Efficacy and safety of Qingda granule versus valsartan capsule in Chinese grade 1 hypertensive patients with low-moderate risk: A randomized, double-blind, double dummy, non-inferiority, multi-center trial.

BACKGROUND: The efficacy and safety of Qingda granule (QDG) in managing blood pressure (BP) among grade 1 hypertensive patients with low-moderate risk remain uncertain. METHODS: In the randomized, double-blind, double dummy, non-inferiority and multicenter trial, 552 patients with grade 1 hypertension at low-moderate risk were assigned at a ratio of 1:1 to receive either QDG or valsartan for 4 weeks, followed up by a subsequent 4 weeks. RESULTS: Post-treatment, clinic systolic/diastolic BPs (SBP/DBP) were reduced by a mean change of 9.18/4.04 mm Hg in the QDG group and 9.85/5.05 mm Hg in the valsartan group (SBP P = 0.47, DBP P = 0.16). Similarly, 24-hour, daytime and nighttime BPs were proportional in both groups (P > 0.05) after 4 weeks treatment. After discontinuing medications for 4 weeks, the mean reduction of clinic SBP/DBP were 0.29/0.57 mm Hg in the QDG group compared to -1.59/-0.48 mm Hg in the valsartan group (SBP P = 0.04, DBP P = 0.04). Simultaneously, the 24-hour SBP/DBP were reduced by 0.9/0.31 mm Hg in the QDG group and -1.66/-1.08 mm Hg in the valsartan group (SBP P = 0.006, DBP P = 0.02). And similar results were observed regarding the outcomes of daytime and nighttime BPs. There was no difference in occurrence of adverse events between two groups (P > 0.05). CONCLUSION: QDG proves to be efficacious for grade 1 hypertension at a low-to-medium risk, even after discontinuation of the medication for 4 weeks. These findings provide a promising option for managing grade 1 hypertension and suggest the potential for maintaining stable BP through intermittent administration of QDG. TRIAL REGISTRATION: ChiCTR2000033890.

Quercetin protects against hypertensive renal injury by attenuating apoptosis: an integrated approach using network pharmacology and RNA-Seq.

Quercetin is kown for its antihypertensive effects. However, its role on hypertensive renal injury has not been fully eucidated. In this study, hematoxylin and eosin staining, terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining, and Annexin V staining were used to assess the pathological changes and cells apoptosis in the renal tissues of Ang II-infused mice and Ang II- stimulated renal tubular epithelial cell line (NRK-52E). A variety of technologies, including network pharmacology, RNA-sequencing, immunohistochemistry, and Western blotting were performed to investigate its underlying mechanisms. Network pharmacology analysis identified multiple potential candidate targets (including TP53, Bcl-2 and Bax) and enriched signaling pathways (including apoptosis and p53 signaling pathway). Quercetin treatment significantly alleviated the pathological changes in renal tissues of Ang II-infused mice and reversed 464 differentially expressed transcripts (DETs), as well as enriched several signaling pathways, including those related apoptosis and p53 pathway. Furthermore, quercetin treatment significantly inhibited the cell apoptosis in renal tissues of Ang II-infused mice and Ang II-stimulated NRK-52E cells. Additionally, quercetin treatment inhibited the upregulation of p53, Bax, cleaved-caspase-9, and cleaved-caspase-3 protein expression and the downregulation of Bcl-2 protein expression in both renal tissue of Ang II-infused mice and Ang II-stimulated NRK-52E cells. Moreover, the molecular docking results indicated a potential binding interaction between quercetin and TP53. Quercetin treatment significantly attenuated hypertensive renal injury and cell apoptosis in renal tissues of Ang II-infused mice and Ang II-stimulated NRK-52E cells, and by targeting p53 may be one of the potential underlying mechanisms.

Generation of robust optical entanglement in cavity optomagnonics.

We propose a scheme to realize robust optical entanglement in cavity optomagnonics, where two optical whispering gallery modes (WGMs) couple to a magnon mode in a yttrium iron garnet (YIG) sphere. The beam-splitter-like and two-mode squeezing magnon-photon interactions can be realized simultaneously when the two optical WGMs are driven by external fields. Entanglement between the two optical modes is then generated via their coupling with magnons. By exploiting the destructive quantum interference between the bright modes of the interface, the effects of initial thermal occupations of magnons can be eliminated. Moreover, the excitation of the Bogoliubov dark mode is capable of protecting the optical entanglement from thermal heating effects. Therefore, the generated optical entanglement is robust against thermal noise and the requirement of cooling the magnon mode is relaxed. Our scheme may find applications in the study of magnon-based quantum information processing.

Dissipation-driven entanglement between two microwave fields in a four-mode hybrid cavity optomechanical system.

The generation and manipulation of highly pure and strongly entangled steady state in a quantum system are vital tasks in the standard continuous-variable teleportation protocol. Especially, the manipulation implemented in integrated devices is even more crucial in practical quantum information applications. Here we propose an effective approach for creating steady-state entanglement between two microwave fields in a four-mode hybrid cavity optomechanical system. The entanglement can be achieved by combining the processes of three beam-splitter interactions and two parametric-amplifier interactions. Due to the dissipation-driven and cavity cooling processes, the entanglement obtained can go far beyond the entanglement limit based on coherent parametric coupling. Moreover, our proposal allows the engineered bath to cool both Bogoliubov modes almost simultaneously. In this way, a highly pure and strongly entangled steady state of two microwave modes is obtained. Our finding may be significant for using the hybrid opto-electro-mechanical system fabricated on chips in various quantum tasks, where the strong and pure entanglement is an important resource.

The difference in pathogenic bacteria between chronic rhinosinusitis in patients with and without Sjogren's syndrome: a retrospective case-control study.

BACKGROUND: Chronic rhinosinusitis (CRS) affects the quality of life of many people worldwide and can cause comorbidities. Our previous research proved that Sjogren's syndrome (SS) is a predisposing factor for CRS, with a 2.5-fold associated risk. Antibiotics are important in CRS treatment; however, there is a paucity of research on the pathogenic bacteria of SS-CRS in the past. We conducted this study to investigate the pathogenic difference of SS-CRS and non-SS-CRS and aimed to give clinicians references when selecting antibiotics to treat SS-CRS. MATERIALS AND METHODS: A total of 14,678 patients hospitalized for CRS operation from 2004 to 2018 were identified from the Chang Gung Research Database. These CRS cases were classified as either SS-CRS or non-SS-CRS. We analyzed their bacterial distribution by studying the results of the pus cultures performed alongside surgery. RESULTS: The top three facultative anaerobic or aerobic isolated bacteria in the SS-CRS group were coagulase-negative Staphylococcus (CoNS: 34.3%), Pseudomonas aeruginosa (28.6%), methicillin-sensitive Staphylococcus aureus (MSSA: 20%), and Staphylococcus epidermidis (20%). In the non-SS-CRS group, S. epidermidis (29.3%), CoNS (25.7%), and MSSA (14.2%) were identified. The top three anaerobic bacterial genera were Cutibacterium (54.3%), Peptostreptococcus (11.4%), and Fusobacterium (11.4%) in the SS-CRS group and Cutibacterium (53.8%), Peptostreptococcus (25%), and Prevotella (12.9%) in the non-SS-CRS group. CONCLUSIONS: P. aeruginosa is a major pathogen in SS-CRS patients. In addition, physicians should be aware of potential Fusobacterium and antibiotic-resistant bacterial infection in patients with SS-CRS.

Clinical and Cellular Evidence of Glycyrrhiza glabra and Platycodon grandiflorus for Vocal Fold Nodules Complementary Treatment.

Vocal fold nodules (VFNs) are the most frequent cause of hoarseness. The management comprised medical, surgical and physical therapy but the effectiveness is not always satisfactory. In this study, we try to figure out an alternative treatment from our clinical experience summary. We retrospectively reviewed VFNs patients who received traditional Chinese medicine (TCM) treatments from July 2018 to August 2020 and traced their Chinese Voice Handicap Index-10 (VHI-C10) and multidimensional voice program (MDVP) analysis results. For further evaluation, we conducted an inflammatory response of porcine vocal fold epithelial (PVFE) cells with 50 ng/mL TNF-alpha. The inflamed PVFE cells were separately cultured in the aqueous extract of Glycyrrhiza glabra (G. glabra) and Platycodon grandifloras (P. grandifloras). In these VFNs patients (n = 22), the average VHI-C10 score decreased from 17.6 to 6.6 (p < 0.001). MDVP analysis revealed improvements in jitter, shimmer, noise-harmonic ratio, and GRBAS scoring system. Of the TCM prescription patterns, G. glabra and P. grandiflorus were used most frequently. In the MTT assay of PVFE cells, no adverse effects of our extracts were observed at doses of 1-200 µg/mL. Western blot analysis revealed downregulation of p65 and mitogen activated protein kinase pathway proteins. The results from both the clinical and in vitro aspects of this study revealed that the herbs G. glabra and P. grandiflorus may offer beneficial outcomes as alternative treatments for VFNs after precise diagnosis.

Preoperative prognostic nutritional index predicts prognosis of patients with oral cavity cancer.

OBJECTIVE: To investigate whether prognostic nutritional index (PNI) predicts patient survival outcomes in oral cavity squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The data of a total of 360 patients subjected to primary surgery for OSCC were retrospectively analysed. Patients were categorised into high-PNI (≥51.75) and low-PNI (<51.75) groups based on the PNI cut-off value attained from receiver operating characteristic analyses (p < .001), and the intergroup differences in clinicopathological features were determined. The Kaplan-Meier method and Cox proportional hazard model were employed to determine the survival prediction ability of the PNI, and a nomogram based on the PNI was established for individualised survival prediction. RESULTS: A low PNI was noted to exhibit a significant association with shorter overall survival (OS) and disease-free survival (DFS) (both p < .001). Multivariate Cox analyses showed that a lower PNI independently indicated shorter OS and DFS (hazard ratio [HR] = 2.187; p = .001 and HR = 1.459; p = .023, respectively). The concordance index and calibration plots of the PNI-based nomogram revealed the high discriminative ability for OS. CONCLUSIONS: Preoperative PNI is a valuable biomarker for predicting OSCC prognosis, and the proposed PNI-based nomogram can provide individualised prognostic prediction.

The efficacy and safety of Hirudin plus Aspirin versus Warfarin in the secondary prevention of Cardioembolic Stroke due to Nonvalvular Atrial Fibrillation: A multicenter prospective cohort study.

Background: To investigate the efficacy and safety of hirudin plus aspirin therapy compared with warfarin in the secondary prevention of cardioembolic stroke due to nonvalvular atrial fibrillation (NVAF). Methods: Patients with cardioembolic stroke due to NVAF were prospectively enrolled from 18 collaborating hospitals from Dec 2011 to June 2015. Fourteen days after stroke onset, eligible patients were assigned to the hirudin plus aspirin group (natural hirudin prescribed as the traditional Chinese medicine Maixuekang capsule, 0.75 g, three times daily, combined with aspirin 100 mg, once daily) or the warfarin group (dose-adjusted warfarin targeting international normalized ratio (INR) 2-3, with an initial daily dose of 1.25 mg). Patients were followed up at 1, 2, 3, 6, 9, and 12 months after stroke onset. Time in therapeutic range (TTR) was calculated according to Rosendaal methodology to evaluate the quality of INR management in the warfarin group. The primary efficacy endpoint was the recurrence of stroke within 12 months after stroke onset. Safety was assessed as the occurrence of the composite event "intracranial hemorrhage and other bleeding events, death, and other serious adverse events". The Cox proportional hazard model and Kaplan-Meier curve were used to analyze the efficacy and safety events. Results: A total of 221 patients entered final analysis with 112 patients in the hirudin plus aspirin group and 109 in the warfarin group. Over the whole duration of our study, TTR for patients taking warfarin was 66.5 % ± 21.5%. A significant difference was not observed in the recurrence of stroke between the two groups (3.57% vs. 2.75%; P = 0.728). The occurrence of safety events was significantly lower in the hirudin plus aspirin group (2.68% vs.10.09%; P = 0.024). The risk for efficacy event was similar between the two groups (hazard ratio (HR), 1.30; 95% confidence interval (CI), 0.29-5.80). The safety risk was significantly lower in the hirudin plus aspirin group (HR, 0.27; 95% CI, 0.07-0.95). Kaplan-Meier analysis revealed significant difference in the temporal distribution in safety events (P = 0.023) but not in stroke recurrence (P = 0.726). Conclusion: Significant difference in efficacy was not detected between warfarin group and hirudin plus aspirin group. Compared with warfarin, hirudin plus aspirin therapy had lower safety risk in the secondary prevention of cardioembolic stroke due to NVAF.

Patients with comorbid rheumatoid arthritis are predisposed to peritonsillar abscess: real-world evidence.

PURPOSE: The peritonsillar abscess (PTA)-rheumatoid arthritis (RA) association remains unclear. Here, the effects of RA on PTA incidence and prognosis are elucidated. METHODS: We compared PTA incidence and prognosis of 30,706 RFCIP-registered patients with RA (RA cohort) with matched individuals without RA from another database of 1 million randomly selected people representing Taiwan's population (non-RA cohort). RESULTS: The RA cohort had significantly higher PTA incidence [incidence rate ratio (IRR) (95% CI) 1.73 (1.10-2.71), P = 0.017) and cumulative incidence (P = 0.016, Kaplan-Meier curves). Cox regression analyses demonstrated RA cohort to have an estimated 1.72-fold increased PTA risk (95% CI 1.09-2.69, P = 0.019). PTA was more likely within the first 5 years of RA diagnosis (for < 1, 1-5, and ≥ 5 postdiagnosis years, IRRs: 2.67, 2.31, and 1.10, respectively, and P = 0.063, 0.021, and 0.794, respectively; average onset duration: 4.3 ± 3.3 years after RA diagnosis). PTA increased length of hospital stay significantly and risk of complication with deep neck infection nonsignificantly [6.5 ± 4.5 vs 4.6 ± 2.8 days (P = 0.045) and 18.52% vs 7.81% (P = 0.155), respectively]. Moreover, RA-cohort patients not receiving RA therapy exhibited 5.06-fold higher PTA risk than those receiving RA-related therapy (95% CI 1.75-14.62, P = 0.003). CONCLUSIONS: In patients with RA, PTA incidence is the highest within 5 years of RA diagnosis, and RA therapy is essential for reducing PTA risk. LEVEL OF EVIDENCE: 4.

Retrospective study on the potential of albumin/globulin ratio as a prognostic biomarker for oral cavity cancer patients.

PURPOSE: Although the serum albumin/globulin ratio (AGR) is recognized as a valuable prognostic biomarker in various cancers, its clinical value in oral cavity squamous cell carcinoma (OSCC) is still unclear. We aimed to probe the prognostic value of AGR in patients with OSCC undergoing curative surgery. METHODS: This retrospective study analyzed 306 patients who were newly diagnosed as having OSCC and receiving curative surgery between 2008 and 2017. The correlation of AGR with survival outcomes was estimated using Cox proportional hazards models and Kaplan-Meier analysis. A nomogram based on AGR was established, and its accuracy was assessed according to the concordance index. RESULTS: The log rank test and Kaplan-Meier analysis indicated that patients who had low AGR had significantly shorter disease-free survival (DFS) as well as 5-year overall survival (OS) than those with high AGR. The multivariate Cox analysis revealed that low AGR was an independent predictor of poor OS and DFS (adjusted hazard ratio [aHR] = 2.812; 95% CI 1.729-4.573; p < 0.001, and aHR = 1.743; 95% CI 1.201-2.530; p = 0.003, respectively). The concordance index of the nomogram model based on TNM staging alone was 0.656 and could increase to 0.783 with the inclusion of AGR and other prognostic variables in the calculation. CONCLUSION: Preoperative AGR may represent an accessible, valuable prognostic biomarker in patients with OSCC. The nomogram model incorporating AGR and clinicopathological prognostic variables may improve the accuracy of prognostic predictions in these patients.

Factors Impacting Survival in Patients With Major Burn-Induced Acute Kidney Injury Postrenal Replacement Therapy: A Nationwide Study With 15 Years Follow-Up in Taiwan.

BACKGROUND: Major burn-induced acute kidney injury (AKI) causes extremely high mortality, even though renal replacement therapy (RRT) was thought of as the most efficient treatment. There was scanty research for investigating the characteristic of burn-AKI-RRT patients during intensive care. This study aims to investigate the factors impacting the survival outcomes in those burn-AKI-RRT cases. METHODS: Using the Taiwan National Health Insurance Research Database and its affiliated database, the Registry for Catastrophic Illness Patients, we defined a cohort composed of 171 patients encountering major burn-induced AKI and receiving RRT during burn care for a 15-year observation period. Demographic characteristic, comorbidities, total body surface area (TBSA), major procedures, and complications were analyzed to explore the factors affecting the survival outcomes during acute burn care and 1 year after discharge. RESULTS: Patients who underwent tracheostomy and skin grafting had higher survival rates during acute burn care (tracheostomy: mortality vs survival, 15.7% vs 30.2%; P = 0.0257; skin grafting: mortality vs survival, 57.4% vs 76.2%; P = 0.0134). Multivariate regression analysis showed that tracheostomy group significantly presented with lower mortality risk by 65% (odds ratio [OR], 0.35; P = 0.0372), and subgroup analysis of delaminating follow-up duration showed that patients with tracheostomy had higher overall survival by 22% (90-day postburn mortality: nontracheostomy vs tracheostomy, 58.3% vs 36.3%; adjusted hazards ratio, 0.39; 95% confidence interval, 0.22-0.69; P = 0.0011), especially during postburn first 30 days (adjusted hazards ratio, 0.15; 95% confidence interval, 0.05-0.49; P = 0.0016). Total body surface area did not significantly affect survival; however, mortality risk was significantly higher in those with a larger TBSA (TBSA, ≥80%; OR, 6.48; P = 0.0022; TBSA, 60-79%; OR, 3.12; P = 0.0518; TBSA, 40-59%; OR, 1.88; P = 0.2402; TBSA, 30-39% as reference). CONCLUSIONS: For patients with major burn-induced AKI receiving RRT, tracheostomy and skin grafting may improve survival in the cases living through acute burn stage.

The Ameliorative Effects of Saikosaponin in Thioacetamide-Induced Liver Injury and Non-Alcoholic Fatty Liver Disease in Mice.

Liver disorders are a major health concern. Saikosaponin-d (SSd) is an effective active ingredient extracted from Bupleurum falcatum, a traditional Chinese medicinal plant, with anti-inflammatory and antioxidant properties. However, its hepatoprotective properties and underlying mechanisms are unknown. We investigated the effects and underlying mechanisms of SSd treatment for thioacetamide (TAA)-induced liver injury and high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in male C57BL/6 mice. The SSd group showed significantly higher food intake, body weight, and hepatic antioxidative enzymes (catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD)) and lower hepatic cyclooxygenase-2 (COX-2), serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and fibroblast growth factor-21 (FGF21) compared with controls, as well as reduced expression of inflammation-related genes (nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS)) messenger RNA (mRNA). In NAFLD mice, SSd reduced serum ALT, AST, triglycerides, fatty acid-binding protein 4 (FABP4) and sterol regulatory element-binding protein 1 (SREBP1) mRNA, and endoplasmic reticulum (ER)-stress-related proteins (phosphorylated eukaryotic initiation factor 2α subunit (p-eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). SSd has a hepatoprotective effect in liver injury by suppressing inflammatory responses and acting as an antioxidant.

The Anti-Cancer Effects of a Zotarolimus and 5-Fluorouracil Combination Treatment on A549 Cell-Derived Tumors in BALB/c Nude Mice.

Zotarolimus is a semi-synthetic derivative of rapamycin and a novel immunosuppressive agent used to prevent graft rejection. The pharmacological pathway of zotarolimus restricts the kinase activity of the mammalian target of rapamycin (mTOR), which potentially leads to reductions in cell division, cell growth, cell proliferation, and inflammation. These pathways have a critical influence on tumorigenesis. This study aims to examine the anti-tumor effect of zotarolimus or zotarolimus combined with 5-fluorouracil (5-FU) on A549 human lung adenocarcinoma cell line implanted in BALB/c nude mice by estimating tumor growth, apoptosis expression, inflammation, and metastasis. We established A549 xenografts in nude mice, following which we randomly divided the mice into four groups: control, 5-FU (100 mg/kg/week), zotarolimus (2 mg/kg/day), and zotarolimus combined with 5-FU. Compared the results with those for control mice, we found that mice treated with zotarolimus or zotarolimus combined with 5-FU retarded tumor growth; increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase (ERK) phosphorylation; decreased inflammation cytokines levels (e.g., IL-1ß, TNF-α, and IL-6); reduced inflammation-related factors such as cyclooxygenase-2 (COX-2) protein and nuclear factor-κB (NF-κB) mRNA; enhanced anti-inflammation-related factors including IL-10 and inhibitor of NF-κB kinase α (IκBα) mRNA; and inhibited metastasis-related factors such as transforming growth factor ß (TGF-ß), CD44, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF). Notably, mice treated with zotarolimus combined with 5-FU had significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with the groups of mice treated with 5-FU or zotarolimus alone. The in vivo study confirmed that zotarolimus or zotarolimus combined with 5-FU could retard lung adenocarcinoma growth and inhibit tumorigenesis. Zotarolimus and 5-FU were found to have an obvious synergistic tumor-inhibiting effect on lung adenocarcinoma. Therefore, both zotarolimus alone and zotarolimus combined with 5-FU may be potential anti-tumor agents for treatment of human lung adenocarcinoma.

Dihydroisotanshinone I as a Treatment Option for Head and Neck Squamous Cell Carcinomas.

Head and neck squamous cell carcinomas (HNSCCs) are the most common cancers of the head and neck, and their prevalence is rapidly increasing. HNSCCs present a clinical challenge because of their high recurrence rate, therapeutic resistance to radiation and chemotherapy drugs, and adverse effects. Hence, traditional Chinese herbal treatment may be advantageous to therapeutic strategies for HNSCCs. Danshen (Salvia miltiorrhiza), a well-known Chinese herb, has been extensively applied in treatments for various diseases, including cancer, because of its high degree of safety and low rate of adverse effects despite its unclear mechanism. Thus, we aimed to explore the possible anticancer effects and mechanisms of dihydroisotanshinone I (DT), a compound in danshen (extract from danshen), on HNSCCs. Three HNSCCs cell lines were used for in vitro studies, and a Detroit 562 xenograft mouse model was chosen for in vivo studies. Our in vitro results showed that DT could initiate apoptosis, resulting in cell death, and the p38 signaling partially regulated DT-initiated cell apoptosis in the Detroit 562 model. In the xenograft mouse model, DT reduced tumor size with no obvious adverse effect of hepatotoxicity. The present study suggests that DT is a promising novel candidate for anti-HNSCCs therapy.

Clozapine Worsens Glucose Intolerance, Nonalcoholic Fatty Liver Disease, Kidney Damage, and Retinal Injury and Increases Renal Reactive Oxygen Species Production and Chromium Loss in Obese Mice.

Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine's adverse metabolic effects-such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy-was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased iNOS and NF-κB expression; a net negative chromium balance occurred because more chromium was excreted through urine, and this influenced chromium mobilization, which did not help overcome the hyperglycemia. Our clozapine group had considerably higher fatty liver scores, which was supported by the findings of lowered adiponectin protein levels and increased FASN protein, PNPLA3 protein, FABP4 mRNA, and SREBP1 mRNA levels. We conclude that clozapine can worsen nonalcoholic fatty liver disease, diabetes, and kidney and retinal injury. Therefore, long-term administration of clozapine warrants higher attention.

Risperidone Exacerbates Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Renal Impairment in Obese Mice.

Risperidone, a second-generation antipsychotic drug used for schizophrenia treatment with less-severe side effects, has recently been applied in major depressive disorder treatment. The mechanism underlying risperidone-associated metabolic disturbances and liver and renal adverse effects warrants further exploration. This research explores how risperidone influences weight, glucose homeostasis, fatty liver scores, liver damage, and renal impairment in high-fat diet (HFD)-administered C57BL6/J mice. Compared with HFD control mice, risperidone-treated obese mice exhibited increases in body, liver, kidney, and retroperitoneal and epididymal fat pad weights, daily food efficiency, serum triglyceride, blood urea nitrogen, creatinine, hepatic triglyceride, and aspartate aminotransferase, and alanine aminotransferase levels, and hepatic fatty acid regulation marker expression. They also exhibited increased insulin resistance and glucose intolerance but decreased serum insulin levels, Akt phosphorylation, and glucose transporter 4 expression. Moreover, their fatty liver score and liver damage demonstrated considerable increases, corresponding to increases in sterol regulatory element-binding protein 1 mRNA, fatty acid-binding protein 4 mRNA, and patatin-like phospholipid domain containing protein 3 expression. Finally, these mice demonstrated renal impairment, associated with decreases in glutathione peroxidase, superoxide dismutase, and catalase levels. In conclusion, long-term administration of risperidone may exacerbate diabetes syndrome, nonalcoholic fatty liver disease, and kidney injury.

Anti-Cancer Effects of Zotarolimus Combined with 5-Fluorouracil Treatment in HCT-116 Colorectal Cancer-Bearing BALB/c Nude Mice.

Zotarolimus is a semi-synthetic derivative of rapamycin and an inhibitor of mammalian target of rapamycin (mTOR) signaling. Currently, zotarolimus is used to prolong the survival time of organ grafts, but it is also a novel immunosuppressive agent with potent anti-proliferative activity. Here, we examine the anti-tumor effect of zotarolimus, alone and in combination with 5-fluorouracil, on HCT-116 colorectal adenocarcinoma cells implanted in BALB/c nude mice. Compared with the control mice, mice treated with zotarolimus or zotarolimus combined with 5-FU showed retarded tumor growth; increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase (ERK) phosphorylation; reduced inflammation-related factors such as IL-1ß, TNF-α, and cyclooxygenase-2 (COX-2) protein; and inhibited metastasis-related factors such as CD44, epidermal growth factor receptor (EGFR), transforming growth factor ß (TGF-ß), and vascular endothelial growth factor (VEGF). Notably, mice treated with a combination of zotarolimus and 5-FU showed significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with mice treated with 5-FU or zotarolimus alone, indicating a strong synergistic effect. This in vivo study confirms that zotarolimus or zotarolimus combined with 5-FU can be used to retard colorectal adenocarcinoma growth and inhibit tumorigenesis. Our results suggest that zotarolimus may increase the chemo-sensitization of tumor cells. Therefore, zotarolimus alone and zotarolimus combined with 5-FU may be potential anti-tumor agents in the treatment of human colon adenocarcinoma. Future research on zotarolimus may lead to the development of new therapeutic strategies.

The Ameliorative Effects of Fucoidan in Thioacetaide-Induced Liver Injury in Mice.

Liver disorders have been recognized as one major health concern. Fucoidan, a sulfated polysaccharide extracted from the brown seaweed Fucus serratus, has previously been reported as an anti-inflammatory and antioxidant. However, the discovery and validation of its hepatoprotective properties and elucidation of its mechanisms of action are still unknown. The objective of the current study was to investigate the effect and possible modes of action of a treatment of fucoidan against thioacetamide (TAA)-induced liver injury in male C57BL/6 mice by serum biochemical and histological analyses. The mouse model for liver damage was developed by the administration of TAA thrice a week for six weeks. The mice with TAA-induced liver injury were orally administered fucoidan once a day for 42 days. The treated mice showed significantly higher body weights; food intakes; hepatic antioxidative enzymes (catalase, glutathione peroxidase (GPx), and superoxide dismutase (SOD)); and a lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and C-reactive protein (CRP) levels. Additionally, a reduced hepatic IL-6 level and a decreased expression of inflammatory-related genes, such as cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) mRNA was observed. These results demonstrated that fucoidan had a hepatoprotective effect on liver injury through the suppression of the inflammatory responses and acting as an antioxidant. In addition, here, we validated the use of fucoidan against liver disorders with supporting molecular data.

Exercise Affects Blood Glucose Levels and Tissue Chromium Distribution in High-Fat Diet-Fed C57BL6 Mice.

Obesity is commonly associated with hyperglycemia and type 2 diabetes and negatively affects chromium accumulation in tissues. Exercise prevents and controls obesity and type 2 diabetes. However, little information is available regarding chromium changes for regulating glucose homeostasis in high-fat diet (HFD)-fed animals/humans who exercise. Therefore, this study explored the effects of exercise and whether it alters chromium distribution in obese mice. Male C57BL6/J mice aged 4 weeks were randomly divided into two groups and fed either an HFD or standard diet (SD). Each group was subgrouped into two additional groups in which one subgroup was exposed to treadmill exercise for 12 weeks and the other comprised control mice. HFD-fed mice that exercised exhibited significant lower body weight gain, food/energy intake, daily food efficiency, and serum leptin and insulin levels than did HFD-fed control mice. Moreover, exercise reduced fasting glucose and enhanced insulin sensitivity and pancreatic ß-cell function, as determined by homeostasis model assessment (HOMA)-insulin resistance and HOMA-ß indices, respectively. Exercise also resulted in markedly higher chromium levels within the muscle, liver, fat tissues, and kidney but lower chromium levels in the bone and bloodstream in obese mice than in control mice. However, these changes were not noteworthy in SD-fed mice that exercised. Thus, exercise prevents and controls HFD-induced obesity and may modulate chromium distribution in insulin target tissues.

Analytical Detection of Sulfonamides and Organophosphorus Insecticide Residues in Fish in Taiwan.

Exposure to residues of antibiotics (e.g., sulfonamides) and insecticides (e.g., organophosphorus insecticides) in aquacultured food can adversely affect humans and animals and thus affect public health globally. Here, using a validated method, we examined the levels of residues of 12 sulfonamides as well as 18 organophosphorus insecticides in aquacultured fish in Taiwan. A total of 52 fish samples (i.e., 20 tilapia, 16 milk fish, and 16 perch samples) were obtained from Taiwanese aquafarms from June 2018 to October 2019. We detected 0.02 and 0.03 mg/kg of sulfamethazine (a sulfonamide) in one tilapia and one milk fish, respectively, and 0.02, 0.05, and 0.03 mg/kg of chlorpyrifos (an organophosphorus insecticide) in one tilapia, one milk fish, and one perch, respectively; thus, among the samples, 3.85% and 5.77% contained sulfonamides and organophosphorus insecticide residues, respectively. Furthermore, we assessed human health risk based on the estimated daily intakes (EDIs) of these residues: EDIs of sulfonamide and organophosphorus insecticide residues were <1.0% of the acceptable daily intake recommended by the Joint Food and Agriculture Organization of the United Nations/World Health Organization Expert Committee on Food Additives. The risk of exposure to sulfonamide and organophosphorus insecticide residue by consuming aquacultured fish in Taiwan was thus negligible, signifying no immediate health risk related to the consumption of fish. Our findings can constitute a reference in efforts geared toward ensuring food safety and monitoring veterinary drug and insecticide residue levels in aquacultured organisms. Residue levels in fish must be continually monitored to further determine possible effects of these residues on human health.