Mechanism of Tianma Gouteng Decoction in the treatment of Parkinson's disease based on network pharmacology and molecular docking.

OBJECTIVE: To explore the pharmacological mechanism and molecular targets of Tianma Gouteng Decoction (TMGTD) in the treatment of Parkinson's disease (PD). METHODS: We applied network pharmacology to screen the active components of TMGTD and predict target genes in multiple Chinese herbal medicine databases and compound databases, and built a drug-ingredient-target network. Then, we used the CytoHubba plug-in to filter out the core components of TMGTD according to the order of degree value. We screened PD-related pathogenic targets in the DrugBank, Genecard and OMIM databases from high to low in Betweenness Centrality (BC) value and Closeness Centrality (CC) value. Subsequently, we determined the intersection target of TMGTD and PD by Venn diagram and performed protein-protein interaction (PPI) analysis, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on core molecules and intersection targets. Finally, molecular docking was performed to verify the binding of the top three core molecules of TMGTD with the top three core targets of PD. RESULTS: The core components of TMGTD are quercetin, kaempferol and palmitic acid. The main targets of TMGTD in the treatment of PD are ALB, GAPDH and AKT1. GO analysis and KEGG analysis showed that the biological process of TMGTD in the treatment of PD is closely related to the activities of neurotransmitter receptors, G protein-coupled receptors and dopamine neurotransmitter receptors. TMGTD possesses therapeutic effects on PD mainly through the PI3K-Akt signaling pathway and MAPK signaling pathway. Molecular docking shows the high affinity of the quercetin, kaempferol and palmitic acid with PD core targets. CONCLUSION: TMGTD plays a pivotal role in the treatment of PD through multiple components, multiple targets and multiple pathways. The results provide a research direction for the subsequent exploration of the mechanism of TMGTD in PD treatment.

[Tianma Gouteng Decoction regulates MFN2 expression to delay vascular aging in spontaneously hypertensive rats].

We studied the effect of Tianma Gouteng Decoction on vascular aging in spontaneously hypertensive rats(SHRs) to explore the molecular mechanism of the decoction in improving arterial vascular aging by regulating the expression of mitofusin 2(MFN2).Twenty 64-weeks-old SHRs were randomly assigned into the aging group and the treatment group(Tianma Gouteng Decoction 5.48 mg·kg~(-1)).Wistar-Kyoto(WKY) rats of 64 weeks old were taken as the normal group and SHR rats of 14 weeks old as the young group.The intervention with Tianma Gouteng Decoction lasted for 12 weeks.We then employed HE staining and Masson staining to observe the morphology of thoracic aorta under an electron microscope and measured the malondialdehyde(MDA) content, superoxide dismutase(SOD) activity, respiratory chain complex Ⅲ level, and thioredoxin peroxidase(TPX) activity.The vascular aging was detected via the biomarker senescence-associated beta-galactosidase(SA-ß-Gal).The expression levels of MFN2 and aging marker proteins silent information regulator 1(SIRT1), Klotho, p21, and p53 in thoracic aorta were detected by immunohistochemistry/fluorescence, qRT-PCR, and Western blot.Compared with the young group and the normal group, the aging group had risen blood pressure, lumen stenosis caused by thickened intima of blood vessels, decreased SOD and TPX activities, increased MDA and mitochondrial respiratory chain complex Ⅲ levels, down-regulated expression of MFN2, SIRT1, and Klotho, and up-regulated expression of p21 and p53(P<0.01 or P<0.05).The treatment with Tianma Gouteng Decoction significantly lowered blood pressure, mitigated vascular intimal thickening, increased SOD and TPX activities, and decreased MDA and mitochondrial respiratory chain complex Ⅲ levels, thus alleviating vascular aging.At the same time, the decoction up-regulated the expression of MFN2, SIRT1, and Klotho, while down-regulated that of p21 and p53(P<0.01 or P<0.05).In summary, Tianma Gouteng Decoction can significantly delay the vascular aging in hypertension.Specifically, it may up-regulate the expression of MFN2 and regulate the expression of aging-related proteins to alleviate oxidative stress.

Stimulation of hair growth by Tianma Gouteng decoction: Identifying mechanisms based on chemical analysis, systems biology approach, and experimental evaluation.

Hair serves important physiological functions, including temperature regulation and scalp protection. However, excessive shedding not only impacts these functions but can also significantly affect mental health and quality of life. Tianma Gouteng decoction (TGD) is a traditional Chinese medicine used for the treatment of various conditions, including hair loss. However, the associated mechanism underlying its anti-alopecia effect remains unknown. Therefore, this study aims to elucidate these mechanisms by employing systematic biology approaches, as well as in vitro and in vivo experimental validation. The chemical constituents of Tianma Gouteng decoction were identified using UHPLC-MS/MS, from which 39 potential bioactive components were screened, while an additional 131 putative Tianma Gouteng decoction beneficial components were extracted from the Traditional Chinese Medicine Database and Analysis Platform (TCMSP) database. We then applied a dual-dimensional network pharmacology approach to analyze the data, followed by validation studies combining molecular docking techniques with in vivo and in vitro experiments. From the 39 bioactive components, including quercetin, luteolin, fisetin, wogonin, oroxylin A, boldine, tetrahydroalstonine, and galangin A, 782 corresponding targets were identified. In particular, GSK3ß and ß-catenin exhibited strong binding activity with the bioactive compounds. Hence, construction of a bioactive component-target network revealed that the mechanism underlying the anti-alopecia mechanism of Tianma Gouteng decoction primarily involved the Wnt/ß-catenin signaling pathway. Moreover, C57BL/6J mice exhibited measurable improvements in hair follicle regeneration following treatment with Tianma Gouteng decoction. Additionally, ß-catenin and p-GSK3ß levels were upregulated, while GSK3ß was downregulated in Tianma Gouteng decoction-treated animals and dermal papilla cells compared to control group. These in vivo and in vitro outcomes validated the targets and pathways predicted in the network pharmacology analysis of Tianma Gouteng decoction. This study provides a systematic analysis approach to identify the underlying anti-alopecia mechanisms of Tianma Gouteng decoction, further providing theoretical support for clinical assessment of Tianma Gouteng decoction.

Tianma Gouteng Decoction regulates oxidative stress and inflammation in AngII-induced hypertensive mice via transcription factor EB to exert anti-hypertension effect.

Hypertension is one of the important causes of cardiovascular diseases, and the imbalance of vascular homeostasis caused by oxidative stress and endothelial inflammation occurs throughout hypertension pathogenesis. Therefore, inhibiting oxidative stress and endothelial inflammation is important for treating hypertension. Tianma Gouteng Decoction (TGD) is a Chinese herbal medicine that is commonly used to treat hypertension in China, and demonstrates clinically effective antihypertensive effects. However, its blood pressure reduction mechanism remains unclear. In this study, we further determined the antihypertensive effects of TGD and revealed its underlying mechanism. We established an AngII-induced hypertension mice model, which was treated with TGD for six weeks. We monitored blood pressure, heart rate, and body weight every week. After six weeks, we detected changes in the structure and function of the heart, the structure of blood vessels, and vasomotor factors. We also detected the expression of oxidative stress and inflammation-related genes. We found that TGD can significantly reduce blood pressure, improve cardiac structure and function, and reverse vascular remodeling, which could be due to the inhibition of oxidative stress and inflammation. We also found that the effect of inhibiting oxidative stress and inflammation could be related to the up-regulation of transcription factor EB (TFEB) expression by TGD. Therefore, we used AAV9 to knock down TFEB and observe the role of TFEB in TGD's antihypertensive and cardiovascular protection properties. We found that after TFEB knockdown, the protective effect of TGD on blood pressure and cardiovascular remodeling in AngII-induced hypertensive mice was inhibited, and that it was unable to inhibit oxidative stress and inflammation. Therefore, our study demonstrated for the first time that TGD could exert anti-oxidative stress and anti-inflammatory effects through TFEB and reverse the cardiovascular remodeling caused by hypertension.

Early intervention combining Chinese and Western medicine in traumatic brain injury with diffuse axonal injury: A report of three cases.

BACKGROUND: Traumatic brain injury (TBI) is characterized by high prevalence, morbidity, and mortality. Diffuse axonal injury (DAI) is a specific type of TBI leading to prolonged consciousness impairment and disability. There is still no standard treatment for DAI, so we introduced traditional Chinese medicine into the treatment of these patients. CASE SUMMARIES: Three patients had TBI after traffic accidents. Their Glasgow Coma Scale (GCS) scores in the intensive care unit (ICU) were E1VEM2-3, E1VEM2-3, and E1VEM2 respectively. All of them were diagnosed with DAI based on magnetic resonance imaging (MRI). Because of continuing consciousness disturbances, their families agreed to combine traditional Chinese medicine and modern medicine treatments through inpatient consultation in Taoyuan General hospital. Two patients took Buyang Huanwu Decoction, and one Tianma Gouteng Decoction twice a day. All of them received 20 min of acupuncture treatments 5 times per week. Acupuncture points included Baihui (GV20), Sishencong (EX-HN1), Shuigou (GV26), Hegu (LI4), and Taichong (LR3). All of them started Traditional Chinese medicine treatment within 2 weeks after TBI. The GCS of all three patients recovered to E4M5V6. CONCLUSIONS: The early addition of traditional Chinese medicine treatments to Western medical care can improve the prognosis of patients with diffuse axonal injury.

[Traditional Chinese medicine insights of newly-diagnosed and young hypertension and clinical practice of Tianma Gouteng Decoction for hypertension treatment].

Hypertension is a global major public health problem. Early intervention and timely blocking are necessary for newly-diagnosed hypertensive and young hypertensive patients. Tianma Gouteng Decoction recorded in Zabing Zhengzhi Xinyi written by HU Guangci has the major functions in treating excess syndrome and wind-Yang disturbance syndrome with effects in calming liver-wind, clearing heat and activating blood, and nourishing liver and kidney. As we known, Tianma Gouteng Decoction is a classical formula for treating hypertension. However, due to the limitation of historical conditions, some problems impede Tianma Gouteng Decoction from being handed down successfully, such as uncertain diagnosis, uncertain antihypertensive efficacy and treatment-course. In this case, we ask whether Tianma Gouteng Decoction can be used as antihypertensive therapy and the exactly decrease of systolic and diastolic blood pressure, and wonder the half-life of Tianma Gouteng Decoction and the relationship with Western medicine. Therefore, defined prescription and syndrome, efficacy, treatment-course are important in clinical practice. According to the findings, ① previously, we thought that hypertension was a liver-Yang hyperactivity and liver-wind stirring syndrome, and the liver-based therapy theory was effective. However, based on our study, long-term treatment with Western medicine could block disease progression, control the increased blood pressure and change the pathogenesis and syndrome of traditional Chinese medicine. Therefore, the frequency of liver-Yang hyperactivity syndrome "fire syndrome" decreased sharply, and the main syndrome was fluid-retention syndrome and deficiency syndrome. The etiology and pathogenesis of hypertension was prone to deficiency syndrome accompanied with excess syndrome. Therefore, it was necessary to intervene hypertension in "liver-wind" and "liver-Yang" excess syndrome stage, and the early intervention and treatment are important. ② The newly-diagnosed hypertensive and young hypertensive patients usually had no Western medicine intervention. Thus, the etiology and pathogenesis of hypertension were free from Western medicine, which maintained the initial stage of hypertension in line with the liver-Yang hyperactivity syndrome. ③ The pathological mechanisms of newly-diagnosed and young hypertension were mainly increase in sympathetic activity, active renin-angiotensin-aldosterone system, change in morphology of vascular smooth muscle cells and endothelial cell dysfunction. ④ According to the syndrome of Tianma Gouteng Decoction, in modern medicine, Tianma Gouteng Decoction was widely used to treat the early-stage hypertension and the early-intervention of hypertension without Western medicine, particularly newly-diagnosed, young hypertension, Ⅲ hypertension, hypertensive crisis and hypertensive emergency. Tianma Gouteng Decoction can treat such symptoms as headache, dizziness, fullness of head, slurring of speech; facial flushing, conjunctival congestion and blurred vision; dysphoria, anxiety, palpitation, insomnia, mental disorder and hot flushes; dry-mouth with bitter taste and sweeting; myasthenia of limbs and lassitude in loin and legs; brown urine with burning sensation during urination; a solid or liquid stool consistency; red tongue, slippery and rapid pulse, wiry and rapid pulse over to Cunkou. ⑤ After treatment with Tianma Gouteng Decoction for three to six months, the blood pressure was decreased, and the symptoms were improved with reduction or even discontinuance of Western medicine. ⑥ According to recent studies, Caul is Polygoni Multiflori of Tianma Gouteng Decoction induced certain hepatotoxicity and increased the risk of long-term treatment. However, with the regular monitoring of biomedical index, long-term treatment with Caulis Polygoni Multiflori(3-10 g·d~(-1) for 3 to 6 months) didn't show hepatic dysfunction. ⑦ The pharmacological activity of Tianma Gouteng Decoction coincided with the pathology and disease mechanism of newly-diagnosed and young hypertension. Therefore, Tianma Gouteng Decoction was the specific recipe for newly-diagnosed and young hypertension. Therefore, further studies of efficacy, safety and molecular mechanism of Tianma Gouteng Decoction may make a medical breakthrough for hypertension treatment.

Pharmacodynamics and metabonomics study of Tianma Gouteng Decoction for treatment of spontaneously hypertensive rats with liver-yang hyperactivity syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Essential hypertension is a prevalence chronic cardiovascular disease, which is treated by traditional Chinese medicine (TCM) in China. Metabolomics approach has achieved more attention in pharmacology studies of natural products. Tianma Gouteng Decoction (TGD) is effective for the therapeutic of hypertension in China. We aimed to investigate antihypertension effect of TGD on spontaneous hypertension rat (SHR) with live-Yang hyperactivity hypertension (Gan Yang Shang Kang, GYSK) and explore the mechanism by metabolomics method. MATERIALS AND METHODS: After establishing the GYSK-SHR model by giving aconite decoction, rats were randomly divided into four groups including model group, TGD qd group (66.88 mg/kg, once a day), TGD bid group (33.44 mg/kg, twice a day), TGD tid group (22.29 mg/kg, three times a day). Blood pressure (BP) and indexes of renin-angiotensin-aldosterone system (RAAS system) were measured. Metabolic profiling of rat plasma samples was performed by UPLC-Q-TOF/MS, which was analyzed with principal component analysis (PCA) and partial least-squares-discriminate analysis (PLS-DA) to explore the relationship between metabolic pathways and hypertension. RESULTS: To better explain the role of TGD on hypertension, we detected three different frequencies of TGD treatment with equal dosage. TGD reduced the BP in GYSH-SHR model and regulated the serum levels of NE, Ang II, ET, 5-HT, CRP, RENIN and ALD especially at TGD bid group. By UPLC-Q-TOF/MS analysis, we found 47 potential biomarkers in GYSK-SHR rats from the plasma metabolites, among which 15 biomarkers were regulated by TGD. Consisted with the antihypertension activity, TGD bid group showed the significantly moderating effect on the regulating biomarkers. CONCLUSIONS: TGD exhibited the antihypertensive activity at the frequency of administration twice a day, which had the association with RAAS system and mediated 15 biomarkers by regulating metabolisms of glycerol phospholipid, sphingomyelin, energy and amino acid.

Traditional Chinese medicine insights of newly-diagnosed and young hypertension and clinical practice of Tianma Gouteng Decoction for hypertension treatment / 中国中药杂志

Hypertension is a global major public health problem. Early intervention and timely blocking are necessary for newly-diagnosed hypertensive and young hypertensive patients. Tianma Gouteng Decoction recorded in Zabing Zhengzhi Xinyi written by HU Guangci has the major functions in treating excess syndrome and wind-Yang disturbance syndrome with effects in calming liver-wind, clearing heat and activating blood, and nourishing liver and kidney. As we known, Tianma Gouteng Decoction is a classical formula for treating hypertension. However, due to the limitation of historical conditions, some problems impede Tianma Gouteng Decoction from being handed down successfully, such as uncertain diagnosis, uncertain antihypertensive efficacy and treatment-course. In this case, we ask whether Tianma Gouteng Decoction can be used as antihypertensive therapy and the exactly decrease of systolic and diastolic blood pressure, and wonder the half-life of Tianma Gouteng Decoction and the relationship with Western medicine. Therefore, defined prescription and syndrome, efficacy, treatment-course are important in clinical practice. According to the findings, ① previously, we thought that hypertension was a liver-Yang hyperactivity and liver-wind stirring syndrome, and the liver-based therapy theory was effective. However, based on our study, long-term treatment with Western medicine could block disease progression, control the increased blood pressure and change the pathogenesis and syndrome of traditional Chinese medicine. Therefore, the frequency of liver-Yang hyperactivity syndrome "fire syndrome" decreased sharply, and the main syndrome was fluid-retention syndrome and deficiency syndrome. The etiology and pathogenesis of hypertension was prone to deficiency syndrome accompanied with excess syndrome. Therefore, it was necessary to intervene hypertension in "liver-wind" and "liver-Yang" excess syndrome stage, and the early intervention and treatment are important. ② The newly-diagnosed hypertensive and young hypertensive patients usually had no Western medicine intervention. Thus, the etiology and pathogenesis of hypertension were free from Western medicine, which maintained the initial stage of hypertension in line with the liver-Yang hyperactivity syndrome. ③ The pathological mechanisms of newly-diagnosed and young hypertension were mainly increase in sympathetic activity, active renin-angiotensin-aldosterone system, change in morphology of vascular smooth muscle cells and endothelial cell dysfunction. ④ According to the syndrome of Tianma Gouteng Decoction, in modern medicine, Tianma Gouteng Decoction was widely used to treat the early-stage hypertension and the early-intervention of hypertension without Western medicine, particularly newly-diagnosed, young hypertension, Ⅲ hypertension, hypertensive crisis and hypertensive emergency. Tianma Gouteng Decoction can treat such symptoms as headache, dizziness, fullness of head, slurring of speech; facial flushing, conjunctival congestion and blurred vision; dysphoria, anxiety, palpitation, insomnia, mental disorder and hot flushes; dry-mouth with bitter taste and sweeting; myasthenia of limbs and lassitude in loin and legs; brown urine with burning sensation during urination; a solid or liquid stool consistency; red tongue, slippery and rapid pulse, wiry and rapid pulse over to Cunkou. ⑤ After treatment with Tianma Gouteng Decoction for three to six months, the blood pressure was decreased, and the symptoms were improved with reduction or even discontinuance of Western medicine. ⑥ According to recent studies, Caul is Polygoni Multiflori of Tianma Gouteng Decoction induced certain hepatotoxicity and increased the risk of long-term treatment. However, with the regular monitoring of biomedical index, long-term treatment with Caulis Polygoni Multiflori(3-10 g·d~(-1) for 3 to 6 months) didn't show hepatic dysfunction. ⑦ The pharmacological activity of Tianma Gouteng Decoction coincided with the pathology and disease mechanism of newly-diagnosed and young hypertension. Therefore, Tianma Gouteng Decoction was the specific recipe for newly-diagnosed and young hypertension. Therefore, further studies of efficacy, safety and molecular mechanism of Tianma Gouteng Decoction may make a medical breakthrough for hypertension treatment.

Common and unique mechanisms of Chinese herbal remedies on ischemic stroke mice revealed by transcriptome analyses.

ETHNOPHARMACOLOGICAL RELEVANCE: Four traditional Chinese herbal remedies (CHR) including Buyang Huanwu decoction (BHD), Xuefu Zhuyu decoction (XZD), Tianma Gouteng decoction (TGD) and Shengyu decoction (SYD) are popular used in treating brain-related dysfunction clinically with different syndrome/pattern based on traditional Chinese medicine (TCM) principles, yet their neuroprotective mechanisms are still unclear. MATERIALS AND METHODS: Mice were subjected to an acute ischemic stroke to examine the efficacy and molecular mechanisms of action underlying these CHR. RESULTS: CHR treatment significantly enhanced the survival rate of stroke mice, with BHD being the most effective CHR. All CHR were superior to recombinant tissue-type plasminogen activator (rt-PA) treatment in successfully ameliorating brain function, infarction, and neurological deficits in stroke mice that also paralleled to improvements in blood-brain barrier damage, inflammation, apoptosis, and neurogenesis. Transcriptome analyses reveals that a total of 774 ischemia-induced probe sets were significantly modulated by four CHR, including 52 commonly upregulated genes and 54 commonly downregulated ones. Among them, activation of neurogenesis-associated signaling pathways and down-regulating inflammation and apoptosis pathways are key common mechanisms in ischemic stroke protection by all CHR. Besides, levels of plasma CX3CL1 and S100a9 in patients could be used as biomarkers for therapeutic evaluation before functional recovery could be observed. CONCLUSION: Our results suggest that using CHR, a combinatory cocktail therapy, is a better way than rt-PA for treating cerebral ischemic-associated diseases through modulating a common as well as a specific group of genes/pathways that may partially explain the syndrome differentiation and treatment principle in TCM.

Essential hypertension treated by wuling powder and modified tianma gouteng decoction: a cohort study without controls.

OBJECTIVE: To evaluate the efficacy and safety of wuling powder and modified tianma gouteng decoction as an open add-on therapy for treating essential hypertension (EH). METHODS: 72 cases of EH patients took wuling powder and modified tianma gouteng decoction for 2 weeks to treat EH without changing their former medication. New York Heart Association (NYHA) heart function classification, heart rate, blood pressure and 6-min walking test were evaluated before and after treatment. RESULTS: Wuling powder and modified tianma gouteng decoction decreased the EH patients' heart rate, systolic pressure, diastolic pressure and increased the 6-min walking distance very significantly (P<0.01). The total effective rate on blood pressure was 91.7%, and the total effective rate on NYHA heart function improvement was 95.1%. No serious side effect appeared. CONCLUSION: From this study, treating EH with wuling powder and modified tianma gouteng decoction as an open add-on therapy seems to be effective and safe. Further randomized trials are needed to test the positive findings.