Hepatic polypeptide nutrient solution improves high-cholesterol diet-induced rats with nonalcoholic fatty liver disease by activating AMP-activated protein kinase signaling pathway.

Hepatic polypeptide nutrient solution (HP) is a mixture of hepatoprotective peptides derived from fresh porcine liver with various effects. However, the role and mechanisms of HP in nonalcoholic fatty liver disease (NAFLD) are still not well understood. We investigated the effects of HP NAFLD rats induced by high-cholesterol diet (HCD) and its underlying mechanisms. Rats were provided with HCD for 4 weeks and then received HP or metformin after 2 weeks of HCD feeding. The study found that HP reduced cholesterol and triglyceride levels in rats with NAFLD (all p < .05). Histopathological examination also showed that HP improved the liver lesions induced by the HCD diet. Furthermore, the oxidative stress and inflammatory responses of NAFLD rats treated with HP were also improved. In addition, it was discovered that HP triggered the activation of AMPK and decreased the expression of SREBP-1c and FAS while enhancing the expression of PPAR α and CPT-1 in liver. These findings indicated that HP might have therapeutic potential for NAFLD, possibly via activating AMPK signaling pathway.

Synergistic Effect of ZIF-8 and Pt-Functionalized NiO/In2O3 Hollow Nanofibers for Highly Sensitive Detection of Formaldehyde.

A rapid and accurate monitoring of hazardous formaldehyde (HCHO) gas is extremely essential for health protection. However, the high-power consumption and humidity interference still hinder the application of HCHO gas sensors. Hence, zeolitic imidazolate framework-8 (ZIF-8)-loaded Pt-NiO/In2O3 hollow nanofibers (ZPNiIn HNFs) were designed via the electrospinning technique followed by hydrothermal treatment, aiming to enable a synergistic advantage of the surface modification and the construction of a p-n heterostructure to improve the sensing performance of the HCHO gas sensor. The ZPNiIn HNF sensor has a response value of 52.8 to 100 ppm HCHO, a nearly 4-fold enhancement over a pristine In2O3 sensor, at a moderately low temperature of 180 °C, along with rapid response/recovery speed (8/17 s) and excellent humidity tolerance. These enhanced sensing properties can be attributed to the Pt catalysts boosting the catalytic activity, the p-n heterojunctions facilitating the chemical reaction, and the appropriate ZIF-8 loading providing a hydrophobic surface. Our research presents an effective sensing material design strategy for inspiring the development of cost-effective sensors for the accurate detection of indoor HCHO hazardous gas.

The effect of respiratory muscle training on children and adolescents with cystic fibrosis: a systematic review and meta-analysis.

BACKGROUND: Cystic fibrosis is a chronic genetic disease that can affect the function of the respiratory system. Previous reviews of the effects of respiratory muscle training in people with cystic fibrosis are uncertain and do not consider the effect of age on disease progression. This systematic review aims to determine the effectiveness of respiratory muscle training in the clinical outcomes of children and adolescents with cystic fibrosis. METHODS: Up to July 2023, electronic databases and clinical trial registries were searched. Controlled clinical trials comparing respiratory muscle training with sham intervention or no intervention in children and adolescents with cystic fibrosis. The primary outcomes were respiratory muscle strength, respiratory muscle endurance, lung function, and cough. Secondary outcomes included exercise capacity, quality of life and adverse events. Two review authors independently extracted data and assessed study quality using the Cochrane Risk of Bias Tool 2. The certainty of the evidence was assessed according to the GRADE approach. Meta-analyses where possible; otherwise, take a qualitative approach. RESULTS: Six studies with a total of 151 participants met the inclusion criteria for this review. Two of the six included studies were published in abstract form only, limiting the available information. Four studies were parallel studies and two were cross-over designs. There were significant differences in the methods and quality of the methodology included in the studies. The pooled data showed no difference in respiratory muscle strength, lung function, and exercise capacity between the treatment and control groups. However, subgroup analyses suggest that inspiratory muscle training is beneficial in increasing maximal inspiratory pressure, and qualitative analyses suggest that respiratory muscle training may benefit respiratory muscle endurance without any adverse effects. CONCLUSIONS: This systematic review and meta-analysis indicate that although the level of evidence indicating the benefits of respiratory muscle training is low, its clinical significance suggests that we further study the methodological quality to determine the effectiveness of training. TRIAL REGISTRATION: The protocol for this review was recorded in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42023441829.

17ß-Estradiol promotes metastasis in triple-negative breast cancer through the Calpain/YAP/ß-catenin signaling axis.

ß-catenin is an important regulator of malignant progression. 17ß-Estradiol (E2), an important sex hormone in women, promotes the growth and metastasis of triple-negative breast cancer (TNBC). However, whether ß-catenin is involved in E2-induced metastasis of TNBC remains unknown. In this study, we show that E2 induces the proliferation, migration, invasion, and metastasis of TNBC cells. E2 induces ß-catenin protein expression and nuclear translocation, thereby regulating the expression of target genes such as Cyclin D1 and MMP-9. The inhibition of ß-catenin reversed the E2-induced cell malignant behaviors. Additionally, E2 activated Calpain by increasing intracellular Ca2+ levels and reducing calpastatin levels. When Calpain was inhibited, E2 did not induce the proliferation, migration, invasion, or metastasis of TNBC cells. In addition, E2 promoted translocation of YAP into the nucleus by inhibiting its phosphorylation. Calpain inhibition reversed the E2-induced YAP dephosphorylation. Inhibition of YAP transcriptional activity reversed the effects of E2 on the proliferation, migration, invasion, and ß-catenin of TNBC cells. In conclusion, we demonstrated that E2 induced metastasis-related behaviors in TNBC cells and this effect was mediated through the Calpain/YAP/ß-catenin signaling pathway.

Malignancy diagnosis of liver lesion in contrast enhanced ultrasound using an end-to-end method based on deep learning.

BACKGROUND: Contrast-enhanced ultrasound (CEUS) is considered as an efficient tool for focal liver lesion characterization, given it allows real-time scanning and provides dynamic tissue perfusion information. An accurate diagnosis of liver lesions with CEUS requires a precise interpretation of CEUS images. However,it is a highly experience dependent task which requires amount of training and practice. To help improve the constrains, this study aims to develop an end-to-end method based on deep learning to make malignancy diagnosis of liver lesions using CEUS. METHODS: A total of 420 focal liver lesions with 136 benign cases and 284 malignant cases were included. A deep learning model based on a two-dimensional convolution neural network, a long short-term memory (LSTM), and a linear classifier (with sigmoid) was developed to analyze the CEUS loops from different contrast imaging phases. For comparison, a 3D-CNN based method and a machine-learning (ML)-based time-intensity curve (TIC) method were also implemented for performance evaluation. RESULTS: Results of the 4-fold validation demonstrate that the mean AUC is 0.91, 0.88, and 0.78 for the proposed method, the 3D-CNN based method, and the ML-based TIC method, respectively. CONCLUSIONS: The proposed CNN-LSTM method is promising in making malignancy diagnosis of liver lesions in CEUS without any additional manual features selection.

Targeting pro-inflammatory T cells as a novel therapeutic approach to potentially resolve atherosclerosis in humans.

Atherosclerosis (AS), a leading cause of cardio-cerebrovascular disease worldwide, is driven by the accumulation of lipid contents and chronic inflammation. Traditional strategies primarily focus on lipid reduction to control AS progression, leaving residual inflammatory risks for major adverse cardiovascular events (MACEs). While anti-inflammatory therapies targeting innate immunity have reduced MACEs, many patients continue to face significant risks. Another key component in AS progression is adaptive immunity, but its potential role in preventing AS remains unclear. To investigate this, we conducted a retrospective cohort study on tumor patients with AS plaques. We found that anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) significantly reduces AS plaque size. With multi-omics single-cell analyses, we comprehensively characterized AS plaque-specific PD-1+ T cells, which are activated and pro-inflammatory. We demonstrated that anti-PD-1 mAb, when captured by myeloid-expressed Fc gamma receptors (FcγRs), interacts with PD-1 expressed on T cells. This interaction turns the anti-PD-1 mAb into a substitute PD-1 ligand, suppressing T-cell functions in the PD-1 ligands-deficient context of AS plaques. Further, we conducted a prospective cohort study on tumor patients treated with anti-PD-1 mAb with or without Fc-binding capability. Our analysis shows that anti-PD-1 mAb with Fc-binding capability effectively reduces AS plaque size, while anti-PD-1 mAb without Fc-binding capability does not. Our work suggests that T cell-targeting immunotherapy can be an effective strategy to resolve AS in humans.

Characteristics of meat flavoring prepared using hydrolyzed plant protein mix by three different heating processes.

Meat flavoring was prepared using mainly enzymatic hydrolysate of plant protein mix, VB1, cysteine, and glucose by three heating processes, including A (80 °C-140 min), B (two-stage, 80 °C-30 min/120 °C-30 min), and C (120 °C-40 min). The A-, B-, and C-heated samples exhibited the strongest fatty and weakest meaty, the strongest meaty and kokumi, and the strongest roasted and bitterness characteristics, respectively. PLS-DA for free amino acids with TAVs and that for SPME/GC-MS results with GC-O and OAVs, suggested three amino acids and eight flavor compounds contributed significantly in differentiating taste or aroma attributes of the three heated samples. Molecular weight distribution and degree of amino substitution suggested 1-5 kDa peptides contributed to kokumi taste. Overall, C- and A-heating exhibited the highest rates in Maillard reaction and lipid oxidation, respectively, while those of B heating were between these two heating processes and responsible for better flavor of meat flavoring.

m6A-Mediated Upregulation of Imprinted in Prader-Willi Syndrome Induces Aberrant Apical-Basal Polarization and Oxidative Damage in RPE Cells.

Purpose: To reveal the clinical significance, pathological involvement and molecular mechanism of imprinted in Prader-Willi syndrome (IPW) in RPE anomalies that contribute to AMD. Methods: IPW expression under pathological conditions were detected by microarrays and qPCR assays. In vitro cultured fetal RPE cells were used to study the pathogenicity induced by IPW overexpression and to analyze its upstream and downstream regulatory networks. Results: We showed that IPW is upregulated in the macular RPE-choroid tissue of dry AMD patients and in fetal RPE cells under oxidative stress, inflammation and dedifferentiation. IPW overexpression in fetal RPE cells induced aberrant apical-basal polarization as shown by dysregulated polarized markers, disrupted tight and adherens junctions, and inhibited phagocytosis. IPW upregulation was also associated with RPE oxidative damages, as demonstrated by intracellular accumulation of reactive oxygen species, reduced cell proliferation, and accelerated cell apoptosis. Mechanically, N6-methyladenosine level of the IPW transcript regulated its stability with YTHDC1 as the reader. IPW mediated RPE features by suppressing MEG3 expression to sequester its inhibition on the AKT serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) pathway. We also noticed that the mTOR inhibitor rapamycin suppresses the AKT/mTOR pathway to alleviate the IPW-induced RPE anomalies. Conclusions: We revealed that IPW overexpression in RPE induces aberrant apical-basal polarization and oxidative damages, thus contributing to AMD progression. We also annotated the upstream and downstream regulatory networks of IPW in RPE. Our findings shed new light on the molecular mechanisms of RPE dysfunctions, and indicate that IPW blockers may be a promising option to treat RPE abnormalities in AMD.

Association of immune inflammatory biomarkers with pathological complete response and clinical prognosis in young breast cancer patients undergoing neoadjuvant chemotherapy.

Background: The persistence of inflammatory stimulus has a tight relationship with the development of age-related diseases, ultimately resulting in a gradual escalation in the prevalence of tumors, but this phenomenon is rare in young cancer patients. Breast cancer arising in young women is characterized by larger tumor diameters and more aggressive subtypes, so neoadjuvant chemotherapy (NACT) can be especially appropriate for this population. Immune inflammatory biomarkers have been reportedly linked to the prognosis of some malignant tumor types, with varying results. In this study, we investigated the possible predictive value of blood-based markers in young breast cancer patients undergoing NACT, in addition to the association between the clinicopathological features and prognosis. Methods: From December 2011 to October 2018, a total of 215 young breast cancer patients referred to Harbin Medical University Cancer Hospital received NACT and surgery were registered in this retrospective study. The pretreatment complete blood counts were used to calculate the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and pan-immune-inflammation value (PIV). Results: NLR, PLR, MLR, and PIV optimal cut-off values were 1.55, 130.66, 0.24, and 243.19, as determined by receiver operating characteristic analysis. Multivariate analysis revealed that PIV, HR status, HER-2 status, and Ki-67 index were all independent predictive factors for pathological complete response. Subgroup analysis revealed that young breast cancer patients in the population characterized by low PIV and HR negative group were more likely to get pCR (P=0.001). The five-year overall survival (OS) rate was 87.9%, and Cox regression models identified PIV as independently related to OS. Conclusion: In the present study, the pretreatment PIV was found to be a useful prognostic indicator for pCR and long-term survival in young breast cancer patients undergoing NACT. High immune and inflammation levels, MLR and PIV were connected to poor clinical prognosis in young breast cancer patients. PIV is a promising biomarker to guide strategic decisions in treating young breast cancer.

Human amniotic MSCs-mediated anti-inflammation of CD206hiIL-10hi macrophages alleviates isoproterenol-induced ventricular remodeling in mice.

BACKGROUND: Human amniotic mesenchymal stem cells (hAMSCs) derived from amniotic membrane have multilineage differentiation, immunosuppressive, and anti-inflammation which makes them suitable for the treatment of various diseases. OBJECTIVE: This study aimed to explore the therapeutic effect and molecular mechanism of hAMSCs in ventricular remodeling (VR). METHODS: hAMSCs were characterized by a series of experiments such as flow cytometric analysis, immunofluorescence, differentiative induction and tumorigenicity. Mouse VR model was induced by isoproterenol (ISO) peritoneally, and the therapeutic effects and the potential mechanisms of hAMSCs transplantation were evaluated by echocardiography, carboxy fluorescein diacetate succinimidyl ester (CFSE) labeled cell tracing, histochemistry, qRT-PCR and western blot analysis. The co-culturing experiments were carried out for further exploring the mechanisms of hAMSCs-derived conditioned medium (CM) on macrophage polarization and fibroblast fibrosis in vitro. RESULTS: hAMSCs transplantation significantly alleviated ISO-induced VR including cardiac hypertrophy and fibrosis with the improvements of cardiac functions. CFSE labeled hAMSCs kept an undifferentiated state in heart, indicating that hAMSCs-mediated the improvement of ISO-induced VR might be related to their paracrine effects. hAMSCs markedly inhibited ISO-induced inflammation and fibrosis, seen as the increase of M2 macrophage infiltration and the expressions of CD206 and IL-10, and the decreases of CD86, iNOS, COL3 and αSMA expressions in heart, suggesting that hAMSCs transplantation promoted the polarization of M2 macrophages and inhibited the polarization of M1 macrophages. Mechanically, hAMSCs-derived CM significantly increased the expressions of CD206, IL-10, Arg-1 and reduced the expressions of iNOS and IL-6 in RAW264.7 macrophages in vitro. Interestingly, RAW264.7-CM remarkably promoted the expressions of anti-inflammatory factors such as IL-10, IDO, and COX2 in hAMSCs. Furthermore, the CM derived from hAMSCs pretreated with RAW264.7-CM markedly inhibited the expressions of fibrogenesis genes such as αSMA and COL3 in 3T3 cells. CONCLUSION: Our results demonstrated that hAMSCs effectively alleviated ISO-induced cardiac hypertrophy and fibrosis, and improved the cardiac functions in mice, and the underlying mechanisms might be related to inhibiting the inflammation and fibrosis during the ventricular remodeling through promoting the polarization of CD206hiIL-10hi macrophages in heart tissues. Our study strongly suggested that by taking the advantages of the potent immunosuppressive and anti-inflammatory effects, hAMSCs may provide an alternative therapeutic approach for prevention and treatment of VR clinically.

Paclitaxel-coated balloon catheter for benign esophageal stenosis in a rabbit model.

Most patients with benign esophageal stenosis require multiple or even continuous balloon dilation treatments to achieve symptom relief. In this study, eighteen rabbits were used to establish an esophageal benign stenosis model and were divided into a control group (n = 6), a balloon group (n = 6) and a PTX-coated balloon group (n = 6) to evaluate the feasibility and effectiveness of paclitaxel (PTX)-coated balloons for the rabbit esophageal benign stenosis model. The weight and esophageal diameter were recorded every 2 weeks until 8 weeks post-surgery. Hematoxylin-eosin staining, Masson's trichrome staining and immunohistochemical staining were performed for pathological analysis. Four weeks post-operation, there was a significant difference in weight between the control group and the balloon group (p = 0.01) and between the control group and the PTX balloon group (p = 0.01). There was a significant difference in the esophageal diameter between the balloon group and the PTX balloon group at 8 weeks post-operation (p = 0.02). Four weeks post-operation, the degree of inflammatory cell infiltration in the PTX balloon group was significantly lower than that in the control group (p = 0.002) and balloon group (p = 0.001). The degree of collagen deposition in the PTX balloon group was significantly lower than that in the control group (p = 0.002) and balloon group (p = 0.03). Eight weeks post-operation, the percentage of cells positive for TGF-ß (p < 0.001), the degree of inflammatory cell infiltration (p = 0.02) and the degree of collagen deposition (p = 0.02) in the PTX balloon group were significantly lower than those in the balloon group. Therefore, PTX-coated balloons may alleviate the local inflammatory response and collagen deposition when used during dilation treatment of benign esophageal stenosis.

Efficacy and safety of olmesartan medoxomil­amlodipine besylate tablets (Sevikar®) in older patients with essential hypertension: Subgroup analysis from the Sevikar study.

Essential hypertension is a notable threat for the older (age, ≥65 years) population. However, to the best of our knowledge, a real-world study assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablets in older Chinese patients with essential hypertension has not been performed. Therefore, the present study aimed to evaluate the efficacy and safety of OM-AML tablets in these patients. A total of 463 older Chinese patients with essential hypertension treated with OM-AML (20/5 mg) tablets (Sevikar®) were analyzed in a prospective, single-arm, multi-center, real-world study. Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, and at week (W)4 and W8 after OM-AML tablet administration were measured. The mean ± standard error change of SeSBP/SeDBP was -10.3±0.8/-4.6±0.5 and -12.5±0.8/-5.6±0.5 mmHg at W4 and W8, respectively. At W4, 74.1 and 26.8% of patients achieved BP target according to the China and American Heart Association (AHA) criteria, while at W8, 78.0 and 38.7% of patients reached these BP targets accordingly. Finally, 76.5 and 80.5% of patients achieved BP response at W4 and W8, respectively. Furthermore, home-measured SeSBP and SeDBP were significantly decreased from W1 to W8 (both P<0.001). Additionally, the satisfaction of both patients and physicians was elevated at W8 compared with at W0 (both P<0.001). The medication possession rate from baseline to W4 and W8 was 95.5 and 92.5%. The most common drug-associated adverse events by system organ classes were nervous system disorder (4.5%), vascular disorder (2.8%), and general disorder and administration site conditions (2.6%), which were generally mild. In conclusion, OM-AML tablets may be considered effective and safe in lowering BP, enabling the achievement of guideline-recommended BP targets in older Chinese patients with essential hypertension.

Effect of tumour necrosis factor-a inhibitors exposure on surgical site infections in rheumatoid arthritis patients undergoing elective orthopaedic surgery: A meta-analysis.

A meta-analysis investigation was executed to evaluate the effect of tumour necrosis factor-a inhibitor exposure on surgical site infections in rheumatoid arthritis patients undergoing elective orthopaedic surgery. A comprehensive literature investigation till October 2023 was applied, and 82 470 individuals with orthopaedic surgery were in the chosen investigations' starting point. Odds ratio (OR) in addition to 95% confidence intervals (CIs) was utilized to compute the value of the effect of tumour necrosis factor-a inhibitors exposure on surgical site infections in rheumatoid arthritis patients undergoing elective orthopaedic surgery by the dichotomous approaches and a fixed or random model. Tumour necrosis factor uses had significantly higher surgical site infections (OR, 1.65; 95% CI, 1.21-2.25, p = 0.001) compared with tumour necrosis factor non-use in rheumatoid arthritis patients undergoing elective orthopaedic surgery. However, no significant difference was found between discontinued and continued tumour necrosis factor on surgical site infections (OR, 0.61; 95% CI, 0.35-1.05, p = 0.07) in rheumatoid arthritis patients undergoing elective orthopaedic surgery.Significantly higher surgical site infections was found comparing tumour necrosis factor uses to non-use; however, no significant difference was found between discontinued and continued tumour necrosis factor on surgical site infections in rheumatoid arthritis patients undergoing elective orthopaedic surgery. However, care must be exercised when dealing with its values because of the low sample size of some of the nominated investigations for the meta-analysis.

Dynamics of Endothelial Cell Generation and Turnover in Arteries During Homeostasis and Diseases.

BACKGROUND: Endothelial cell (EC) generation and turnover by self-proliferation contributes to vascular repair and regeneration. The ability to accurately measure the dynamics of EC generation would advance our understanding of cellular mechanisms of vascular homeostasis and diseases. However, it is currently challenging to evaluate the dynamics of EC generation in large vessels such as arteries because of their infrequent proliferation. METHODS: By using dual recombination systems based on Cre-loxP and Dre-rox, we developed a genetic system for temporally seamless recording of EC proliferation in vivo. We combined genetic recording of EC proliferation with single-cell RNA sequencing and gene knockout to uncover cellular and molecular mechanisms underlying EC generation in arteries during homeostasis and disease. RESULTS: Genetic proliferation tracing reveals that ≈3% of aortic ECs undergo proliferation per month in adult mice during homeostasis. The orientation of aortic EC division is generally parallel to blood flow in the aorta, which is regulated by the mechanosensing protein Piezo1. Single-cell RNA sequencing analysis reveals 4 heterogeneous aortic EC subpopulations with distinct proliferative activity. EC cluster 1 exhibits transit-amplifying cell features with preferential proliferative capacity and enriched expression of stem cell markers such as Sca1 and Sox18. EC proliferation increases in hypertension but decreases in type 2 diabetes, coinciding with changes in the extent of EC cluster 1 proliferation. Combined gene knockout and proliferation tracing reveals that Hippo/vascular endothelial growth factor receptor 2 signaling pathways regulate EC proliferation in large vessels. CONCLUSIONS: Genetic proliferation tracing quantitatively delineates the dynamics of EC generation and turnover, as well as EC division orientation, in large vessels during homeostasis and disease. An EC subpopulation in the aorta exhibits more robust cell proliferation during homeostasis and type 2 diabetes, identifying it as a potential therapeutic target for vascular repair and regeneration.

Efficacy and safety of olmesartan medoxomil-amlodipine besylate tablet in Chinese patients with essential hypertension: A prospective, single-arm, multi-center, real-world study.

There lacks real-world study with a large sample size assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM-AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM-AML (20/5 mg) tablet were analyzed in the current prospective, single-arm, multi-center, real-world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was -10.8 ± 0.4/-6.6 ± 0.3 mmHg at W4 and -12.7 ± 0.5/-7.6 ± 0.3 mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home-measured SeSBP and SeDBP decreased from W1 to W8 (both p < .001). Besides, patients' and physicians' satisfaction were elevated at W8 compared with W0 (both p < .001). The medication possession rate was 94.8% from baseline to W4 and 91.3% from baseline to W8. The most common drug-related adverse events were nervous system disorders (4.6%), vascular disorders (2.6%), and general disorders and administration site conditions (2.3%) by system organ class, which were generally mild and manageable. In conclusion, OM-AML tablet is one of the best antihypertensive agents in patients with essential hypertension.

Tolterodine ameliorates inflammatory response and ferroptosis against LPS in human bladder epithelial cells.

Bacterial endotoxin lipopolysaccharide (LPS)-induced inflammatory response and ferroptosis play an important role in urinary tract infections. Tolterodine has been used as a urinary tract antispasmodic and anticholinergic agent. However, the effects of Tolterodine against LPS-induced insults in human bladder epithelial cells (hBECs) have not been reported before. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release assays to determine the cell viability, reactive oxygen species (ROS) and malondialdehyde level detection were used to determine the level of oxidative stress, enzyme-linked immunosorbent assay and Western blot analysis were used to detect the protein level. In the current study, we found that Tolterodine ameliorated LPS-induced production of ROS and lipid oxidation in hBECs. Interestingly, Tolterodine inhibited the production of interleukin 6, interleukin-1ß, and tumor necrosis factor α. Also, Tolterodine reduced the levels of Fe2+ and suppressed ferroptosis by reducing the levels of glutathione peroxidase 4, prostaglandin-endoperoxide synthase 2, and acyl-CoA synthetase long-chain family member 4 in LPS-challenged bladder epithelial cells. Mechanistically, it was shown that Tolterodine restored the nuclear factor E2-related factor 2 (Nrf2)/nuclear factor-κB signaling. Importantly, inhibition of Nrf2 with its specific inhibitor ML385 abolished the protective effects of Tolterodine in the inflammatory response and ferroptosis, suggesting that the effects of Tolterodine are mediated by Nrf2. Based on these findings, we conclude that Tolterodine might serve as a promising agent for the treatment of LPS-induced bladder inflammation.

Vaccarin alleviates cisplatin-induced acute kidney injury via decreasing NOX4-derived ROS.

Cisplatin is a chemotherapeutant widely used in treating solid tumors, with the common side effect of acute kidney injury (AKI). Developing effective useful agent for preventing or treating cisplatin-induced AKI is of great importance. In this study, we investigate the protective effect of vaccarin, a chemical entity of flavonoid glycoside, against cisplatin-induced AKI. Cisplatin-treated C57BL/6J mice and human kidney-2 (HK-2) cells were used as the model of cisplatin-induced AKI. The levels of blood urea nitrogen (BUN) and creatine (Cr) levels and periodic acid-Schiff staining (PAS) scores decreased when vaccarin was administrated. Vaccarin had no impact on renal platinum accumulation, which was detected by the ICP-MS 6 h after cisplatin injection. Moreover, vaccarin can significantly alleviate the product of reactive oxygen species and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) in cisplatin-induced AKI, both in vivo and in vitro. In addition, vaccarin decreased the receptor-interacting protein kinase 1 (RIPK1) related programmed necrosis (necroptosis), cell apoptosis (shown by the protein levels of cleaved-caspase3 and flow cytometry) and inflammation (shown by the decreased levels of NLRP3, p-P65 and the mRNA of several inflammatory factors). NOX4 inhibitor GLX351322 (GLX) and NOX4 kowndown by siRNA have equivalent protective effect of vaccarin in vitro. When vaccarin was administered together with GLX or NOX4 siRNA, this protective effect of vaccarin did not further increase, as indicating by the index of oxidative stress, cell viability, necroptosis and apoptosis. In conclusion, vaccarin can alleviate cisplatin-induced AKI via inhibiting NOX4.

Semisynthesis and in Vitro Anti-cancer Effect of New Magnolol Derivatives on the Cell Proliferation, Apoptosis, Migration, and Invasion of Human Hepatocellular Carcinoma SMMC-7721 Cells.

Four new magnolol derivatives were synthesized and evaluated for their in vitro anti-cancer properties. Among these, compound 3 showed the most potent cytotoxic activity against the SMMC-7721, SUN-449, and HepG2 human hepatocellular carcinoma cell lines, with IC50 values of 3.39, 4.11, and 6.88 µM, respectively. Compound 3 also induced apoptosis of SMMC-7721 cells by down-regulating Bcl-2 and Akt protein levels, up-regulating of Bax protein level, and cleaving caspase-9 and -3. In addition, transwell assays showed that compound 3 significantly suppressed the migration and invasion of SMMC-7721 cells, which was confirmed based on the down-regulation of hypoxia inducible factor-1α (HIF-1α), matrix metalloproteinase-2 and -9 (MMP-2, and MMP-9) protein levels.

Elaiophylin Elicits Robust Anti-Tumor Responses via Apoptosis Induction and Attenuation of Proliferation, Migration, Invasion, and Angiogenesis in Pancreatic Cancer Cells.

Pancreatic cancer remains a formidable challenge in oncology due to its aggressive nature and limited treatment options. In this study, we investigate the potential therapeutic efficacy of elaiophylin, a novel compound, in targeting BxPC-3 and PANC-1 pancreatic cancer cells. We comprehensively explore elaiophylin's impact on apoptosis induction, proliferation inhibition, migration suppression, invasion attenuation, and angiogenesis inhibition, key processes contributing to cancer progression and metastasis. The results demonstrate that elaiophylin exerts potent pro-apoptotic effects, inducing a substantial increase in apoptotic cells. Additionally, elaiophylin significantly inhibits proliferation, migration, and invasion of BxPC-3 and PANC-1 cells. Furthermore, elaiophylin exhibits remarkable anti-angiogenic activity, effectively disrupting tube formation in HUVECs. Moreover, elaiophylin significantly inhibits the Wnt/ß-Catenin signaling pathway. Our findings collectively demonstrate the multifaceted potential of elaiophylin as a promising therapeutic agent against pancreatic cancer via inhibition of the Wnt/ß-Catenin signaling pathway. By targeting diverse cellular processes crucial for cancer progression, elaiophylin emerges as a prospective candidate for future targeted therapies. Further investigation of the in vivo efficacy of elaiophylin is warranted, potentially paving the way for novel and effective treatment approaches in pancreatic cancer management.

Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration.

BACKGROUND: The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of heart disease. Previous studies demonstrated that knockdown of the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) inhibits mitochondrial translation and thereby causes a mitonuclear protein imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the role of these processes on cardiomyocyte proliferation. METHODS: We deleted a single allele of MRPS5 in mice and used left anterior descending coronary artery ligation surgery to induce myocardial damage in these animals. We examined cardiomyocyte proliferation and cardiac regeneration both in vivo and in vitro. Doxycycline treatment was used to inhibit protein translation. Heart function in mice was assessed by echocardiography. Quantitative real-time polymerase chain reaction and RNA sequencing were used to assess changes in transcription and chromatin immunoprecipitation (ChIP) and BioChIP were used to assess chromatin effects. Protein levels were assessed by Western blotting and cell proliferation or death by histology and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. Adeno-associated virus was used to overexpress genes. The luciferase reporter assay was used to assess promoter activity. Mitochondrial oxygen consumption rate, ATP levels, and reactive oxygen species were also analyzed. RESULTS: We determined that deletion of a single allele of MRPS5 in mice results in elevated cardiomyocyte proliferation and cardiac regeneration; this observation correlates with improved cardiac function after induction of myocardial infarction. We identified ATF4 (activating transcription factor 4) as a key regulator of the mitochondrial stress response in cardiomyocytes from Mrps5+/- mice; furthermore, ATF4 regulates Knl1 (kinetochore scaffold 1) leading to an increase in cytokinesis during cardiomyocyte proliferation. The increased cardiomyocyte proliferation observed in Mrps5+/- mice was attenuated when one allele of Atf4 was deleted genetically (Mrps5+/-/Atf4+/-), resulting in the loss in the capacity for cardiac regeneration. Either MRPS5 inhibition (or as we also demonstrate, doxycycline treatment) activate a conserved regulatory mechanism that increases the proliferation of human induced pluripotent stem cell-derived cardiomyocytes. CONCLUSIONS: These data highlight a critical role for MRPS5/ATF4 in cardiomyocytes and an exciting new avenue of study for therapies to treat myocardial injury.