Herbal medicine (Oryeongsan) for fluid and sodium balance in renal cortex of spontaneously hypertensive rats.

Background: Herbal medicine Oryeongsan (ORS), also known as Wulingsan in Chinesehas been used for the treatment of impaired body fluid balance. However, the mechanisms involved are not clearly defined. The purpose of the present study was to identify the actions of ORS on the renal excretory function and blood pressure (BP) and to define the mechanisms involved in association with renin-angiotensin system (RAS) and natriuretic peptide system (NPS) in spontaneously hypertensive rats (SHR), an animal model of human essential hypertension. Methods: Changes in urine volume (UV), excretion of electrolytes including Na+ (urinary excretion of Na+ (UNaV)) were measured. RT-PCR was performed to trace the changes in expression of RAS, NPS and sodium (Na+)-hydrogen (H+) exchanger 3 (NHE3) in the renal cortex. Results: In the SHR treated with vehicle (SHR-V) group, UV and UNaV were suppressed and the Na+ balance was maintained at the higher levels leading to an increase in BP compared to WKY-V group. These were accompanied by an increase in NHE3 expression with an accentuation of angiotensin I converting enzyme-angiotensin II type 1 (ACE-AT1) receptor and concurrent suppression of angiotensin II type 2 (AT2) receptor/ACE2-Mas receptor expression in the renal cortex. Chronic treatment with ORS increased UV and UNaV, and decreased the Na+ and water balance with a decrease in BP in the ORS-treated SHR-ORS group compared to SHR-V. These were accompanied by a decrease in NHE3 expression with a suppression of ACE-AT1 receptor and concurrent accentuation of AT2/ACE2-Mas receptor. Conclusion: The present study shows that ORS reduced BP with a decrease in Na+ and water retention by a suppression of NHE3 expression via modulation of RAS and NPS in SHR. The present study provides pharmacological rationale for the treatment of hypertension with ORS in SHR.

The efficacy and safety of Wulingsan modified formulas for chronic heart failure patients: a systematic review and meta-analysis.

Background: Chronic heart failure (CHF) is one of the most common cardiovascular diseases, which has caused huge economic burden worldwide. Wulingsan modified formulas have been historically used for CHF in China. However, the efficacy of its treatment for CHF has not been summarized by scholars and lacks of clinical evidence. This study aimed to assess the efficacy and safety of Wulingsan modified formulas for patients with CHF. Methods: A comprehensive literature search was performed in the PubMed, EMBASE, Cochrane Library, Web of Science, Medline (Ovid), China National Knowledge Infrastructure, WanFang, China Science and Technology Journal Database, and SinoMed databases from the date of their inception up to 1st November, 2021. Only randomized controlled trials evaluating Wulingsan modified formulas in patients with CHF were included. The primary outcome of this study was efficacy of Wulingsan modified formulas in the treatment of CHF, and the secondary outcomes included brain natriuretic peptide, left ventricular ejection fractions, and any other changes in the patients' condition. The risk ratio was applied to evaluate efficiency, and the weighted mean difference (WMD) and 95% confidence interval (CI) were used to merge the continuous variables. The I2 statistic was used to assess the heterogeneity. Sensitivity analysis was used to evaluate whether the single research affected the whole results. Data were extracted by two independent investigators. The Cochrane Risk of Bias tool (version 2.0) was utilized to evaluate the included studies, STATA (version 15.0) was applied for sensitivity analysis, and RevMan 5.3 software was used to conduct the systematic review and meta-analysis. Results: Nineteen studies with a total of 1,631 were included in this meta-analysis. The meta-analysis results were as follows: efficiency, the risk ratio =1.21, 95% CI: 1.15, 1.27; brain natriuretic peptide, WMD =-269.14, 95% CI: -349.25, -189.04; and left ventricular ejection fractions, WMD =8.80, 95% CI: 5.93, 11.68. All of these findings were statistically significant. No statistically significant adverse events were reported in the included articles. Discussion: Wulingsan modified formulas are a reasonable and relatively safe adjuvant therapy for the treatment of CHF.

Clinical Efficacy on Addition and Subtraction Therapy of Zhibai Dihuangwan Combined with Wulingsan on Children with Refractory Nephrotic Syndrome / 中国实验方剂学杂志

Objective:This study aims to investigate the clinical effect of addition and subtraction therapy of Zhibai Dihuangwan combined with Wulingsan in the treatment of refractory nephrotic syndrome （RNS） with Yin deficiency of liver and kidney and its regulatory effect on immune inflammatory response. Method:In this study， 108 children were randomly divided into observation group （54 cases） and control group （54 cases）. Patients in two groups were treated with prednisone acetate tablets combined with tacrolimus capsules . Patients in control group took Liuwei Dihuang oral liquid， 5-10 mL/time， twice a day. Patients in control group were prescribed the addition and subtraction therapy of Zhibai Dihuangwan combined with Wulingsan， 1 dose/day. The course of treatment for both groups was 6 months. The 24 h urine total protein （24 h-UTP）， serum albumin （ALB）， serum creatinine （Scr）， blood urea nitrogen （BUN）， total cholesterol （TC）， triglyceride （TG）， low density lipoprotein （LDL）， high density lipoprotein （HDL）， liver and kidney Yin deficiency syndrome score， fibrinogen （FIB）， <italic>D</italic>-dimer （<italic>D</italic>-D）， prothrombin time （PT） and activated partial thromboplastin time （APTT） were compared before and after treatment. Also， tumor necrosis factor-<italic>α</italic> （TNF- <italic>α</italic>）， interleukin-6（IL-6）， IL-10， IL-17， CD4⁺ and CD8⁺， helper T lymphocytes17 （Th17）， regulatory T cell （Treg） were detected before and after treatment， and CD4⁺/CD8⁺andTh17/Treg were also calculated. Result:The levels of 24 h-UTP， TC， TG， LDL， FIB， <italic>D</italic>-D， TNF-<italic>α</italic>， IL-10， IL-6 and IL-17 in observation group were all lower than those in control group （<italic>P</italic><0.01）， and the levels of CD8⁺， Th17 and Th17/Treg were alsolower than those in control group （<italic>P</italic><0.05）. While the levels of HDL，ALB， CD4⁺， Treg and CD4⁺/CD8⁺ in observation group were higher than those in control group （<italic>P</italic><0.05）. The comprehensive efficacy in observation group was better than that in control group （<italic>Z</italic>=2.02， <italic>P</italic><0.05）， and the traditional Chinese medicine （TCM） syndrome efficacy of observation group was better than that of control group （<italic>Z</italic>=2.10， <italic>P</italic><0.05）. Conclusion:Based on the treatment of hormone combined with Tacrolimus， Zhibai Dihuangwan combined with Wulingsan can reduce urinary protein， improve lipid metabolism disorder and hypercoagulability， and regulate immune inflammatory reaction in patients with RNS and Yin deficiency of liver and kidney， with remarkable comprehensive effect and TCM syndrome effect.

Clinical and Experimental Research Progress of Wulingsan in Treatment of Renal Diseases： A Review / 中国实验方剂学杂志

Wulingsan， a classic prescription first recorded in the Treatise on Cold Damage （Shang Han Lun） by ZHANG Zhong-jing for patients with water retention syndrome due to the disturbance of Qi transformation in bladder， has often been modified by ancient and modern doctors for the treatment of renal diseases. It produced satisfactory outcomes without inducing adverse reactions. The databases including China National Knowledge Infrastructure （CNKI）， Wanfang Data Knowledge Service Platform， and PubMed were searched for articles concerning the clinical application and pharmacological mechanism of Wulingsan in the treatment of renal diseases published by domestic and foreign scholars in recent years. The summary of the included articles revealed that Wulingsan has been widely employed for the treatment of renal edema， diabetic nephropathy， acute and chronic glomerulonephritis， nephrotic syndrome， renal insufficiency， abnormal urination， etc.， and the resulting outcomes were satisfactory. Wulingsan alone or in combination with western medicine yielded better clinical outcomes than the western medicine alone. In the exploration of its pharmacological mechanism， there existed some individual reports by Korean scholars， while Chinese scholars tended to work as a team. After years of research， each team has found that Wulingsan was superior to Wulingsan decoction in excreting water， which might be related to the absence of massive low-polarity and volatile components in the decoction that were responsible for regulating the expression of aquaporins （AQP） in kidney of saline-loaded rats. Wulingsan regulates the endocrine state of rats with kidney yang deficiency， inhibits the reabsorption of water， increases the activity of Na+-K+-ATPase， and reduces the expression of AQP 1， AQP 2， AQP 3， and AQP 4. Besides， it bi-directionally regulates the human water metabolism， which is achieved via the dual-directional regulation of purinergic P2X3 receptor expression on bladder detrusor. The efficacy of Wulingsan in treating chronic renal failure is attributed to its protection against the damaged renal tissue，structure and fanction. Hence， this paper summarized the research progress of Wulingsan in the treatment of renal diseases in recent years， aiming to provide a reference for the clinical and basic exploration of Wulingsan against renal diseases in the future.

Wulingsan (Oryeongsan/Goreisan) ameliorate lipid metabolism of obesity rats via regulation of the plasma metabolic profiling.

OBJECTIVES: Wulingsan has been used to cure disease about disorders related to fluid balance for thousands of years. The clinical practice of modern Chinese medicine has found that Wulingsan has the effect on reducing weight and fat, but its mechanism is not clear. This study investigated its effects on obesity rats and explored the underlying mechanisms by analyzing the plasma metabolic profiling. METHODS: The effects of Wulingsan on obesity were evaluated with obesity rats induced by high-fat diet. Ultra high performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-Q-TOF/MS) was performed to discover potential biomarkers and evaluate whether Wulingsan could regulate these biomarkers. The levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL-C), and low-density lipoprotein (LDL-C) in serum were assessed by ELISA kits. RESULTS: Remarkably, TG, TC, HDL-C and LDL-C in obesity rats were ameliorated after oral administration of Wulingsan. Further investigation indicated that the plasma metabolic profiles were clearly improved. Twelve potential biomarkers were identified. After intervention, these biomarkers turned back to normal level at some extent. CONCLUSION: The results showed that Wulingsan extract groups were normalized. Additionally, this study also showed that the metabonomics method was a promising tool to unravel how traditional Chinese medicines worked and these data can provide scientific basis for clinical application of Wulingsan.

Effect of Xiao Chaihutang and Wulingsan on Protection of Residual Renal Function in Patients with Maintenance Peritoneal Dialysis and Effect on Peritoneal Fibrosis and Micro-inflammation / 中国实验方剂学杂志

Objective: To observe the protective effect of Xiao Chaihutang and Wulingsan on residual renal function in patients with maintenance peritoneal dialysis (PD) and investigate its effect on peritoneal fibrosis and microinflammation.Method: The 65 patients with PD who were admitted to our hospital from June 2016 to June 2017 were enrolled in the study, and divided into control group (32 cases) and study group (33 cases) according to the random number table. The control group received routine treatment. The study group received routine treatment+Xiao Chaihutang and Wulingsan. The fasting venous blood was taken before treatment and 3 months after treatment to measure serum creatinine (SCr) and urea nitrogen (BUN). Urine was collected; 24 hour urine volume was recorded; 24 h urine protein (24 h UP) was measured by colorimetry; glomerular filtration rate (eGFR) was calculated; residual renal function (RRF) was expressed with residual renal creatinine clearance. Inflammatory factors were detected by using chemiluminescence, including interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) levels. Serum Janus Kinase (JAK) 2 as well as signal transducer and activator of transcription (STAT) 3 levels were determined by double antibody sandwich enzyme-linked immunosorbent assay (ELISA). E-cadherin and α-smooth muscle actin (α-SMA) levels were determined by Western blot.Result: Before treatment, there was no significant difference in the residual renal function between two groups. After treatment, the residual renal function of the study group was significantly better than that of control group (PPα in study group were lower than those in control group (PPPα-SMA protein was significantly increased after treatment (Pα-SMA protein after treatment.Conclusion: Xiao Chaihutang and Wulingsan can protect the residual renal function of PD patients, and the mechanism may be related to the improvement of peritoneal fibrosis and the reduction of micro-inflammation of the body, showing a high application value.

Mechanism of Wulingsan in Treatment of Rheumatoid Arthritis Based on Network Pharmacology / 中国实验方剂学杂志

Objective:To study the mechanism of Wulingsan (WLS) in the treatment of rheumatoid arthritis (RA) by network pharmacology. Method:The active components of WLS were screened on traditional Chinese medicine systems pharmacology(TCMSP) platform, and the targets were predicted in DragBank database. The "component-target" network was constructed by Cytoscape 3.2.1 software. Disease targets were searched in TTD, DrugBank and DisGenet databases. The Venn diagram was built to extract the target of WLS in the treatment of RA, and the gene oesthetics(GO) function annotation and Kyoto Encyclopedin of Genes and Genomes(KEGG) signal pathway enrichment analysis were performed by cluego plugin. The TCM-component-target-pathway network of WLS was constructed, and the network feature analysis was made by Network Analyzer. Result:Totally 52 components and 297 potential targets in WLS and 1 845 targets relating to RA were excavated, and 49 common targets of WLS-RA were obtained. The common targets were mainly enriched in 322 biological processes and 31 signaling pathways. Conclusion:WLS may regulate targets, such as prostaglandin epoxide synthase 2 (PTGS2), transforming growth factor-β1 (TGF-β1), cysteine aspartate protein-3 (Caspase-3), transcription factor p65 (RELA), progesterone receptor (PGR), and adjust cancer-related pathways, tumor necrosis factor(TNF) signaling pathways, interleukin-17(IL-17) signaling pathways, nuclear factor-κB(NF-κB) signaling pathways, Th17 cell differentiation, so as to inhibit the inflammatory response, regulate immune function and adjust apoptosis to treat rheumatoid arthritis.

Herbal Medicine, Oreongsan for Recurrent Chronic Subdural Hematoma: A Case Report.

Recently, the East-Asian herbal complex Oreongsan (Goreisan in Japanese and Wulingsan in Chinese) has been noted for its usefulness in preventing postoperative recurrence of chronic subdural hematoma (CSDH). Here, we present a case of CSDH, an 84-year-old man which had recurred four times, despite three previous burr-hole surgeries. Following the fourth burr-hole surgery, an herbal medicine called Oreongsan (TJ-17, Tsumura, Japan, 15g/d) was administered to the patient in hopes of preventing another CSDH recurrence. This case was successfully treated with Oreongsan in an attempt to prevent any further recurrences. The potential mechanism of action of Oreongsan is hydrostatic modulation. The inhibitory effect of the Oreongsan on aquaporin-4 found on the CSDH membrane could contribute to its ability to reduce and prevent the aggravation of SDH.

Wu-Ling-San formula prophylaxis against recurrent calcium oxalate nephrolithiasis - a prospective randomized controlled trial.

Wu-Ling-San (WLS) formula has been proved to prevent calcium oxalate nephrolithiasis both in vitro and in vivo. This is the first prospective, randomized and placebo-controlled clinical trial of WLS in calcium oxalate nephrolithiasis prevention. All patients who enrolled were asked to drink enough fluid to urinate at least 2 L daily during the study period. A 24-hour urine collection was performed to establish the baseline levels of multiple urinary parameters before taking the medicine. The patients were randomized and divided into two groups. The medication group took 2 gm WLS formula three times daily for 1 month. The control group took 2 gm placebo three times daily for 1 month. A 24-hour urine collection was performed to evaluate multiple urinary and serum parameters from all patients during the study period. A total of 39 patients were enrolled and 28 patients completed the study. Fourteen patients were allocated to WLS group and 14 patients to placebo group. After treatment, the mean urine output level increased to 2796.4 ± 525.7 ml/day (percentage of change, 13.9 %) in the WLS formula group. With placebo therapy, the mean decreased slightly to 2521.4 ± 762.7ml/day (percentage of change, -5.7 %). The percentage of change was significantly different between the two groups (independent t-test, P=0.02). No patient complained of side effects, such as fatigue, dizziness, musculoskeletal symptoms, or gastrointestinal disturbance. WLS formula is a promising adjunct to surgical and medical management of kidney stones. Active therapy with WLS formula has a positive effect on diuresis without leading to electrolyte imbalance.

Traditional uses, phytochemistry, pharmacology, pharmacokinetics and quality control of Polyporus umbellatus (Pers.) Fries: a review.

ETHNOPHARMACOLOGICAL RELEVANCE: Polyporus umbellatus (Pers.) Fries (Polyporaceae, Zhuling ) has been commonly used in medicine for a wide range of ailments related to the edema, scanty urine, vaginal discharge, urinary dysfunction, as well as jaundice and diarrhea. AIM OF THE REVIEW: The present paper reviewed the traditional uses, propagation, phytochemistry, pharmacology, pharmacokinetics and quality control of Polyporus umbellatus. MATERIALS AND METHODS: All the available information on Polyporus umbellatus was collected via a library and electronic search (using Web of Science, Pubmed, ScienceDirect, Splinker, Google Scholar, etc.). RESULTS: Phytochemical studies showed the presence of many valuable secondary metabolites such as steroids, polysaccharides, anthraquinones and nucleosides. Crude extracts and isolated compounds showed a wide spectrum of pharmacological activities including diuretic, nephroprotective, anti-cancer, immuno-enhancing, hepatoprotective, anti-inflammatory and antioxidative activities. The pharmacokinetic studies demonstrated that the ergosterol and ergone had a high distribution and absorption in the plasma and the two main components of Polyporus umbellatus were mainly excreted by faeces. The determination of multiple chemical components was successfully applied to the quality control of Polyporus umbellatus. CONCLUSIONS: Modern phytochemical, pharmacological and metabonomic investigations showed that the crude extracts and isolated compounds from Polyporus umbellatus possess many kinds of biological functions, especially in the diuretic activities and the treatment of kidney diseases as well as anti-cancer, immuno-enhancing and hepatoprotective activities. The pathways of the distribution, absorption, metabolism and excretion of main steroidal compounds were clarified by pharmacokinetic studies. Most of the pharmacological studies were conducted using crude and poorly characterized extracts of Polyporus umbellatus in animals especially in case of diuretic activities and the treatment of kidney diseases. Thus, more bioactive components especially diuretic compounds should be identified using bioactivity-guided isolation strategies and the possible mechanism of action as well as potential synergistic or antagonistic effects of multi-component mixtures derived from Polyporus umbellatus need to be evaluated integrating pharmacological, pharmacokinetic, bioavailability-centered and physiological approaches. In addition, more experiments including in vitro, in vivo and clinical studies should be encouraged to identify any side effects or toxicity. These achievements will further expand the existing therapeutic potential of Polyporus umbellatus and provide a beneficial support to its future further clinical use in modern medicine.

The selected traditional chinese medicinal formulas for treating diabetic nephropathy: perspective of modern science.

With the increasing patients and limited therapeutic options, diabetic nephropathy (DN) is a long-term complication of diabetic mellitus. The precise mechanism of DN is not yet fully understood and the effective blockade of the progression of nephropathy remains a therapeutic challenge. Application of traditional Chinese medicine (TCM) for diabetes and its related complications has received increasing attention due to its wide availability, low side effects, and proven therapeutic mechanisms and benefits. In the current review, we mainly focus on the recent laboratory studies of the TCM formulas including Wu-Ling-San (Poria Five Powder; Wǔ Líng Sǎn), Danggui-Buxue-Tang (Tangkuei and Astragalus Decoction; Dang Gui Bǔ Xuè Tang), and Danggui-Shaoyao-San (Tangkuei and Paeonia Formula; Dang Gui Sháo Yào Sǎn), conducted by the Committee on Chinese Medicine and Pharmacy at the Department of Health of Taiwan Government, in the amelioration of DN. These selected TCM formulas have anti-diabetic properties, with antihyperglycemic activity accompanied by amelioration of advanced glycation end product-mediated renal damage in streptozotocin-induced diabetic rats. However, the renoprotective effects of the selected TCM formulas did not correlate with suppressing renal renin-angiotensin system hyperactivity in diabetic rats. These TCM formulas also have the capacity to ameliorate the defective antioxidative defense system, leading to modulation of the oxidative stress, thereby resulting in downregulation of nuclear factor-kB as well as transforming growth factor-ß1 and, consequently, attenuation of extracellular matrix components such as fibronectin or type IV collagen expression in diabetic renal cortex tissue. More detailed mechanistic researches and long-term clinical evaluations, as well as evaluation of safety of the selected TCM formulas are needed for their future applications in DN therapy.

Differences between the Effects of Sho-saiko-to, Gorei-san and Toki-shakuyaku-san on the Sphincter of Oddi. An intraoperative cholangiomanometric study / 日本東洋医学雑誌

Female patients suffering from gallbladder stone disease were administered Sho-saiko-to (Xiao-Chai-Hu-Tang), Gorei-san (Wu-Ling-San) or Toki-shakuyaku-san (Dang-Gui-Shao-Yao-San) preoperatively, and were examined by cholangiomanometry during operation. Perfusion pressure was significantly elevated, when Sho-saiko-to or Gorei-san were administered, meaning that the pressure threshold of the sphincter of Oddi for volume load in the bile duct was lowered. This phenomenon tended to be more obvious in Gorei-san group, and will prevent duodenal fluid from transpapillary reflux. Parameters concerning the declining curve (T_1/2, T_1/4, T_1/5) showed a significantly rapid relaxation of the sphincter of Oddi only in Sho-saiko-to group, which will result in a prevention of stasis of bile. These modulating functions of Sho-saiko-to and Gorei-san for the sphincter of Oddi would be one of the main reasons why these formulas are used for hypochondriac fullness and distress or excessively accumulated intestinal fluid. Toki-shakuyaku-san showed no such effects on the sphincter of Oddi.