Chronopharmacology of diuresis via metabolic profiling and key biomarker discovery of the traditional Chinese prescription Ji-Ming-San using tandem mass spectrometry in rat models.

BACKGROUND: Ji-Ming-Shan (JMS) is a traditional prescription used for patients with rheumatism, tendons swelling, relief of foot pain, athlete's foot, diuresis, gout. Although many studies have investigated the active compounds in each herb, the functional mechanism behind its therapeutic effect remains unclear. STUDY DESIGN: Metabolic cages for sample collection. The serum components obtained from the experimental animals were analyzed using LC-MS/MS. Furthermore, cross-analysis using the software MetaboAnalyst and Venn diagrams were used to investigate chronopharmacology of JMS in the animal models. PURPOSE: The aim of this study is to analyze the diuretic effects of JMS and to explore their chronopharmacology involved in organ regulation through four-quarter periods from serum samples of rat models. METHODS: Metabolic cages were used for collecting the urine samples and PocketChem UA PU-4010, Fuji DRI-CHEM 800 were used to examine the urine biochemical parameters. The serum components were identified through ultra-performance liquid chromatography-quadrupole time-of-flight (UPLC-Q-TOF) with a new developed method. Cross analysis, Venn diagram, MetaboAnalyst were used to investigate the key biomarker and major metabolism route with the oral administration of the drug. RESULT: JMS significantly changed the 6 h urine volume with no observed kidney toxicity. Urine pH value ranges from 7.0 to 7.5. The chronopharmacology of JMS diuresis activity were 0-6 and 6-12 groups. UPLC-Q-TOF analyses identified 243 metabolites which were determined in positive mode and negative mode respectively. With cross analysis in the Venn diagram, one key biomarker naringenin-7-O-glucoside has been identified. Major metabolic pathways such as 1: Glycerophospholipid metabolism, 2: Primary bile acid biosynthesis, 3: Sphingolipid metabolism, 4: Riboflavin metabolism, 5: Linoleic acid metabolism, 6: Butanoate metabolism. CONCLUSION: JMS significantly changed the urine output of animals in the 0-6 and 6-12 groups. No change in urine pH was observed and also kidney toxicity. A new UPLC-Q-TOF method was developed for the detection of the metabolites of JMS after oral administration. The cross analysis with Venn diagram and identified the key biomarker of JMS namely naringenin-7-O-glucoside. The results showed that six major pathways are involved in the gastrointestinal system and the liver. This study demonstrated the capability of JMS prescription in the regulation of diuresis and identified a key biomarker that is responsible for its therapeutic effect.

Sesamin: A Promising Therapeutic Agent for Ameliorating Symptoms of Diabetes.

Diabetes is a chronic metabolic disease characterized by improperly regulating proteins, carbohydrates, and lipids due to insulin deficiency or resistance. The increasing prevalence of diabetes poses a tremendous socioeconomic burden worldwide, resulting in the rise of many studies on Chinese herbal medicines to discover the most effective cure for diabetes. Sesame seeds are among these Chinese herbal medicines that were found to contain various pharmacological activities, including antioxidant and anti-inflammatory properties, lowering cholesterol, improving liver function, blood pressure and sugar lowering, regulating lipid synthesis, and anticancer activities. These medicinal benefits are attributed to sesamin, which is the main lignan found in sesame seeds and oil. In this study, Wistar rat models were induced with type 2 diabetes using streptozotocin (STZ) and nicotinamide, and the effect of sesamin on the changes in body weight, blood sugar level, glycosylated hemoglobin (HbA1c), insulin levels, and the states of the pancreas and liver of the rats were evaluated. The results indicate a reduced blood glucose level, HbA1c, TG, and ALT and AST enzymes after sesamin treatment, while increased insulin level, SOD, CAT, and GPx activities were also observed. These findings prove sesamin's efficacy in ameliorating the symptoms of diabetes through its potent pharmacological activities.

In Silico Analysis of Anti-Inflammatory and Antioxidant Properties of Bioactive Compounds from Crescentia cujete L.

Crescentia cujete is widely known as a medical plant with broad indigenous ethnomedicinal uses, including anti-inflammatory, and antioxidant. Despite being used for remedies and ethnomedicinal purposes, the benefits obtained from C. cujete still need to be fully utilized. The underwhelming studies on its pharmacological potential, bioactive compounds, and mechanism of action keep the pharmacological and new drug discovery progress of this plant slow. This study focuses on the incorporation of in silico analyses such as ADME prediction and molecular docking simulations on the bioactive compounds identified in the plant to assess their potential for antioxidant and anti-inflammatory applications. A comparison of the ADME properties and molecular docking scores showed that naringenin, pinocembrin, and eriodictyol had the most potential to act as inhibitors of the target proteins involved in inflammation and oxidation pathways against the positive controls.

Interactive deciphering electron-shuttling characteristics of Coffea arabica leaves and potential bioenergy-steered anti-SARS-CoV-2 RdRp inhibitor via microbial fuel cells.

Due to the pandemics of COVID-19, herbal medicine has recently been explored for possible antiviral treatment and prevention via novel platform of microbial fuel cells. It was revealed that Coffea arabica leaves was very appropriate for anti-COVID-19 drug development. Antioxidant and anti-inflammatory tests exhibited the most promising activities for C. arabica ethanol extracts and drying approaches were implemented on the leaf samples prior to ethanol extraction. Ethanol extracts of C. arabica leaves were applied to bioenergy evaluation via DC-MFCs, clearly revealing that air-dried leaves (CA-A-EtOH) exhibited the highest bioenergy-stimulating capabilities (ca. 2.72 fold of power amplification to the blank). Furthermore, molecular docking analysis was implemented to decipher the potential of C. arabica leaves metabolites. Chlorogenic acid (-6.5 kcal/mol) owned the highest binding affinity with RdRp of SARS-CoV-2, showing a much lower average RMSF value than an apoprotein. This study suggested C. arabica leaves as an encouraging medicinal herb against SARS-CoV-2.

In vitro and in vivo anti-osteoarthritis effects of tradition Chinese prescription Ji-Ming-San.

ETHNOPHARMACOLOGICAL RELEVANCE: Ji-Ming-Shan (JMS) is a traditional herbal prescription consisting of seven herbs including Areca cathechu Burm.f., Citrus reticulata Blanco, Chaenomeles speciosa (Sweet) Nakai, Euodia ruticarpa (A. Juss.) Benth., Perilla frutescens (L.) Britton, Zingiber officinale Roscoe, Platycodon grandiflorus (Jacq.). It was first recorded during the Song dynasty and has been used extensively for protection against rheumatism, treatment of swelling of tendons, relief from foot pain, gout and diuresis and other forms of inflammation. AIM OF THE STUDY: The aim of this study is to evaluate the anti-inflammatory and anti-osteoarthritis activity of JMS extracts with the use of different cell lines (RAW 264.7 cells, SW1353 cells and primary cultured rat chondrocytes). MIA-induced rat animal models were used to assess the anti-osteoarthritis activity of the extract. MATERIALS AND METHODS: This study investigated the anti-inflammatory activity of JMS-95E on LPS-induced RAW 264.7 macrophages and IL-1ß-stimulated chondrocytes. For the in vivo study, male Wistar rats were used and they were randomly assigned in different groups: blank, control, positive control and three different JMS-95E treatment groups (200, 400, 800 mg/kg/d). Paw edema, hind-limb weight bearing, serum inflammatory cytokines including hematoxylin and eosin (HE) staining experiments were used to assess the efficacy of the extract in the rat model. RESULT: JMS 95% ethanol extract (JMS-95E, marker substance: narirutin (5.10 mg/g) and hesperidin (11.33 mg/g) has been identified in the extract using high pressure liquid chromatography. For in vitro assays, JMS-95E did not exhibit cytotoxicity and was able to downregulate the protein expression of iNOS, COX-2 and MMP-13. The production of inflammatory mediators such as NO and PGE2 were also reduced with an increase in dose-dependent manner in various cell lines. Inhibitory activity on the key enzyme xanthine oxidase was also observed in this study. In rat animal models, JMS-95E reduced the inflammatory responses such as acute swelling, chondrocyte degradation and pain section of paw edema in rat model. Molecular marker studies of inflammation demonstrated that JMS-95E significantly decrease PGE2 expression in MIA model. CONCLUSION: JMS-95E inhibited the inflammatory pathway leading to the production or expression levels of NO, iNOS, COX-2 and PGE2 in macrophage cells. In primary cultured rat chondrocytes iNOS and SW1353 MMP-13 expression were downregulated after JMS-95E treatment. For the in vivo study JMS-95E significantly reduced the paw volume of carrageenan-induced rat paw edema through each dose and significantly inhibited paw volume, counterweight the distribution of hind-paw weight bearing through the MIA model which means JMS-95E could promote recovery of the acute swelling and chondrocyte degradation of the ankle joints. The above results provided the multiple mechanism of JMS-95E in OA treatment of the scientific founding which supported the description of JMS in traditional use.

Synergistic deciphering of bioenergy production and electron transport characteristics to screen traditional Chinese medicine (TCM) for COVID-19 drug development.

Background: Traditional Chinese medicine (TCM) has been used as an "immune booster" for disease prevention and clinical treatment since ancient China. However, many studies were focused on the organic herbal extract rather than aqueous herbal extract (AHE; decoction). Due to the COVID-19 pandemics, this study tended to decipher phytochemical contents in the decoction of herbs and derived bioactivities (e.g., anti-oxidant and anti-inflammatory properties). As prior works revealed, the efficacy of Parkinson's medicines and antiviral flavonoid herbs was strongly governed by their bioenergy-stimulating proficiency. Methods: Herbal extracts were prepared by using a traditional Chinese decoction pot. After filtration and evaporation, crude extracts were used to prepare sample solutions for various bioassays. The phytochemical content and bioactivities of AHEs were determined via ELISA microplate reader. Microbial fuel cells (MFCs) were used as a novel platform to evaluate bioenergy contents with electron-transfer characteristics for antiviral drug development. Significant findings: Regarding 18 TCM herbal extracts for the prevention of SARS and H1N1 influenza, comparison on total polyphenol, flavonoid, condensed tannins and polysaccharides were conducted. Moreover, considerable total flavonoid contents were detected for 11 herb extracts. These AEHs were not only rich in phytonutrient contents but also plentiful in anti-oxidant and anti-inflammatory activities. Herbs with high polyphenol content had higher antioxidant activity. Forsythia suspensa extract expressed the highest inhibition against nitric oxide production for anti-inflammation. MFC bioenergy-stimulating studies also revealed that top ranking COVID-19 efficacious herbs were both bioenergy driven and electron mediated. That is, electron transfer-controlled bioenergy extraction was significant to antiviral characteristics for anti-COVID-19 drug development.

Drug treatment strategies for osteoporosis in stroke patients.

INTRODUCTION: Osteoporosis and subsequent fractures are well-recognized complications of stroke. However, drug treatment strategies for osteoporosis after stroke have been rarely discussed in the current guidelines for the management of stroke or osteoporosis. AREAS COVERED: The authors review the epidemiology, characteristics, pathophysiology, and risk prediction of post-stroke osteoporosis and fractures. Then they provide an overview of existing evidence regarding drug treatment strategies for osteoporosis in stroke patients. They also review the effects on bone mineral density (BMD) and fractures for those drugs commonly used in stroke patients. EXPERT OPINION: Currently, there is scarce evidence. A small randomized control trial suggested that a single use of 4 mg of intravenous zoledronate within 5 weeks of stroke onset was beneficial for preserving BMD, while simultaneous use of calcium and vitamin D supplements may be effective in preventing hypocalcemia. Further studies are needed to address several important issues of post-stroke osteoporosis, including who (the eligibility for treatment), when (the best timing of treatment), what (which drug), and how long (the best duration of treatment). On the other hand, physicians should bear in mind that drugs commonly used for stroke, such as statins or warfarin, may have beneficial or adverse effects on BMD and fracture risks.

Stroke severity may predict causes of readmission within one year in patients with first ischemic stroke event.

INTRODUCTION: Readmissions after stroke are costly. Risk assessment using information available upon admission could identify high-risk patients for potential interventions to reduce readmissions. Baseline stroke severity has been suspected to be a factor in readmission; however, the exact nature of the impact has not been adequately understood. METHODS: Hospitalized adult patients with first-ever ischemic stroke were identified from a nationwide administrative database. Stroke severity was assessed using a validated claims-based stroke severity index. Cox proportional hazards models were used to investigate the relationship between stroke severity and first readmission within one year. RESULTS: Of the 10,877 patients, 4295 (39.5%) were readmitted in one year. The cumulative risk of readmission was 34.1%, 44.7%, and 62.9% in patients with mild, moderate, and severe stroke, respectively. Patients with greater stroke severity had a significantly higher adjusted risk of first readmission for infection, metabolic disorders, neurological sequelae, and pulmonary diseases, whereas those with lesser stroke severity were prone to first readmission due to accidents. Stroke severity did not affect the risk of first readmission for recurrent stroke/transient ischemic attack, other cardiovascular events, malignancy, ulcers/upper gastrointestinal bleeding, kidney diseases, and others. CONCLUSIONS: Stroke severity in patients with first-ever ischemic stroke not only predicts readmission but also relates to the cause of readmission. Our results might provide important information for tailoring discharge planning to prevent readmissions.

Net clinical benefit of oral anticoagulants: a multiple criteria decision analysis.

BACKGROUND: This study quantitatively evaluated the comparative efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, and apizaban) and warfarin for treatment of nonvalvular atrial fibrillation. We also compared these agents under different scenarios, including population with high risk of stroke and for primary vs. secondary stroke prevention. METHODS: We used multiple criteria decision analysis (MCDA) to assess the benefit-risk of these medications. Our MCDA models contained criteria for benefits (prevention of ischemic stroke and systemic embolism) and risks (intracranial and extracranial bleeding). We calculated a performance score for each drug accounting for benefits and risks in comparison to treatment alternatives. RESULTS: Overall, new agents had higher performance scores than warfarin; in order of performance scores: dabigatran 150 mg (0.529), rivaroxaban (0.462), apixaban (0.426), and warfarin (0.191). For patients at a higher risk of stroke (CHADS2 score≥3), apixaban had the highest performance score (0.686); performance scores for other drugs were 0.462 for dabigatran 150 mg, 0.392 for dabigatran 110 mg, 0.271 for rivaroxaban, and 0.116 for warfarin. Dabigatran 150 mg had the highest performance score for primary stroke prevention, while dabigatran 110 mg had the highest performance score for secondary prevention. CONCLUSIONS: Our results suggest that new oral anticoagulants might be preferred over warfarin. Selecting appropriate medicines according to the patient's condition based on information from an integrated benefit-risk assessment of treatment options is crucial to achieve optimal clinical outcomes.

Validating the diagnosis of acute ischemic stroke in a National Health Insurance claims database.

BACKGROUND/PURPOSE: The National Health Insurance Research Database, which uses claims data from hospitals contracted with the National Health Insurance (NHI) program in Taiwan, has been widely used for stroke research. The diagnostic accuracy of the NHI claims data with regard to acute ischemic stroke (AIS) has rarely been validated. The aim of this study was to validate the diagnosis of AIS in NHI claims data using the Taiwan Stroke Registry (TSR) as a reference. METHODS: We retrieved patients' data with a discharge diagnosis of AIS [five-digit International Classification of Diseases Code, 9(th) version (ICD-9 code): 433xx or 434xx] in a single medical center from August 2006 to December 2008. We then linked these patients to the TSR to validate their AIS diagnosis in the claims data. The positive predictive value (PPV) and sensitivity were determined. RESULTS: We reviewed the claims data of 1736 consecutive AIS patients, of whom 1299 (74.8%) were linked successfully to the stroke registry database. After reviewing the medical records and imaging results of other patients not linked to the registry database (n = 437), 235 patients were found to have had an AIS. The PPV was 88.4% [95% confidence interval (CI): 86.8-89.8%] and sensitivity was 97.3% (95% CI: 96.4-98.1%). Forty-four (21.8%) of the false-positive cases (n = 202) were coded as 433x0 or 434x0. CONCLUSION: The PPV of a diagnosis of AIS in the NHI claims data was high. Using five-digit ICD-9 codes to identify AIS cases will markedly decrease the false-positive rate compared with using the commonly used three-digit method.

Rhabdomyolysis and pancreatitis associated with coadministration of danazol 600 mg/d and lovastatin 40 mg/d.

BACKGROUND: Danazol is a steroid analogue with anabolic and androgenic effects and is indicated for the treatment of endometriosis, fibrocystic diseases of the breast, and hereditary angioedema. Lovastatin has been prescribed to lower total cholesterol and low-density lipoprotein cholesterol, reducing cardiovascular-related morbidity and mortality in patients with hypercholesterolemia. As monotherapies, both danazol and lovastatin have been reported to induce myopathy and pancreatitis. CASE SUMMARY: A 59-year-old Asian woman (height, 155 cm; weight, 54 kg; and body mass index, 22.5 kg/m2) presented to the outpatient neurology clinic with acute progressive quadriparesis and generalized myalgia (without focal sensory loss, numbness, dizziness, diplopia, dysarthria, dysphagia, or sphincter incontinence), lasting for 5 days. She was admitted to the National Cheng Kung University Hospital, Tainan, Taiwan. The patient's medical history revealed multiple comorbidities (eg, end-stage renal disease, hypertension, diabetes mellitus) for which she was receiving concomitant medication. Her medication history revealed that at the time the patient presented, she was also receiving calcium bicarbonate 1500 mg/d, labetalol 100 mg/d, and glipizide 10 mg/d in the treatment of her other comorbid illnesses. The patient was also receiving alprazolam 0.5 mg/d for insomnia. Her medical records also revealed that lovastatin 40 mg/d (a particularly high dose and not recommended) had been administered for 7 weeks, and danazol 600 mg/d was added ( approximately 15 days later) to treat thrombocytopenia due to hypoplastic bone marrow. Laboratory findings revealed elevated creatine kinase (68,193 U/L), elevated pancreatic enzymes (amylase/lipase, 361/2788 U/L), and elevated liver enzymes (aspartate/alanine aminotransferase, 1496/1493 U/L), consistent with rhabdomyolysis and pancreatitis. After discontinuation of both drugs, the symptoms improved 5 days after admission and completely disappeared 1 month after admission. In addition, laboratory abnormalities completely normalized approximately 2 months after admission. Danazol was resumed to treat persistent thrombocytopenia, while lovastatin was replaced with ezetimibe 10 mg QD to treat high cholesterol (dyslipidemia). CONCLUSION: The coadministration of high-dose lovastatin and danazol was probably associated with rhabdomyolysis and pancreatitis in this patient with multiple underlying comorbidities for which concomitant medications were being administered.