Male Wistar rats were categorized into four groups: control, control + vindoline, CP (5 mg/kg), and CP + vindoline (20 mg/kg). The CP group was administered a onetime intraperitoneal injection of CP, while the CP + vindoline group was administered vindoline for 10 days. Renal injury was evaluated through analyses of nephrotic markers like creatinine, urea, and blood urea nitrogen (BUN) by using kit method. Oxidative stress markers like malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities was measured using specific assay kits. Apoptosis-related protein expression (B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3 and 9) in renal tissues was determined via Western blotting method. Our findings indicated that vindoline had the potential to significantly (P<0.05) reduce the levels of BUN and serum creatinine and attenuate CP-induced nephrotoxicity. Additionally, vindoline inhibited CP-induced oxidative stress by decreasing the level of MDA and significantly increasing the activities of GSH, SOD, and CAT (P<0.05). Vindoline attenuated CP-induced mononuclear cell infiltration, decreased (P<0.05) tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-1β levels, and inhibited nuclear factor kappaB (NF-κB) activation in renal tissues. Further, vindoline mitigated CP-induced apoptosis in renal tissues. Vindoline also considerably reduced p38, ERK1/2, and c-Jun-N-terminal kinase (JNK) expression. The findings indicate that vindoline mitigates CP-mediated nephrotoxicity by regulating oxidative imbalance, inflammation, and apoptosis through the ERK pathway.

We aimed to evaluate the clinical efficacy of different doses of atorvastatin in patients with acute coronary syndrome (ACS) following percutaneous coronary intervention (PCI). In this prospective, randomized controlled study, we enrolled 147 patients with ACS who underwent PCI at our hospital between April 2020 and June 2021. Participants were randomly assigned to three groups based on their post-PCI atorvastatin dose: low-dose (20 mg/day, n=49), medium-dose (40 mg/day, n=49), and high-dose (80 mg/day, n=49). We assessed clinical parameters including blood lipid profiles, inflammatory marker levels, creatine kinase (CK) levels and liver and kidney function before and after atorvastatin treatment. Adverse reactions were monitored to evaluate the safety and efficacy of the different atorvastatin doses. The mean follow-up duration was 13.76±1.27 months (range 12-15 months). No significant differences in baseline blood lipid levels, CK levels and inflammatory markers were observed among the groups (all P>0.05). Post-treatment, the high-dose atorvastatin group showed a more pronounced reduction in blood lipid levels and higher CK levels compared to the medium-dose and low-dose groups. Similarly, the medium-dose group had better outcomes than the low-dose group, with these differences being statistically significant (P<0.05). The high-dose group also exhibited significantly lower levels of inflammatory markers than both the medium-dose and low-dose groups after treatment (P<0.05). Adverse reactions were relatively infrequent across all groups: 4.08% in the low-dose group (1 case of nausea, 1 case of insomnia), 8.16% in the medium-dose group (1 case of insomnia, 1 case of dyspnea, 1 case of nausea, and 1 case of muscular soreness ), and 16.33% in the high-dose group (2 cases of nausea, 1 case of dyspnea, 2 cases of insomnia, and 3 cases of muscular soreness). There was no statistically significant difference in the incidence of adverse reactions among the groups (χ²=4.421, P=0.110). To sum up the results, high-dose atorvastatin significantly improved blood lipid profiles and reduced inflammatory markers in ACS patients following PCI, without adversely affecting liver or kidney function. Furthermore, the high-dose regimen demonstrated a favorable safety profile, suggesting its potential benefit in managing these patients population.

Subarachnoid hemorrhage (SAH) is a hemorrhagic stroke with high short-term mortality that can lead to cognitive and neurological impairment. Accurate and appropriate treatment strategies are urgently needed. Nimodipine (NDP) can not only improve blood circulation in SAH patients but also repair ischemic neuronal damage. microRNAs (miRNAs) are abundantly expressed in the brain and are involved in brain injury. Therefore, this study investigated the possible regulatory mechanisms of nimodipine on miRNAs in the process of cognitive dysfunction and neurological injury after SAH. The SAH rat model was established, miR-31-5p and hypoxia-inducible factor 1 subunit alpha inhibitor (HIF1AN) expressions were detected 48 h after modeling, and neurobehavioral function, neuronal apoptosis, activation of microglia, and inflammation were evaluated. Finally, the targeting relationship between miR-31-5p and HIF1AN was verified. The study findings explained that NDP treatment could effectively improve cognitive dysfunction, brain injury, neuronal injury, and neuroinflammation in SAH rats. SAH rats expressed down-regulated miR-31-5p and up-regulated HIF1AN. Overexpressing miR-31-5p or knocking down HIF1AN ameliorated cognitive dysfunction and brain damage in SHA rats. Mechanistically, nimodipine can promote miR-31-5p expression, and HIF1AN took part in the development of SAH as a downstream target gene of miR-31-5p. In conclusion, NDP ameliorates cognitive dysfunction and neurological damage in SHA rats by miR-31-5p/HIF1AN axis.

The pineal gland synthesizes indoles including melatonin, neurosteroids, and possibly catecholamines. Peritonitis induced in chickens hatched in winter inhibited pineal melatonin biosynthesis, while having the opposite effect during summer. Therefore, the aim of this study was to obtain more information concerning the impact of peritonitis on the pineal gland in chickens hatched in summer. Specifically, we aimed to investigate: 1) the concentration of melatonin (MEL), its substrates, and other indoles; 2) the levels of catecholamines and neurotransmitters such as noradrenaline, dopamine, and their substrates and metabolites; 3) the mRNA levels of genes encoding peptide neurotransmitters, such as vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide, along with their receptors and adrenoceptor alpha 2A; and 4) the mRNA levels of genes encoding elements of the immune system, including pro-inflammatory cytokines interleukin-1β, interleukin-6, interleukin-18, as well as interleukin-6 and interleukin-18 receptors, and Toll-like receptors 4, 15, and 21. Peritonitis was initiated 2 hours before the lights were turned off via intraperitoneal injection of thioglycollate, and 4 hours later, the pineal glands and trunk blood were isolated. High-performance liquid chromatography (HPLC) analysis revealed a significant increase in the levels of 5-hydroxytryptophan (P<0.01), N-acetylserotonin (P<0.05), melatonin (P<0.001), 5- hydroxytryptophol (P<0.05), and 3,4-dihydroxy-L-phenylalanine (P<0.05), along with a decrease in serotonin, dopamine (P<0.001), and noradrenaline (P<0.001) in the pineal glands, following immune system activation. Additionally, RT-qPCR analysis showed a significant increase in the expression of genes encoding cytokines such as interleukin-1β (P<0.001), interleukin-18 (P<0.05), Toll-like receptor 4 (P<0.01), and interleukin-6 receptors (P<0.01), while mRNA level encoding receptors for vasoactive intestinal peptide (P<0.05) and pituitary adenylate cyclase-activating polypeptide (P<0.001) experienced a decrease. These results expand our knowledge about the impact of the immune system activation on the pineal gland, confirming the presence of seasonal differences in this influence and suggesting that these variations may be associated with a shift in energy allocation from immune functions to other traits.