Design and synthesis of sulfonamide phenothiazine derivatives as novel ferroptosis inhibitors and their therapeutic effects in spinal cord injury.

Ferroptosis is a novel style of cell death, and studies have shown that ferroptosis is strongly associated with spinal cord injury (SCI). A large number of ferroptosis inhibitors have been reported, but so far no ferroptosis inhibitor has been used clinically. Therefore there is an urgent need to discover a better inhibitor of ferroptosis. In this study, 24 novel sulfonamide phenothiazine ferroptosis inhibitors were designed and synthesized, followed by structure-activity relationship studies on these compounds. Among them, compound 23b exhibited the best activity in Erastin-induced PC12 cells (EC50 = 0.001 µM) and demonstrated a low hERG inhibition activity (IC50 > 30 µM). Additionally, compound 23b was identified as a ROS scavenger and showed promising therapeutic effects in an SD rat model of SCI. Importantly, 23b did not display significant toxicity in both in vivo and in vitro experiments and show good pharmacokinetic properties. These findings suggest that compound 23b, a novel ferroptosis inhibitor, holds potential as a therapeutic agent for spinal cord injury and warrants further investigation.

Effects of combined morbid insomnia and sleep apnea on long-term cardiovascular risk and all-cause mortality in elderly patients: a prospective cohort study.

PURPOSE: It is reported that insomnia and obstructive sleep apnea (OSA) increase the incidence of adverse cardiovascular events. The aim of this study was to analyze the risk of cardiovascular disease and mortality in elderly patients with comorbid insomnia and obstructive sleep apnea (COMISA). METHODS: We included 868 elderly patients with OSA who underwent sleep monitoring at a multicenter sleep room from January 2015 to October 2017. We collected demographic data, clinical features, medical history, sleep parameters, and laboratory findings. Cox proportional hazards analysis was used to identify the relationship between COMISA and adverse cardiovascular events and all-cause mortality. RESULTS: There were 181 elderly patients with COMISA. The median follow-up was 43 months, during which we observed major adverse cardiac events (MACE) in 90 patients. The Kaplan-Meier survival curve indicated a significant relationship between COMISA and MACE (Plog Rank < 0.001). Multivariate Cox regression analysis showed that COMISA increased the incidence of MACE (HR = 2.328, 95% CI: 1.349-4.018, P = 0.002), hospitalization for unstable angina (HR = 2.915, 95% CI: 1.397-6.081, P = 0.004), and the combination of all events (HR = 2.301, 95% CI: 1.393-3.803, P = 0.001). However, there were no significant differences in cardiovascular death, all-cause mortality, myocardial infarction, or hospitalized heart failure in patients with COMISA (P > 0.05). Subgroup analyses showed that among COMISA patients, male sex (HR = 2.800, 95% CI: 1.458-5.377, P = 0.002), age < 70 years (HR = 4.050, 95% CI: 2.022-8.115, P < 0.001), and overweight and obesity (HR = 2.482, 95% CI: 1.383-4.453, P = 0.002) were associated with a higher risk of MACE. CONCLUSIONS: Our results showed that COMISA increased the risk of MACE, unstable angina, and the compound occurrence of all events. Male, overweight or obese COMISA patients under 70 years of age have an increased risk of MACE.

Apelin promotes hepatic fibrosis through ERK signaling in LX-2 cells.

Apelin participates in cardiovascular functions, metabolic disease, and homeostasis disorder. However, the biological function of apelin in liver diseases, especially liver fibrosis is still under investigation. The present study aimed to investigate the expression of apelin in nonalcoholic fatty liver disease (NAFLD) and the mechanism of apelin promoting hepatic fibrosis through ERK signaling in hepatic stellate LX-2 cells. The results showed that the ALT and AST levels in serum were increased in the mice fed HFC. The histological staining revealed that hepatocellular steatosis and ballooning degeneration was severe, and fibrogenesis appeared as increased pericellular collagen deposition along with pericentral (lobular) collagen deposition in the mice fed HFC. Immunochemistry and qRT-PCR results showed that the expression of apelin and profibrotic genes was higher as compared to the control group. The in vitro experiments demonstrated that apelin-13 upregulated the transcription and translation levels of collagen type I (collagen-I) and α-smooth muscle actin (α-SMA) in LX-2 cells. The immunofluorescent staining, qRT-PCR, and Western blot results showed that the overexpression of apelin markedly increased the expression of α-SMA and cyclinD1. The LX-2 cells treated with apelin-13 displayed an increased expression of pERK1/2 in a time-dependent manner, while the pretreatment with PD98059 abolished the apelin-induced expression of α-SMA and cyclinD1. Furthermore, the in vivo and in vitro assays suggested a key role of apelin in promoting liver fibrosis, and the underlying mechanism might be ascribed to the apelin expression of profibrotic genes via ERK signaling pathway.

Analysis of current situation and influencing factors of cognitive dysfunction associated with type 2 diabetes and follow-up study on treatment effectiveness.

Background: Many studies have explored the risk factors associated with cognitive impairment in patients with Type 2 diabetes mellitus (T2DM). However, research on determining the optimal threshold for these risk factors and comparative studies on the therapeutic effects of insulin and metformin is limited. This study aims to establish the optimal threshold for cognitive impairment risk factors in T2DM patients and compare the efficacy of insulin and metformin in treating mild cognitive impairment (MCI). Methods: A total of 308 patients with T2DM were included. The optimal threshold for cognitive impairment risk factors was determined using receiver operating characteristic curve and binary logistic regression models. MCI patients were divided into three groups: insulin, metformin, and insulin with metformin. The treatment effect was evaluated after a 6-month follow-up. Results: The study identified several factors that influenced cognitive function in T2DM patients, including female gender, duration of diabetes >13.50 years, years of education >7.50 years, and serum sodium level > 141.90 mmol/L. Metformin and insulin with metformin showed superior therapeutic effects compared to insulin alone, but no difference was observed between metformin and combination therapy. Conclusion: Special attention should be given to female and those with diabetes duration >13.50 years, as well as to individuals with educational level ≤ 7.50 years and serum sodium concentration ≤ 141.90 mmol/L. Metformin and insulin with metformin effectively improve MCI in patients with T2DM and outperform insulin monotherapy. The efficacy of metformin and combination therapy was found to be comparable.

Effect of hypoglycemia on cognitive performance in older patients with diabetes: A meta-analysis.

GOALS: The goal of this study was to use meta-analysis to compile information from various studies to investigate the existence and severity of cognitive impairment in elderly diabetes patients who have hypoglycemic episodes. MATERIALS AND TECHNIQUES: For research studies on the relationship between hypoglycemia and cognitive decline or dementia in persons older than 45 years, we searched the PubMed, EMBASE, Cochrane Library, CNKI, WanFang, CBM and VIP databases for the period 1989 to 2022. We conducted random effects inverse variance on the meta-analysis and used the I2 statistic to assess heterogeneity. RESULT: We selected 44 of the 518 studies we retrieved, 7 being appropriate for meta-analysis. Six thousand and forty-five individuals were involved in total. Both types of older diabetic patients with hypoglycemia performed considerably worse on tests of general intelligence than control participants (standardized mean difference, 0.58; 95% CI, 0.88-0.28). Also, elderly type-2 diabetes patients with hypoglycemic episodes had significantly worse memory performance (standardized mean difference, 0.19; 95% CI, 0.29-0.09). Additionally, we found that older type-2 diabetes patients with hypoglycemia had significantly poorer psychomotor function than those without hypoglycemia (standardized mean difference, 0.51; 95% CI, 0.38-0.63).

Improving ecosystem services supply provides insights for sustainable landscape planning: A case study in Beijing, China.

Promoting land use planning through ecosystem service (ES) protection is a crucial approach for maintaining landscape sustainability. Identifying ES bundles to serve landscape functional zoning can provide a new perspective for sustainable land use planning. Taking the Beijing metropolitan region as a study area, we quantitatively assessed the spatiotemporal distributions of multiple ESs, from 1980 to 2017, based on land use changes. By combining ES patterns and comprehensive ecosystem service (CES), distinct ES bundles were identified through the clustering method. Based on the ES bundles, landscape functional zones were then established. We further developed improved land use scenarios to conserve ESs in selected towns of different functional zones by exploring dominant factors influencing ESs. Results showed that most of ESs decreased due to the expansion of developed lands. According to the classification of ES bundles, Beijing can be classified into three landscape functional zones at town level: the ecological conservation region (ECR), food production region (FPR), and urban development region (UDR). For each landscape functional zone, the town with the greatest decline in CES value was selected. Associated with the influencing factors of ESs, local land use patterns, and ecological protection policies, corresponding multi-step improved land use scenarios were designed. These scenarios were demonstrated to be effective in conserving ESs in the selected towns: (1) the agricultural expansion scenario, which enhanced food provision services in the ECR; (2) the forest conservation scenario, which enhanced habitat and recreational services in the FPR; and (3) the developed land optimization scenario, which enhanced a range of regulating services in the UDR. Overall, this study used landscape functional zoning as a nexus to connect ES patterns and land use management. The optimized land use strategies can provide references for conserving ESs and enhancing landscape sustainability in Beijing and other similar metropolitan areas worldwide.

Mechanism of KLF4 Protection against Acute Liver Injury via Inhibition of Apelin Signaling.

Krüppel-like factor 4 (KLF4) is a key transcription factor that regulates genes involved in the proliferation or differentiation in different tissues. Apelin plays roles in cardiovascular functions, metabolic disease, and homeostatic disorder. However, the biological function of apelin in liver disease is still ongoing. In this study, we investigated the mechanism of KLF4-mediated protection against acute liver injury via the inhibition of the apelin signaling pathway. Mice were intraperitoneally injected with carbon tetrachloride (CCl4; 0.2 mL dissolved in 100 mL olive oil, 10 mL/kg) to establish an acute liver injury model. A KLF4 expression plasmid was injected through the tail vein 48 h before CCl4 treatment. In cultured LX-2 cells, pAd-KLF4 or siRNA KLF4 was overexpressed or knockdown, and the mRNA and protein levels of apelin were determined. The results showed that the apelin serum level in the CCl4-injected group was higher than that of control group, and the expression of apelin in the liver tissues was elevated while KLF4 expression was decreased in the CCl4-injected group compared to the KLF4-plasmid-injected group. HE staining revealed serious hepatocellular steatosis in the CCl4-injected mice, and KLF4 alleviated this steatosis in the mice injected with KLF4 plasmid. In vitro experiments showed that tumor necrosis factor-alpha (TNF-α) could downregulate the transcription and translation levels of apelin in LX-2 cells and also upregulate KLF4 mRNA and protein expression. RT-PCR and Western blotting showed that the overexpression of KLF4 markedly decreased basal apelin expression, but knockdown of KLF4 restored apelin expression in TNF-α-treated LX-2 cells. These in vivo and in vitro experiments suggest that KLF4 plays a key role in inhibiting hepatocellular steatosis in acute liver injury, and that its mechanism might be the inhibition of the apelin signaling pathway.

Effects of paroxetine on spatial memory function and protein kinase C expression in a rat model of depression.

The aim of the present study was to investigate the effects of paroxetine on the spatial memory and expression level of protein kinase C (PKC) in a rat model of depression. Rat models of depression were established by chronic unpredictable mild stress. The spatial learning and memory function of the rats were assessed by the Morris water maze test. The expression levels of PKC in the hippocampus were detected by western blotting. The results showed that, compared with the control group, the escape latency was prolonged and the percentage of time in the target quadrant and the number of times the rats crossed the platform were reduced in the model group; however, the impaired spatial learning and memory function in these rat models could be restored by paroxetine, almost to a level comparable with that in the normal control animals. In addition, the expression of PKC in the model group was significantly decreased compared with that in the control group, and the expression could also be elevated by paroxetine treatment. These results suggest an association between PKC levels and the pathogenesis of depression. The application of paroxetine can improve the spatial memory and reverse the changes in PKC levels in the hippocampus in the rat model of depression. The present findings have enhanced the understanding of the pathogenesis of depression, and provide experimental evidence for the treatment of depression with paroxetine.