Tetrahydropiperine, a natural alkaloid with neuroprotective effects in ischemic stroke.

BACKGROUND: Ischemic stroke (IS) is a life-threatening neurological disease with various pathological mechanisms. Tetrahydropiperine (THP) is a natural alkaloid with protective effects against multiple diseases, such as seizure, and pain. This study was to examine the impact of THP on IS and investigate its potential mechanism. MATERIAL AND METHODS: We employed network pharmacology and molecular docking techniques to identify the target proteins of THP for intervention in IS. Adult male Sprague-Dawley rats were used to create a permanent middle cerebral artery occlusion model. PC-12 cells were chosen to establish an oxygen-glucose deprivation (OGD) cell model. Disease modeling followed by nimodipine (NIMO); 3-methyladenine (3-MA) and rapamycin (RAP) interventions. Open field test, Longa score, balance beam test, and forelimb grip test were used to measure motor and neurological functions. The degree of neurological damage recovery was assessed through behavioral analysis, and cerebral infarction volume was determined using TTC staining. Morphological changes were examined through HE and Nissl staining, and ultrastructural changes in neurons were observed using transmission electron microscopy. The protein expression of autophagy and related pathways was analyzed through Western blot (WB). The appropriate hypoxia time and drug concentration were determined using CCK-8 assay, which also measured cell survival rate. RESULTS: The network pharmacology findings indicated that the impact of THP on IS was enhanced in the PI3K/Akt signaling pathway. THP demonstrated robust docking capability with proteins associated with the autophagy and PI3K/Akt/mTOR, as indicated by the molecular docking outcomes. THP significantly improved behavioral damage, reduced the area of cerebral infarction, ameliorated histopathological damage from ischemia, increase neuronal survival, and alleviated ultrastructural damage in neurons (P < 0.05). THP enhanced the survival of PC-12 cells induced by OGD and ameliorated the morphological harm to the cells (P < 0.05). THP was found to elevate the quantities of P62, LC3-Ⅰ, PI3K, P-AKt/Akt, and P-mTOR/mTOR proteins while reducing the levels of Atg7 and Beclin1 proteins. The results of transmission electron microscopy showed no autophagosomes in the THP, 3-MA, and 3-MA + THP groups. CONCLUSION: The activation of the PI3K/Akt/mTOR signaling pathway by THP inhibits autophagy and provides relief from neurological damage in IS.

Prefrontal cortex-specific Dcc deletion induces schizophrenia-related behavioral phenotypes and fail to be rescued by olanzapine treatment.

Multiple genome studies have discovered that variation in deleted in colorectal carcinoma (Dcc) at transcription and translation level were associated with the occurrences of psychiatric disorders. Yet, little is known about the function of Dcc in schizophrenia (SCZ)-related behavioral abnormalities and the efficacy of antipsychotic drugs in vivo. Here, we used an animal model of prefrontal cortex-specific knockdown (KD) of Dcc in adult C57BL/6 mice to study the attention deficits and impaired locomotor activity. Our results supported a critical role of Dcc deletion in SCZ-related behaviors. Notably, olanzapine rescued the SCZ-related behaviors in the MK801-treated mice but not in the cortex-specific Dcc KD mice, indicating that Dcc play a critical in the mechanism of antipsychotic effects of olanzapine. Knockdown of Dcc in prefrontal cortex results in glutamatergic dysfunction, including defects in glutamine synthetase and postsynaptic maturation. As one of the major risk factors of the degree of antipsychotic response, Dcc deletion-induced glutamatergic dysfunction may be involved in the underlying mechanism of treatment resistance of olanzapine. Our findings identified Dcc deletion-mediated SCZ-related behavioral defects, which serve as a valuable animal model for study of SCZ and amenable to targeted investigations in mechanistic hypotheses of the mechanism underlying glutamatergic dysfunction-induced antipsychotic treatment resistance.

Sodium alginate/poly(vinyl alcohol)/taxifolin nanofiber mat promoting diabetic wound healing by modulating the inflammatory response, angiogenesis, and skin flora.

Diabetes-related ulcers are still a therapeutic problem because of their susceptibility to infection, ongoing inflammation, and diminished vascularization. The design and development of novel dressings are clinically urgent for the treatment of chronic wounds due to diabetic ulcers. In this study, we made taxifolin (TAX) loaded sodium alginate (SA)/poly(vinyl alcohol) (PVA) nanofibers for the treatment of chronic wounds. The SA/PVA/TAX nanofibers that have been created are smooth and bead-free, with good thermal stability, hydrophilicity, and mechanical properties. The release profile indicated a sustained drug release, with a cumulative release rate of 64.6 ± 3.7 % at 24 h. In vitro experiments have shown that SA/PVA/TAX has good antibacterial activity, antioxidant activity, and biocompatibility. In vivo experiments have shown that SA/PVA/TAX exhibits desirable biochemical properties and is involved in the diabetic wound healing process by promoting cell proliferation (Ki67), angiogenesis (CD31, VEGFA), and alleviating inflammation (CD68). Western blotting experiments suggest that SA/PVA/TAX may promote diabetic wound healing by inhibiting the TLR4/NF-κB/NLRP3 signaling pathway and upregulating the expression of VEGFA and PDGFA. The 16S rRNA sequencing results showed that SA/PVA/TAX increased the wound surface flora's diversity and reversed the skin microbiota's structural imbalance. Therefore, SA/PVA/TAX can promote diabetic wound healing by modulating the inflammatory response, angiogenesis, and skin flora and has the potential to be an excellent wound dressing.

A phellinus igniarius polysaccharide/chitosan-arginine hydrogel for promoting diabetic wound healing.

Inadequate angiogenesis and inflammation at the wound site have always been a major threat to skin wounds, especially for diabetic wounds that are difficult to heal. Therefore, hydrogel dressings with angiogenesis and antibacterial properties are very necessary in practical applications. This study reported a hydrogel (PCA) based on L-arginine conjugated chitosan (CA) and aldehyde functionalized polysaccharides of Phellinus igniarius (OPPI) as an antibacterial and pro-angiogenesis dressing for wound repair in diabetes for the first time. and discussed its possible mechanism for promoting wound healing. The results showed that PCA had good antioxidant, antibacterial, biological safety and other characteristics, and effectively promoted the healing course of diabetic wound model. In detail, the H&E and Masson staining results showed that PCA promoted normal epithelial formation and collagen deposition. The Western blot results confirmed that PCA decreased the inflammation by inhibiting the IKBα/NF-κB signaling pathway and enhanced angiogenesis by adjusting the level of HIF-1α. In conclusion, PCA is a promising candidate for promoting wound healing in diabetes. Graphic abstract.

Commissural and coronary alignment of the Venus-A valve after transcatheter aortic valve replacement: a retrospective cross-sectional study.

Background: Previous studies have shown that neo-commissural orientation of transcatheter heart valve (THV) can influence coronary obstruction during transcatheter aortic valve replacement (TAVR), long-term durability of THV, and coronary artery access for reintervention after TAVR. Specific initial orientations of Evolut R/Pro and Acurate Neo aortic valves can improve commissural alignment. However, the method of achieving commissural alignment with the Venus-A valve remains unknown. Therefore, this study aimed to evaluate the extent of commissural and coronary alignment of the Venus-A self-expanding valve after TAVR using a standard system delivery technique. Methods: A retrospective cross-sectional study was performed. At the time of enrollment, patients who underwent pre- and post-procedural electrocardiographically-gated contrast-enhanced CT with a second-generation 64-row multidetector scanner were selected for the study. Commissural alignment was categorized as aligned (0-15° angle deviation), mild (15-30°), moderate (30-45°), or severe (45-60°) commissural misalignment (CMA). Coronary alignment was categorized as having no coronary overlap (CO) (>35°), moderate CO (20-35°), or severe CO (≤20°). The results were represented as proportions to assess the extent of commissural and coronary alignment. Results: Forty-five TAVR patients were ultimately included in the analysis. THVs were shown to be randomly implanted: 20.0% of THVs were aligned, 33.3% had mild CMA, 26.7% had moderate CMA, and 20.0% had severe CMA. The incidence of severe CO was 24.4% with the left main coronary artery, 28.9% with the right coronary artery, 6.7% with both coronary arteries, and 46.7% with one or both coronary arteries. Conclusions: The results showed that commissural or coronary alignment could not be achieved with the Venus-A valve using a standard system delivery technique. Therefore, specific methods to attain alignment with the Venus-A valve need to be identified.

Anatomical spatial distribution of the bilateral coronary ostia and aortic valve commissures relative to the aortic arch.

Background: Previous studies have shown the importance of achieving commissural alignment during transcatheter aortic valve replacement (TAVR). However, the anatomical spatial distribution of the bilateral coronary ostia and aortic valve commissures relative to the aortic arch is still unknown. This study aimed to evaluate this anatomical relationship. Methods: A retrospective cross-sectional study was designed. Patients who underwent pre-procedural electrocardiographically gated computed tomography (CT) angiography with a second-generation dual-source CT scanner were enrolled in this study. Three-dimensional reconstruction was performed, and the inner curve (IC) of the aortic arch was defined. The angles between the coronary arteries or aortic valve commissures and the IC were measured. Results: Ultimately, 80 patients were included in the analysis. The angle from the IC to the left main (LM) was 48.0°±17.5°, and the angle from the IC to the right coronary artery (RCA) was 172.6°±15.2°. The median angle from the IC to the non-coronary cusp (NCC)/left coronary cusp (LCC) commissure was -12.8° with an interquartile range (IQR) of -21.5° to -2.2°, the angle from the IC to the LCC/right coronary cusp (RCC) commissure was 102.4°±15.1°, and the angle from the IC to the RCC/NCC commissure was 219.9°±13.9°. Conclusions: This study found a fixed angular relationship between the coronary ostia or aortic valve commissures and the IC of the aortic arch. This relationship could help to establish an individualized implantation method that would enable commissural and coronary alignment to be achieved in TAVR.

Cyclophilin D-mediated angiotensin II-induced NADPH oxidase 4 activation in endothelial mitochondrial dysfunction that can be rescued by gallic acid.

Vascular endothelial dysfunction plays a central role in the most dreadful human diseases, including stroke, tumor metastasis, and the coronavirus disease 2019 (COVID-19). Strong evidence suggests that angiotensin II (Ang II)-induced mitochondrial dysfunction is essential for endothelial dysfunction pathogenesis. However, the precise molecular mechanisms remain obscure. Here, polymerase-interacting protein 2 (Poldip 2) was found in the endothelial mitochondrial matrix and no effects on Poldip 2 and NADPH oxidase 4 (NOX 4) expression treated by Ang II. Interestingly, we first found that Ang II-induced NOX 4 binds with Poldip 2 was dependent on cyclophilin D (CypD). CypD knockdown (KD) significantly inhibited the binding of NOX 4 to Poldip 2, and mitochondrial ROS generation in human umbilical vein endothelial cells (HUVECs). Similar results were also found in cyclosporin A (CsA) treated HUVECs. Our previous study suggested a crosstalk between extracellular regulated protein kinase (ERK) phosphorylation and CypD expression, and gallic acid (GA) inhibited mitochondrial dysfunction in neurons depending on regulating the ERK-CypD axis. Here, we confirmed that GA inhibited Ang II-induced NOX 4 activation and mitochondrial dysfunction via ERK/CypD/NOX 4/Poldip 2 pathway, which provide novel mechanistic insight into CypD act as a key regulator of the NOX 4/Poldip 2 axis in Ang II-induced endothelial mitochondrial dysfunction and GA might be beneficial in the treatment of wide variety of diseases, such as COVID-19, which is worthy further research.

Transfemoral transcatheter aortic valve replacement for severe aortic stenosis with concomitant left ventricular diverticulum: a case report.

Background: Left ventricular diverticulum (LVD) is a rare cardiac malformation in patients with severe aortic stenosis (AS). Transcatheter aortic valve replacement (TAVR) is not recommended due to the risk of diverticulum injury. However, for patients considered inoperable or at high surgical risk, TAVR might be the only treatment option. The safety and feasibility of TAVR for severe AS with concomitant LVD are still unclear. Case summary: An 80-year-old Asian woman complaining of shortness of breath was admitted to our hospital, whose echocardiogram showed calcified severe AS and a diverticulum in the left ventricular apex. A transfemoral 26 mm Venus-A prosthetic aortic valve was successfully implanted. Pre- and post-procedural cardiac magnetic resonance imaging revealed a remarkable volume reduction of LVD. Discussion: Transfemoral TAVR was not preferred because the straight-tip hydrophilic wire and catheter tip could injure the fragile diverticulum wall. If we could avoid the injury of the diverticulum, TAVR would be a good option for patients at high surgical risk.

Generation of ultra-treatment-resistant schizophrenia patient-derived induced pluripotent stem cell line UJSi002-A.

Schizophrenia is a chronic, serious and disabling mental disorder. Most patients can effectively control their condition through drug treatment, but there are still some patients who are difficult to gain benefits from drug treatment. Among them, the failure to respond to clozapine full-scale treatment is ultra-treatment-resistant schizophrenia. We generated induced pluripotent stem cells (iPSCs) from an ultra-treatment-resistant schizophrenia patient by electroporation of peripheral blood mononuclear cells (PBMCs) with episomal plasmids encoding OCT 4, SOX 2, NANOG, LIN 28, KLF 4 and MYC. The iPSCs demonstrated normal karyotype, expressed pluripotency markers and differentiated into the three germ layers in vivo.

Alginate/chitosan microcapsules for in-situ delivery of the protein, interleukin-1 receptor antagonist (IL-1Ra), for the treatment of dextran sulfate sodium (DSS)-induced colitis in a mouse model.

Targeted delivery of bioactive compounds such as proteins to the colon has numerous advantages for the therapeutic treatment of inflammatory bowel disease. The present study sought to fabricate alginate/chitosan microcapsules containing IL-1Ra (Alg/Chi/IL-1Ra MC) via a single-step electrospraying method. Two important factors of efficacy were measured-the pH-responsiveness of the microcapsule and the in-vitro drug release profile. The DSS-induced colitis mouse model was used to evaluate the therapeutic effect of the Alg/Chi/IL-1Ra microcapsules, with results showing the protective effect of the Alg/Chi microcapsules for the passage of IL-1Ra through the harsh environment of the upper gastrointestinal tract. This effect was owing to the pH-sensitive response of the microcapsule, which allowed the targeted release of IL-1Ra in the colon. DAI evaluation, colon length, colon tissue morphology, histologic damage scores and relative protein concentrations (MPO, TNF-α and IL-1ß) demonstrated that the Alg/Chi/IL-1Ra microcapsules alleviated DSS-induced colitis in mice. The present study thus demonstrates a practical means of oral delivery of proteins, in-situ colon release, and a promising application of IL-1Ra in the treatment of autoimmune and inflammatory diseases.