Kidney Yang Deficiency Syndrome Research Articles

Characterizing metabolomic and transcriptomic changes, and investigating the therapeutic mechanism of Psoralea corylifolia linn. In the treatment of kidney-yang deficiency syndrome in rats

Kidney-yang deficiency syndrome (KYDS) is characterized by a metabolic disorder stemming from neuroendocrine dysregulation, often associated with hepatic dysfunction. In traditional Chinese medicine, Psoralea corylifolia Linn. (BGZ) is commonly utilized for treating KYDS. However, the specific therapeutic effects of BGZ on liver function regulation remain unclear. To evaluate the protective effects of BGZ against KYDS in rats, organ index, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and other biochemical indices were analyzed. Hematoxylin and eosin (HE) staining was utilized to assess liver histopathology. Additionally, transcriptomic and metabolomic analyses were conducted to identify potential biomarkers. BGZ treatment led to a significant reduction in ALT and AST levels, accompanied by improvements in liver histopathology in rats with KYDS. Moreover, BGZ induced significant alterations in 92 differentially expressed genes (DEGs) and 20 metabolites in the KYDS rat model. The comprehensive examination of metabolites and DEGs identified potential mechanisms underlying the therapeutic effects of BGZ, highlighting the neuroactive ligand-receptor interaction, cAMP signaling pathway, calcium signaling pathway, and cytokine-cytokine receptor interaction as key mechanisms. Validation of key targets within the cAMP pathway was substantiated through enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction. The cAMP pathway emerges as a plausible mechanism through which BGZ exerts protective effects against KYDS. The findings of this study contribute to an improved understanding of the therapeutic actions of BGZ and establish a groundwork for further research into the complex pathways involved, as well as the potential for drug-targeted therapies for KYDS.

Decreasing of Trimethylamine N-Oxide by Cecal Microbiota and Choline-Trimethylamine Lyase are Associated with Sishen Pill on Diarrhea with Kidney-Yang Deficiency Syndrome.

Sishen Pill (SSP) is a traditional Chinese medicine prescription commonly used to treat diarrhea with kidney-yang deficiency syndrome. The aim was to investigate the underlying mechanisms of SSP's therapeutic effects, providing experimental evidence for its mechanism of action. A mouse model of diarrhea with kidney-yang deficiency syndrome was induced using adenine combined with Folium sennae. After successful model replication, SSP decoction was administered. CutC activity, TMAO, IL-6, TNF-α levels, and cecal content microbiota were measured. SSP significantly improved the general behavioral characteristics of diarrhea mice, and reduced CutC activity, TMAO and IL-6 levels. Sequencing results indicated significant changes at the phylum and genus levels. Correlation analysis revealed a positive correlation between CutC activity and Faecalibaculum (p<0.05) and Chryseobacterium (p<0.05), and a significant negative correlation with Prevotellaceae UCG-001, Rikenella (p<0.05), Acinetobacter (p<0.05), Parasutterella (p<0.05), and Lacticaseibacillus (p<0.05). TNF-α levels showed a significant negative correlation with Lacticaseibacillus (p<0.05), Prevotellaceae UCG-001 (p<0.01), Parasutterella (p<0.05), and Candidatus Saccharimonas (p<0.05). IL-6 levels exhibited a significant negative correlation with Rikenella (p<0.05), Acinetobacter (p<0.05), Prevotellaceae UCG-001 (p<0.05), Lacticaseibacillus (p<0.01), and Parasutterella (p<0.05), and a significant positive correlation with Faecalibaculum (p<0.05), Chryseobacterium (p<0.01), and A2. Serum TMAO levels showed a significant positive correlation with Faecalibaculum (p<0.05) and Chryseobacterium (p<0.01), and hepatic TMAO levels exhibited a significant positive correlation with Chryseobacterium (p<0.05). SSP significantly alleviated the symptoms of diarrhea with kidney-yang deficiency syndrome by modulating the cecal microbiota, downregulating CutC activity, and reducing TMAO and inflammatory factor levels. The cecal microbiota-CutC-TMAO-inflammatory cytokine axis may be a key mechanism underlying the therapeutic effects of SSP.

Based on Serum Pharmacochemistryand MetabolomicsStudied the Pharmacodynamic Material Basis and Mechanism of Rubi Fructus(Fupenzi)in Improving the Symptom of Kidney-Yang Deficiency.

Rubi fructus (Fupenzi)is the Chinese medicine for both food and medicine, which canbe usedtotonify kidney yang, strengthen essence and shrink urine, but its effective components and mechanism are not clear.In this paper, the active components of Fupenziin vivo and in vitro were detected. Adenine was used to replicate the model of kidney yang deficiency, and organ index, biochemical index and histopathology were used to evaluate the effect of different doses of Fupenzion tonifying kidney yang. Metabonomics technique was used to analyze the metabolic regulation mechanism of Fupenziin improving kidney yang deficiency syndrome. The results showed that 61 chemical constituents of Fupenziwere identified in vitro. A total of 51 chemical components were identified, including 30 prototype components and 21 metabolic components, which may be theeffective components of Fupenzi. The results of pharmacodynamicsshowed that Fupenzican effectively improve the symptom of kidney-yang deficiency, which may be mainly through primary bile acid biosynthesis, linoleic acid metabolism, steroid hormone biosynthesis, β-alanine metabolism, glutathione metabolism, porphyrin and chlorophyll metabolism, unsaturated fatty acid biosynthesis, arachidonic acid metabolism, arginine and proline metabolism and other metabolic pathways to improve adenine-induced metabolic disorders in rats with kidney-yang deficiency syndrome.

Study on Shenbao Tablet in Treating Kidney-yang Deficiency Syndromebased on Metabolomics.

The aim of this study was to elucidate the mechanism of action of Shenbao tablets using metabolomics approach. Kidney-Yang deficiency is a common syndrome type in traditional Chinese Medicine (TCM) syndrome typology, closely related to disorders of multiple metabolic pathways and is the root cause and underlying syndrome type of many diseases. Shenbao tablets can significantly improve the main symptoms of kidney yang deficiency syndrome, but the mechanism of action of Shenbao tablets on kidney yang deficiency syndrome is still unknown. The rats were intraperitoneally injected with hydrocortisone once a day for 40 days to simulate the syndrome. Traditional pharmacodynamic indicators (body mass, biochemical indicators and pathology) were used to evaluate the efficacy of the medicine. Serum, urine and feces were collected from rats. UPLC/MS metabolomics method was used to study the overall metabolic profile of serum, while GC/MS metabolomics method was used to study the metabolic spectrum of urine and feces. Results showed that the syndrome was significantly improved in the treatment group, and obvious metabolic disorders were observed in rats with the syndrome, with 47 potential biomarkers identified. Pathway analysis showed that nicotinate and nicotinamide metabolism, glycine, serine and trione metabolism, aminoacyl tRNA biosynthesis, glycoxylate and dicarboxylate metabolism were the major ways for Shenbao tablet to improve kidney-yang deficiency syndrome. The mechanism of action of Shenbao tablet in improving the syndrome involves the regulation of energy metabolism, amino acid metabolism, bile acid metabolism, fatty acid metabolism and intestinal microorganisms. This work shows that metabolomics is a promising tool for studying the essence of syndrome theory in TCM and the mechanisms of TCM.

A dual-recognition strategy based on pH-responsive molecularly imprinted membrane for highly selective capture of catecholamines: From construction to practical application

BackgroundCatecholamines (CAs) are involved in a wide range of physiological and pathological processes in the body and are progressively being used as important biomarkers for a variety of diseases. It is of great significance for accurate quantification of CAs to the diagnosis and treatment of diseases. However, the separation of CAs from complex biological matrices is still a great challenge due to the trace levels of CAs and the limited selectivity of existing pretreatment methods. ResultsIn this work, a dual-recognition imprinted membrane (BA-MIM) was developed to utilize the synergistic action of pH-responsive boron affinity and molecular imprinted cavities for highly selective capture and release of CAs. The prepared BA-MIM possessed remarkable adsorption capacity (maximum capacity, 43.3 mg g−1), desirable surface hydrophilicity (46.2°), superior selectivity (IF = 6.2, α = 14.3), as well as favorable reusability (number of cycles, 6 times). On this basis, an integrated analytical method based on BA-MIM extraction combined with ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was innovatively developed to highly selective separation, enrichment, and detection of CAs in rat brain tissue. Under the optimum conditions, a low quantitation limits (0.05–0.10 ng mL−1), wide linear range (10–1000 ng mL−1), good linearity (r2 > 0.99), and satisfactory recoveries (88.5%–98.5 %) were obtained for CAs. The proven method was further applied to kidney-yang-deficiency-syndrome (KYDS) group rat model, revealed the intrinsic connection between kidney disease and catecholamine metabolism. SignificanceThis work provides an excellent reference paradigm for the effective construction of dual-recognition functional membrane material to the high-selective analysis of trace targets in complex matrices. Additionally, this integrated analytical strategy demonstrates its efficiency, sustainability, versatility, and convenience, showing remarkable prospect in a variety of applications for biological sample analysis.

TMAO is involved in kidney-yang deficiency syndrome diarrhea by mediating the “gut-kidney axis”

BackgroundTrimethylamine-N-oxide (TMAO) is a harmful metabolite dependent on the intestinal microbiota and excreted through the kidneys. According to numerous investigations, rich circulation concentrations of TMAO have been linked to kidney and gastrointestinal disorders. Through the “gut-kidney axis” mediated by TMAO, this research attempted to clarify the microbiological causes of kidney-yang deficiency syndrome diarrhea. MethodsAdenine and Folium Sennae were used to create a mouse model of kidney-yang deficiency syndrome diarrhea. 16S rRNA sequencing was used to identify the traits of the intestinal mucosal microbiota. ELISA was used to assess TMAO, transforming growth factor-β1 (TGF-β1), interleukin-1β (IL-1β), and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). Kidney tissue fibrosis was evaluated using Masson's trichrome staining, and immunohistochemical labeling was used to investigate the protein expression of occludin and Zonula Occludens-1(ZO-1) in small intestine tissue. Microbial activity was determined by using fluorescein diacetate (FDA) hydrolysis spectrophotometry. ResultsTMAO showed a positive correlation with NLRP3, IL-1β and TGF-β1, all of which exhibited substantial increases (P < 0.05). Significant renal fibrosis and decreased ZO-1 and occludin expression in small intestine tissues were detected in the model group. The sequencing results revealed alterations in both α and β diversities of small intestinal mucosal microbiota. Elevated TMAO concentrations were potentially associated with increasing Firmicutes/Bacteroidota (F/B) ratios, Streptococcus, Pseudomonas and unclassified Clostridia UCG 014, but with decreasing Rothia and RB41 abundances. ConclusionThis study establishes a link between intestinal microbiota dysbiosis and elevated TMAO concentrations. TMAO can activate inflammatory responses and cytokines, contributing to kidney-yang deficiency syndrome diarrhea via the “gut-kidney axis”. Moreover, TMAO may coincide with disruptions in the intestinal barrier and renal fibrosis. Dysfunction of the “gut-kidney axis” further elevates TMAO levels, perpetuating a vicious cycle.

Clinical Nursing Intervention of Moxibustion on Abdominal Distension Symptoms in Heart Failure (Heart and Kidney Yang Deficiency and Blood Stasis Blocking Collaterals Syndrome)

Objective: To investigate the clinical nursing intervention effect of moxibustion on abdominal distension symptoms in heart failure (heart and kidney yang deficiency and blood stasis blocking collaterals syndrome). Methods: 62 patients with heart failure (heart and kidney yang deficiency and blood stasis blocking collaterals syndrome) admitted to our hospital from February 2023 to February 2024 were selected and divided into the observation group (n = 31) and the control group (n = 31) by using the random numerical table method. The control group adopted conventional nursing interventions, and the observation group received the nursing program of the control group with the addition of moxibustion nursing interventions. The nursing effectiveness, quality of life scores, and nursing satisfaction were compared between the two groups. Results: The nursing effectiveness of the observation group was significantly higher than the control group (P &lt; 0.05); the quality of life score of the observation group was significantly higher than the control group (P &lt; 0.05); the nursing satisfaction of the observation group was significantly higher than that of the control group (P &lt; 0.05). Conclusion: The use of moxibustion nursing intervention in patients with heart failure (heart and kidney yang deficiency and blood stasis blocking collaterals syndrome) can effectively relieve the symptoms of abdominal distension, improve patients’ quality of life, and increase nursing satisfaction, which has promotion and application values.

Pharmacokinetics, safety, and efficacy of Fuqi Guben Gao in the treatment of kidney-yang deficiency syndrome: a randomized, double-blind phase I trial.

Introduction: Fuqi Guben Gao (FQGBG) is a botanical drug formulation composed of FuZi (FZ; Aconitum carmichaelii Debeaux [Ranunculaceae; Aconiti radix cocta]), Wolfberry (Lycium barbarum L. [Solanaceae; Lycii fructus]), and Cinnamon (Neolitsea cassia (L.) Kosterm. [Lauraceae; Cinnamomi cortex]). It has been used to clinically treat nocturia caused by kidney-yang deficiency syndrome (KYDS) for over 30years and warms kidney yang. However, the pharmacological mechanism and the safety of FQGBG in humans require further exploration and evaluation. Methods: We investigated the efficacy of FQGBG in reducing urination and improving immune organ damage in two kinds of KYDS model rats (hydrocortisone-induced model and natural aging model), and evaluated the safety of different oral FQGBG doses through pharmacokinetic (PK) parameters, metabonomics, and occurrence of adverse reactions in healthy Chinese participants in a randomized, double-blind, placebo-controlled, single ascending dose clinical trial. Forty-two participants were allocated to six cohorts with FQGBG doses of 12.5, 25, 50, 75, 100, and 125g. The PKs of FQGBG in plasma were determined using a fully validated LC-MS/MS method. Results: FQGBG significantly and rapidly improved the symptoms of increased urination in both two KYDS model rats and significantly resisted the adrenal atrophy in hydrocortisone-induced KYDS model rats. No apparent increase in adverse events was observed with dose escalation. Major adverse drug reactions included toothache, thirst, heat sensation, gum pain, diarrhea, abdominal distension, T-wave changes, and elevated creatinine levels. The PK results showed a higher exposure level of benzoylhypaconine (BHA) than benzoylmesaconine (BMA) and a shorter half-life of BMA than BHA. Toxic diester alkaloids, aconitine, mesaconitine, and hypaconitine were below the lower quantitative limit. Drug-induced metabolite markers primarily included lysophosphatidylcholines, fatty acids, phenylalanine, and arginine metabolites; no safety-related metabolite changes were observed. Conclusion: Under the investigated dosing regimen, FQGBG was safe. The efficacy mechanism of FQGBG in treating nocturia caused by KYDS may be related to the improvement of the hypothalamus-pituitary-adrenal axis function and increased energy metabolism. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=26934, identifier ChiCTR1800015840.

Targeting the Gut-Kidney Axis in Diarrhea with Kidney-Yang Deficiency Syndrome: The Role of Sishen Pills in Regulating TMAO-Mediated Inflammatory Response.

BACKGROUND Sishen Pills (SSPs) are commonly used to treat diarrhea with kidney-yang deficiency syndrome. Trimethylamine-N-oxide (TMAO) is produced through the metabolism of gut microbiota and can participate in diarrhea in kidney-yang deficiency syndrome by mediating the "gut-kidney axis" to transmit inflammatory factors. This study combined network pharmacology with animal experiments to explore whether SSPs can treat diarrhea with kidney-yang deficiency syndrome by affecting the interaction between TMAO and gut microbiota. MATERIAL AND METHODS A mouse model of diarrhea with kidney-yang deficiency syndrome was constructed by using adenine and Folium sennae decoction, and SSP decoction was used for treatment. This study utilized network pharmacology to predict the potential mechanisms of SSPs in treating diarrhea with kidney-yang deficiency syndrome. 16S rRNA high-throughput sequencing was used to analyze gut mucosal microbial characteristics. ELISA was used to measure TMAO, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), interleukin-1ß (IL-1ß), and transforming growth factor-ß1 (TGF-ß1) levels. We performed Masson and immunohistochemical (Occludin, ZO-1) staining of kidney and small intestinal tissues. The fluorescein diacetate (FDA) hydrolysis spectrophotometric method was used to assess the microbial activity in contents of the small intestine. RESULTS Network pharmacology analysis revealed that SSPs can modulate 108 target points involved in the development of diarrhea, including IL-1ß and TNF. The experimental results demonstrated that SSP decoction significantly improved the general behavioral profiles of the mice, and also reduced TMAO, NLRP3, IL-1ß, and TGF-ß1 levels (P<0.05). Correlation analysis revealed significant positive correlations between TMAO concentrations and NLRP3, IL-1ß and TGF-ß1 levels (P<0.05). Pathological analysis revealed improvements in renal fibrosis and increased expression of the Occludin and ZO-1 proteins in intestinal tissue. In the SSP group, there was a significant increase in microbial activity (P<0.001). According to the sequencing results, the characteristic bacteria of the SSP and NR groups included Succinatimonas hippei, uncultured Solirubrobacter sp., and Clostridium tyrobutyricum. Furthermore, TMAO, NLRP3, IL-1ß, and TGF-ß1 were significantly positively correlated (P<0.05) with Succinatimonas hippei and Clostridium tyrobutyricum. By modulating Firmicutes, Succinatimonas hippei, and Clostridium tyrobutyricum, SSP decoction lowers TMAO levels to alleviate diarrhea with kidney-yang deficiency syndrome. CONCLUSIONS TMAO likely plays a significant role in the "gut-kidney axis" of diarrhea with kidney-yang deficiency syndrome. By adjusting gut microbiota to reduce the inflammatory response that is transmitted through the "gut-kidney axis" as a result of elevated TMAO levels, SSP decoction can alleviate diarrhea with kidney-yang deficiency syndrome.

Integrated serum pharmacochemistry, network pharmacology, and pharmacokinetics to clarify the effective components and pharmacological mechanisms of the proprietary Chinese medicine Jinkui Shenqi Pill in treating kidney yang deficiency syndrome

The proprietary Chinese medicine Jinkui Shenqi Pill (PCM-JKSQP) is a classic compound used for the effective clinical treatment of kidney yang deficiency syndrome (KYDS), a metabolic disease accompanied by kidney injury. However, its active ingredients and therapeutic mechanisms are not clear. This study employed serum pharmacochemistry, network pharmacology, and pharmacokinetics (PK) to identify the bioactive components of PCM-JKSQP and preliminarily clarify its mechanism in treating KYDS. One hundred and forty chemical components of PCM-JKSQP, 47 (20 parent compouds and 27 metabolites) of which were absorbed into the blood, were identified by ultra-high-performance liquid chromatography-quadrupole-orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS). The topological parameters of network pharmacology and high concentrations in blood found six parent components as PK markers (cinnamic acid, paeonol, loganin, morroniside, apigenin, and poricoic acid A). PK analysis further identified these six compounds as active ingredients. Protein-protein interaction (PPI) analysis and molecular docking simulation predicted and verified eight core targets (TP53, ESR1, CTNNB1, EP300, EGFR, AKT1, ERBB2, and TNF). Most were concentrated in the MAPK, HIF-1, and PI3K-AKT signaling pathways, indicating that these six active ingredients may mainly exert therapeutic effects through these three pathways via their core targets. The PK results also showed these six components were absorbed quickly, although cinnamic acid and paeonol were rapidly metabolized, with a short half-life and retention time. Loganin and morroniside did not have high peak concentrations, and apigenin and poricoic acid A had long retention times. This study provides a new overall perspective for exploring the bioactive components and mechanisms underlying the effects of PCM-JKSQP in treating KYDS.

Comparing the pharmacological effects of the prepared folium of Epimedium brevicornu Maxim. and Epimedium sagittatum Maxim. on kidney-Yang deficiency syndrome and liver injury complications

Yinyanghuo, a famous herb, includes the folium of Epimedium brevicornu Maxim. and Epimedium sagittatum Maxim. It is believed that their processed products, the prepared slices of the folium of Epimedium brevicornu Maxim. (PFEB) and Epimedium sagittatum Maxim. (PFES) have greater efficacy in tonifying kidney Yang to treat kidney-Yang deficiency syndrome (KDS). However, there are few studies comparing the pharmacological effects of PFEB and PFES, and the underlying mechanisms. This study compared their effects on improving hypothalamic-pituitary-adrenal (HPA) axis, immune system and sexual characteristic, as well as repairing liver injury complications in the KDS model mice. Additionally, the mechanisms of the effects relevance to their main components were explored. It was found that PFEB was more effective than PFES in increasing cAMP/cGMP ratio, SOD activity, CRH and ACTH levels, eNOS and testosterone levels, splenic lymphocytes proliferation, while in decreasing MDA content, atrophy of spleen and thymus, splenic lymphocytes apoptosis, and PDE5 level. PFES showed stronger protection than PFEB in decreasing triglyceride and hepatic lipid. The contents of baohuoside I and epimedin A, B were much higher in PFEB, while Epimedin C, Icariin, 2-O″-rhamnosylicaridide II were higher in PFES. Consequently, PFEB exhibits superior efficacy over PFES in tonifying the kidney-Yang by improving the neuroendocrine-immune network, including HPA axis, immune systems, and corpus cavernosum. However, PFES has better recovery effect on mild hepatic lipid caused by KDS. The efficacy difference between PFEB and PFES in kidney-Yang and liver may be attributed to the content variations of baohuoside I.

Integrated untargeted and targeted testicular metabolomics to reveal the regulated mechanism of Gushudan on the hypothalamic-pituitary-gonadal axis of kidney-yang-deficiency-syndrome rats.

Modern studies have shown that neuroendocrine disorders caused by the dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis are one of the important pathogenetic mechanisms of kidney-yang-deficiency-syndrome (KYDS). The preventive effect of Gushudan on KYDS has been reported, but its regulatory mechanisms on the HPG axis have not been elucidated. In this study, we developed an integrated untargeted and targeted metabolomics analysis strategy to investigate the regulatory mechanism of Gushudan on the HPG axis in rats with KYDS. In untargeted metabolomics, we screened 14 potential biomarkers such as glycine, lysine, and glycerol that were significantly associated with the HPG axis. To explore the effect of changes in the levels of potential biomarkers on KYDS, all of them were quantified in targeted metabolomics. With the quantitative results, correlations between potential biomarkers and testosterone, a functional indicator of the HPG axis, were explored. The results showed that oxidative stress, inflammatory response, and energy depletion, induced by metabolic disorders in rats, were responsible for the decrease in testosterone levels. Gushudan improves metabolic disorders and restores testosterone levels, thus restoring HPG axis dysfunction. This finding elucidates the special metabolic characteristics of KYDS and the therapeutic mechanism of Gushudan from a new perspective.

Effect of Curcuma longa extract on reproduction function in mice and testosterone production in Leydig cells.

Curcuma longa, best known for its culinary application as the main constituent of curry powder, has shown potential impact on the reproductive system. This study aimed to investigate the efficacy of Curcuma longa extract (CLE) on Kidney-Yang deficiency mice induced by hydrocortisone and the possible roles in testosterone secretion in Leydig cells. We evaluated male sexual behaviour, reproductive organ weight, testosterone levels, and histological tissue changes in hydrocortisone-induced mice. CLE effectively reversed hydrocortisone-induced Kidney-Yang deficiency syndrome by improving sexual behaviour, testis and epididymis weight, testosterone levels and reducing pathological damage. Our invitro study further indicated that CLE stimulated testosterone production via upregulating the mRNA and protein expression of steroidogenic enzymes in Leydig cells. It significantly improved H89-inhibited protein expression of StAR and cAMP-response element-binding (CREB), as well as melatonin-suppressed StAR protein expression. The data obtained from this study suggest that CLE could alleviate Kidney-Yang deficiency symptoms and stimulate testosterone production by upregulating the steroidogenic pathway. This research identifies CLE as a potential nutraceutical option for addressing testosterone deficiency diseases.

The acute toxic effect of Chinese medicine Fuzi is exacerbated in kidney yang deficiency mice due to metabolic difference

Ethnopharmacological relevanceThe proper application of toxic medicines is one of the characteristics of traditional Chinese medicines, and the use of traditional Chinese medicines follows the principle of dialectical treatment. It is necessary to combine different “syndrome” or “disease” states with the toxicity of traditional Chinese medicines to form a reliable toxicity evaluation system. Fuzi, the lateral root of Aconitum carmichaelii Debx, is recognized as a panacea for kidney yang deficiency syndrome, however, its toxic effects significantly limit its clinical application. Aim of the studyHerein, our research aimed to explore the toxic effects of Fuzi on syndrome models, and tried to reveal the underlying mechanisms. Materials and methodsFirstly, the mouse model of kidney yang deficiency syndrome was established through intramuscular injection of 25 mg/kg hydrocortisone per day for 10 consecutive days. Then, the acute toxicity of Fuzi in normal mice and kidney yang deficiency model mice was explored. Finally, the plasma metabolite concentrations and liver CYP3A4 enzyme activity were analyzed to reveal the possible mechanisms of the different pharmacological and toxicological effects of Fuzi in individuals with different physical constitutions. ResultsIt was found that the treatment with Fuzi (138 g/kg) had serious toxic effects on kidney yang deficiency mice, leading to the death of 80% of the mice, whereas it showed no lethal toxicity in normal mice. This indicates that Fuzi induced greater toxicity in kidney yang deficiency mice than in normal ones. The liver CYP3A4 enzyme activity in kidney yang deficiency mice was decreased by 20% compared to the controls, resulting in slower metabolism of the toxic diester diterpenoid alkaloids in Fuzi. ConclusionIn conclusion, our study showed that changes of the metabolic enzyme activity in individuals with different syndromes led to different toxic effects of Chinese medicines, emphasizing the crucial importance of considering individual physical syndromes in the clinical application of traditional Chinese medicine, and the significance of conducting safety evaluations and dose predictions on animal models with specific syndromes for traditional Chinese medicines.

Dysfunction of cecal microbiota and CutC activity in mice mediating diarrhea with kidney-yang deficiency syndrome.

Previous studies have indicated that diarrhea with kidney-yang deficiency syndrome leads to a disorder of small intestine contents and mucosal microbiota. However, the relationship of TMA-lyase (CutC) activity and TMAO with diarrhea with kidney-yang deficiency syndrome remains unexplored. Therefore, this study explores the relationship between cecal microbiota and choline TMA-lyase (CutC) activity, as well as the correlation between trimethylamine oxide (TMAO), inflammatory index, and CutC activity. Twenty SPF-grade male KM mice were randomly divided into the normal group (CN) and the diarrhea model group (CD). Diarrhea mouse models were established by adenine combined with Folium sennae administration. CutC activity, TMAO, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels were detected, and the cecal content microbiota was sequenced. After 14 days, diarrhea occurred in the CD group. Compared with the CN group, there was no significant change in the activity of CutC in the small intestine of the CD group, while the activity of CutC in the cecum was significantly increased, and the levels of TMAO, IL-6, and TNF-α showed a significant increase. The Chao1 index, Observed_species index, Shannon index, and Simpson index all exhibited a decreasing trend. The main changes at the bacterial genus level were Alistipes, Enterorhabdus, Desulfovibrio, Bacteroides, Candidatus_Saccharimonas, and [Ruminococcus]_torques_group. The results of LEfSe analysis, random forest analysis and ROC curve analysis revealed Paludicola, Blautia, Negativibacillus, Paraprevotella, Harryflintia, Candidatus_Soleaferrea, Anaerotruncus, Oscillibacter, Colidextribacter, [Ruminococcus]_torques_group, and Bacteroides as characteristic bacteria in the CD group. Correlation analysis showed a significant negative correlation between cecal CutC activity and Ligilactobacillus, and a significant positive correlation with Negativibacillus and Paludicola. The level of TMAO was significantly positively correlated with CutC activity and IL-6. Diarrhea with kidney-yang deficiency syndrome significantly affects the physiological status, digestive enzyme activity, CutC activity, TMAO levels, and inflammatory response in mice. Additionally, there are changes in the composition and function of cecal microbiota, indicating an important impact of diarrhea with kidney-yang deficiency syndrome on the host intestinal microbiota balance. The occurrence of diarrhea with kidney-yang deficiency syndrome may be associated with dysbiosis of intestinal microbiota, increased CutC activity, elevated TMAO levels, and heightened inflammatory factor levels.

Study on the intervention effect of Epimedium before and after suet-oil-processed on kidney yang deficiency rats based on intestinal flora and fecal metabolomics

Epimedium is a Chinese herbal medicine commonly used in clinical practice to reinforce yang. Previous studies have shown that Epimedium fried with suet oil based has the best effect on warming kidney and promoting yang. Evidence suggests a relationship between kidney yang deficiency syndrome (KYDS) and metabolic disorders of the intestinal microflora. However, the specific interaction between KYDS and the intestinal microbiome, as well as the internal regulatory mechanism of the KYDS intestinal microbiome regulated by Epimedium fried with suet oil, remain unclear. The purpose of this study was to investigate the regulatory effects of different processed products of Epimedium on intestinal microflora and metabolites in rats with kidney yang deficiency, and to reveal the processing mechanism of Epimedium fried with suet oil warming kidney and helping yang. 16S rRNA and LC-MS/MS technology were used to detect fecal samples. Combined with multivariate statistical analysis, differential intestinal flora and metabolites were screened. Then the content of differential bacteria was then quantified using quantitative real-time fluorescence PCR. Furthermore, the correlation between differential bacterial flora and metabolites was analyzed using Spearman's method. The study found that the composition of intestinal flora in rats with kidney yang deficiency changed compared to healthy rats. Epimedium fried with suet oil could increase the levels of beneficial bacteria, while significantly reducing the levels of harmful bacteria. Real-time quantitative PCR results were consistent with 16S rRNA gene sequencing analysis. Fecal metabolomics revealed that KYDS was associated with 30 different metabolites, involving metabolic pathways steroid hormone biosynthesis etc. Moreover, differential bacteria were closely correlated with potential biomarkers. Epimedium could improve metabolic disorders associated with KYDS by acting on the intestinal flora, with Epimedium fried with suet oil demonstrating the most effective regulatory effect. Its potential mechanism may involve the regulation of abnormal metabolism and the impact on the diversity and structure of the intestinal flora.

Adenine's impact on mice's gut and kidney varies with the dosage administered and relates to intestinal microorganisms and enzyme activities.

This study aimed to investigate the effects of different dosages of adenine on intestinal microorganisms and enzyme activities, laying the experimental groundwork for subsequent exploration of the microbial mechanisms underlying diarrhea with kidney yang deficiency syndrome. Twenty-four mice were assigned to the following four groups: the control (NC) group, low-dosage adenine (NML) group, middle-dosage adenine (NMM) group, and high-dosage adenine (NMH) group. Mice in the NML, NMM, and NMH groups received 25mg/(kg·d), 50mg/(kg·d), and 100mg/(kg·d) of adenine, respectively, 0.4mL/each, once a day for 14days. The NC group received 0.4mL sterile water. Parameters including body weight, rectal temperature, intestinal microorganisms, enzyme activities, and microbial activity were measured. Results indicated that mice in the experimental group displayed signs of a poor mental state, curled up with their backs arched, and felt sleepy and lazy, with sparse fur that was easily shed, and damp bedding. Some mice showed fecal adhesion contamination in the perianal and tail areas. Dosage-dependent effects were observed, with decreased food intake, body weight, rectal temperature, and microbial activity and increased water intake and fecal water content. Enzyme activity analyses revealed significantly higher activities of protease, sucrase, amylase, and cellulase in intestinal contents and lactase, sucrase, amylase, and cellulase in the mucosa of the NMM group compared to those of other groups. Ultimately, the higher adenine dosage was associated with more pronounced symptoms of kidney yang deficiency syndrome, with 50mg/kg adenine exhibiting the most substantial impact on the number of intestinal microbial colonies and enzyme activities.

Integrated UHPLC-MS untargeted metabolomics and gut microbe metabolism pathway-targeted metabolomics to reveal the prevention mechanism of Gushudan on kidney-yang-deficiency-syndrome rats

Gushudan (GSD) was a traditional Chinese prescription with the remarkable effect of kidney-tonifying and bone-strengthening. However, the potential prevention mechanisms of the GSD on kidney-yang-deficiency-syndrome (KYDS) and its regulation on gut microbe metabolism still need to be further systematically investigated. This study established untargeted urinary metabolomics based on RP/HILIC-UHPLC-Q-Orbitrap HRMS and combined with multivariate statistical analysis to discover differential metabolites and key metabolic pathways. And the gut microbe metabolism pathway-targeted metabolomic based on HILIC-UHPLC-MS/MS was developed and validated to simultaneously determine 15 gut microbe-mediated metabolites in urine samples from the control group (CON), KYDS model group (MOD), GSD-treatment group (GSD) and positive group (POS). The results showed that a total of 36 differential metabolites were discovered in untargeted metabolomics. These differential metabolites included proline, cytosine, butyric acid and nicotinic acid, which were primarily involved in the gut microbe metabolism, amino acid metabolism, energy metabolism and nucleotide metabolism. And GSD played a role in preventing KYDS by regulating these metabolic pathways. The targeted metabolomics found that the levels of 10 gut microbe-mediated metabolites had significant differences in different groups. Among them, compared with the CON group, the levels of lysine, tryptophan, phenylacetylglycine and hippuric acid were increased in the MOD group, while the levels of threonine, leucine, dimethylamine, trimethylamine, succinic acid and butyric acid were decreased, which verified the disorders of gut microbe metabolism in the KYDS rats and GSD had a significant regulatory effect on this disorder. As well as by comparing analysis, it was found that the experimental results were consistent with previous metabolomics and microbiomics of fecal samples. Therefore, this integrated strategy of untargeted and targeted metabolomics not only elucidated the potential prevention mechanism of GSD on KYDS, but also provided a scientific basis for GSD preventing KYDS via the “gut-kidney” axis.

The Water Element, Zang-fu Kidney and Jin Gui Shen Qi Wan

The Water Element, as part of the Traditional Chinese Medicine (TCM) Five Elements, is associated with winter, coldness, darkness and the Zang-fu organs Kidney and Bladder. The TCM Kidney, encompasses far more than the Western concept of an organ which produces and excretes the waste product urine. It controls water and fluid metabolism; a primordial generator (Ming-men Fire, Essence, Jing, promotes growth, skeleton, marrow, innate constitution); Yin-Yang dynamics (innate Yin and Yang); receives Qi; life functions (sexual behavior, reproduction, neuroendocrine axis, nervous system, urinary system, manufacture Blood, acute sense of hearing, controls the 2 lower orifices, assists respiration); as well as supports good life/living (houses commitment, will power, memory). Diseases of the Kidney can manifest as congenital deficiencies, fearful attitude, pathological changes (Yin and Yang Deficiencies, chronic debilitation), and physiological deficiencies associated with senescence. Some of the more common clinical signs of Kidney (Water Element) disease include renal/reproduction disorders, lumbar pain, hind end weakness, teeth/hair loss, deafness, lassitude, neuroendocrine disorders, asthma, congenital disease and bone disorders. One of the most famous formulas to treat Kidney Yang Deficiency and decline of Ming-men Fire is the classical herbal formula Jin Gui Shen Qi Wan. The strategy of this formula is to tonify Kidney Yin to raise Kidney Yang, (since Yin and Yang are mutually dependent), with the addition of warm herbs to ignite the Fire of Ming-men. From a Chinese medical perspective, Kidney Yang Deficiency syndrome may cause endocrine system disorders, immune-deficiency, neurological, renal, and reproductive disorders. This paper will review the Zang-fu Kidney function, and the classic Chinese herbal medicine, Jin Gui Shen Qi Wan (Kidney Qi Pill from the Golden Cabinet).

The dysfunction in intestinal microorganisms and enzyme activity as significant contributors to diarrhea with kidney-yang deficiency syndrome.

To investigate the pathogenesis of diarrhea with kidney-yang deficiency syndrome by examining characteristic changes in intestinal microorganisms, enzyme activities, oxidative stress, and metabolism indices. Twenty mice were randomly and equally divided into control group (NC) and model group (NM). Mice in NM group received adenine suspension at a dosage of 50 mg/(kg⋅day) by gavage, 0.4 mL/time, once a day for 14 days, and Folium sennae decoction at a dosage of 10 g/(kg⋅day) by gavage, 0.4 mL/time, once a day for 7 days, starting on 8th day. Mice in NC group were administered an equivalent amount of sterile water by gavage once a day for 7 days, and twice a day from the 8th day. After modeling, assessments encompassed microbial culture, organ index calculation, microbial and enzyme activity detection, malondialdehyde (MDA) content determination, superoxide dismutase (SOD) activity, blood biochemical tests, and observation of kidney tissue pathological changes. The results showed that in NM group, a reduction in the number of Lactobacillus and Bifidobacteria was noted, accompanied by an increase in the number of bacteria and E. coli. Xylanase activity in the intestinal contents and mucosa, protease activity in the intestinal mucosa, and intestinal mucosa microbial activity were diminished. Conversely, the activities of amylase, sucrase, and lactase increased in intestinal mucosa. Additionally, there was an elevation in the level of MDA. Renal tubular dilatation and inflammatory cell infiltration were observed in the renal interstitium. These dysfunctions in intestinal microorganisms and enzyme activities suggest potential involvement in diarrhea with kidney-yang deficiency syndrome.