The potential of herbal drugs to treat heart failure: The roles of Sirt1/AMPK.

Heart failure (HF) is a highly morbid syndrome that seriously affects the physical and mental health of patients and generates an enormous socio-economic burden. In addition to cardiac myocyte oxidative stress and apoptosis, which are considered mechanisms for the development of HF, alterations in cardiac energy metabolism and pathological autophagy also contribute to cardiac abnormalities and ultimately HF. Silent information regulator 1 (Sirt1) and adenosine monophosphate-activated protein kinase (AMPK) are nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and phosphorylated kinases, respectively. They play similar roles in regulating some pathological processes of the heart through regulating targets such as peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), protein 38 mitogen-activated protein kinase (p38 MAPK), peroxisome proliferator-activated receptors (PPARs), and mammalian target of rapamycin (mTOR). We summarized the synergistic effects of Sirt1 and AMPK in the heart, and listed the traditional Chinese medicine (TCM) that exhibit cardioprotective properties by modulating the Sirt1/AMPK pathway, to provide a basis for the development of Sirt1/AMPK activators or inhibitors for the treatment of HF and other cardiovascular diseases (CVDs).

Huang-Lian-Jie-Du decoction drug-containing serum inhibits IL-1ß secretion from D-glucose and PA induced BV2 cells via autophagy/NLRP3 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Lian-Jie-Du decoction (HLJDD), a famous traditional Chinese medicine prescription with heat-clearing and detoxifying effects, has been widely used to treat diabetes, dementia, stroke, and other diseases. However, the detailed mechanisms of HLJDD against type 2 diabetes associated cognitive dysfunction (DACD) through inhibiting interleukin-1ß (IL-1ß) mediated neuroinflammation remain to be further elucidated. AIM OF THE STUDY: The aim of this study was to investigate the effect and potential mechanism of HLJDD on IL-1ß secretion in a DACD model of BV2 cells induced by D-glucose and palmitic acid (PA). MATERIALS AND METHOD: sUltra-performance liquid chromatography-quadrupole/electrostatic field orbital well high-resolution mass spectrometry technology was used to analyze the compounds in HLJDD drug-containing serum. The cytotoxicity was detected by cell counting kit-8. Enzyme-linked immunosorbent assay was used to measure the secretion of IL-1ß in BV2 cells. Reactive oxygen species, glutathione, superoxide dismutase, and malondialdehyde kits were used to detect the intracellular oxidative stress levels. The autophagy level was determined by autophagy staining kit and transmission electron microscope. The expression levels of autophagy-related 7 (Atg7), P62, LC3, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3(NLRP3), Caspase1, and IL-1ß were detected by real-time PCR, immunofluorescence, and western blotting. The Atg7siRNA was transfected into BV2 cells to produce autophagy inhibitory effect. Then the effect of HLJDD drug-containing serum on IL-1ß secretion in D-glucose and PA induced BV2 cells and the potential mechanism of autophagy-NLRP3 inflammasome activation were further observed. RESULTS: Eighty-eight compounds were preliminarily identified in HLJDD drug-containing serum, among which geniposide, baicalin, palmatine, berberine, wogonoside, wogonin, and geniposidic acid were identified as the main prototype components of HLJDD into the blood. In this study, the DACD model of BV2 cells induced by high concentrations of glucose and PA was successfully constructed. HLJDD drug-containing serum significantly reduced the secretion of IL-1ß and the activity of NLRP3 inflammasome with improving the oxidative stress level. Interestingly, the enhanced autophagy level was also found. After transfection of Atg7siRNA into BV2 cells, the effect of HLJDD drug-containing serum on autophagy promotion was reversed, but the inhibitory effects on IL-1ß secretion, NLRP3 inflammasome activation, and oxidative stress were reduced. CONCLUSIONS: These results indicated that the inhibition of HLJDD drug-containing serum on the IL-1ß secretion in D-glucose and PA induced BV2 cells was related to autophagy promotion, the decreased NLRP3 inflammasome activation, and the improved oxidative stress. Moreover, the improvement of HLJDD drug-containing serum on IL-1ß secretion, NLRP3 inflammasome activation, and oxidative stress were all closely associated with Atg7 mediated autophagy promotion. Geniposide, baicalin, palmatine, berberine, wogonoside, wogonin, and geniposidic acid may be the potential active ingredients of HLJDD drug-containing serum.

Fatty acid metabolism disorders and potential therapeutic traditional Chinese medicines in cardiovascular diseases.

Cardiovascular diseases are currently the primary cause of mortality in the whole world. Growing evidence indicated that the disturbances in cardiac fatty acid metabolism are crucial contributors in the development of cardiovascular diseases. The abnormal cardiac fatty acid metabolism usually leads to energy deficit, oxidative stress, excessive apoptosis, and inflammation. Targeting fatty acid metabolism has been regarded as a novel approach to the treatment of cardiovascular diseases. However, there are currently no specific drugs that regulate fatty acid metabolism to treat cardiovascular diseases. Many traditional Chinese medicines have been widely used to treat cardiovascular diseases in clinics. And modern studies have shown that they exert a cardioprotective effect by regulating the expression of key proteins involved in fatty acid metabolism, such as peroxisome proliferator-activated receptor α and carnitine palmitoyl transferase 1. Hence, we systematically reviewed the relationship between fatty acid metabolism disorders and four types of cardiovascular diseases including heart failure, coronary artery disease, cardiac hypertrophy, and diabetic cardiomyopathy. In addition, 18 extracts and eight monomer components from traditional Chinese medicines showed cardioprotective effects by restoring cardiac fatty acid metabolism. This work aims to provide a reference for the finding of novel cardioprotective agents targeting fatty acid metabolism.

A review: Pharmacokinetics and pharmacology of aminoalcohol-diterpenoid alkaloids from Aconitum species.

ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum medicinal materials, such as Aconitum carmichaelii Debeaux (Chinese: Wutou/) and Aconitum kusnezoffii Reichb. (Chinese: Caowu/), are a kind of important Traditional Chinese Medicine (TCM) with great medicinal value. Statistics show that there are over 600 efficient TCM formulations comprising Aconitum medicinal materials. But high toxicity limits their clinical application. Clinically, the Aconitum medicinal materials must undergo a complex processing process that includes soaking, steaming, and boiling with pharmaceutical excipients, which makes highly toxic ester diterpenoid alkaloids are hydrolyzed to form less toxic aminoalcohol-diterpenoid alkaloids (ADAs). AIM OF THE STUDY: This review aims to summarize the pharmacokinetic and pharmacological activities of low-toxicity ADAs, providing a reference for future ADAs research and drug development. MATERIALS AND METHODS: Accessible literature on ADAs published between 1984 and 2022 were screened and obtained from available electronic databases such as PubMed, Web of Science, Springer, Science Direct and Google Scholar, followed by systematic analysis. RESULTS: ADAs are secondary products of plant metabolism, widely distributed in the Aconitum species and Delphinium species. The toxicity of ADAs as pharmacodynamic components of Aconitum medicinal materials is much lower than that of other diterpenoid alkaloids due to the absence of ester bonds. On the one hand, the pharmacokinetics of ADAs have received little attention compared to other toxic alkaloids. The research primarily focuses on aconine and mesaconine. According to existing studies, ADAs absorption in the gastrointestinal tract is primarily passive with a short Tmax. Simultaneously, efflux transporters have less impact on ADAs absorption than non-ADAs. After entering the body, ADAs are widely distributed in the heart, liver, lungs, and kidney, but less in the brain. Notably, aconine is not well metabolized by liver microsomes. Aconine and mesaconine are excreted in urine and feces, respectively. ADAs, on the other hand, have been shown to have a variety of pharmacological activities, including cardiac, analgesic, anti-inflammatory, anti-tumor, antioxidant, and regenerative effects via regulating multiple signaling pathways, including Nrf2/ARE, PERK/eIF2α/ATF4/Chop, ERK/CREB, NF-κB, Bcl-2/Bax, and GSK3ß/ß-catenin signaling pathways. CONCLUSIONS: ADAs have been shown to have beneficial effects on heart disease, neurological disease, and other systemic diseases. Moreover, ADAs have low toxicity and a wide range of safe doses. All of these suggest that ADAs have great potential for drug development.

Hezi inhibits Tiebangchui-induced cardiotoxicity and preserves its anti-rheumatoid arthritis effects by regulating the pharmacokinetics of aconitine and deoxyaconitine.

ETHNOPHARMACOLOGICAL RELEVANCE: Tiebangchui (TBC, dried roots of Aconitum pendulum Busch. and Aconitum flavum Hand.-Mazz.) is a well-known Tibetan medicine for dispelling cold and relieving pain. In China, it is widely used in prevention and treatment of various diseases, such as rheumatoid arthritis (RA), traumatic injury, and fracture. However, its cardiotoxicity and neurotoxicity seriously restrict its clinical application. Traditionally, Hezi (HZ, dry ripe fruit of Terminalia chebula Retz. and Terminalia chebula Retz. var. tomentella Kurt.) is generally used in combination with TBC for the purpose of toxicity reducing and efficacy enhancing, but so far we still can't clearly elucidate the compatibility effect and mechanism of the classical herbal pair. AIM OF STUDY: To investigate the compatibility effect and mechanism of TBC co-administered with HZ. METHODS: In the present study, we clarified the cardioprotective role of HZ on the cardiotoxicity induced by TBC. The electrocardiogram, the levels of serum cardiac troponin T (cTnT), the activities of cardiac superoxide dismutase (SOD), malonaldehyde (MDA), and histopathology of heart tissue have been determined in each group. Meanwhile, the anti-RA effect of each group was investigated by paw swelling measurement and histopathological examination of synovial. To explore the underlying mechanism, we performed the pharmacokinetic studies of aconitine (AC) and deoxyaconitine (DE) in TBC group and TBC + HZ group by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) system. RESULTS: TBC co-administered with HZ could significantly inhibit the increased heart rate and the prolonged QTc interval induced by TBC (p < 0.01). And TBC + HZ group had lower levels of serum cTnT, cardiac MDA, and higher levels of cardiac SOD compared with TBC group (p < 0.01). In addition, the combination of TBC and HZ could preserve the anti-RA effect of TBC. Both TBC administration alone and TBC + HZ combination administration could effectively alleviate the paw swelling (p < 0.01). Furthermore, TBC co-administered with HZ could significantly decrease the area under the concentration-time curve (AUC(0-∞)) and maximum concentration (Cmax) of AC and DE comapred with TBC administration alone (p < 0.01 or p < 0.05). Meanwhile, it was observed that the time to reach the peak concentration (Tmax), elimination half-life (t1/2), mean retention time (MRT) of AC and DE in TBC group were significantly higher than those in TBC + HZ group (p < 0.01 or p < 0.05). CONCLUSIONS: TBC co-administered with HZ could reduce TBC-induced cardiotoxicty and preserve its anti-RA efficacy. The underlying mechanism is associated with the change of pharmacokinetic process of AC and DE.

Huang-Lian-Jie-Du decoction attenuates cognitive dysfunction of rats with type 2 diabetes by regulating autophagy and NLRP3 inflammasome activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Lian-Jie-Du decoction (HLJDD) is a traditional Chinese formula that is efficacious in treating diabetes mellitus, Alzheimer's disease, and diabetic encephalopathy; the underlying mechanisms of HLJDD in diabetes-associated cognitive dysfunction remain unclear. AIM OF THE STUDY: This study investigated the neuroprotective effects of HLJDD on cognitive function, and the possible underlying mechanisms in type 2 diabetes mellitus (T2DM) in a rat model of cognitive impairment. MATERIALS AND METHODS: Twelve active ingredients in HLJDD were detected using high-performance liquid chromatography analysis. An animal model of cognitive dysfunction in T2DM was induced via a high-sugar and high-fat diet combined with a low dose of streptozotocin. Sprague-Dawley rats were randomly divided into six groups: control, T2DM, metformin (0.34 g/kg/day), and HLJDD groups (3, 1.5, and 0.75 g/kg/day). All treatments were intragastrically administrated for nine continuous weeks after the development of T2DM. Body weight, food and water intake, fasting blood glucose, insulin sensitivity, and blood lipid levels were measured. Spatial learning and memory of the rats were assessed using the Morris water maze test. Hematoxylin and eosin and Nissl staining were performed to evaluate neuronal morphology and vitality. Glutathione, malondialdehyde, and superoxide dismutase levels were measured to determine the level of oxidative stress in the hippocampus. Transmission electron microscopy was performed to observe the synaptic morphology and structure of hippocampal neurons. IL-1ß levels in the hippocampus and cerebrospinal fluid were determined. The protein expression of NLRP3, cleaved caspase-1, mature IL-1ß, ATG7, P62, LC3, and brain-derived neurotrophic factor (BDNF) was determined using western blotting and immunofluorescence analysis. RESULTS: HLJDD attenuated cognitive dysfunction in rats with T2DM as shown by the decreased escape latency, increased times crossing the platform and time spent in the target quadrant in the Morris water maze test (P < 0.05), improvement in hippocampal histopathological changes, and an elevated level of cell vitality. HLJDD treatment also reduced blood glucose and lipid levels, ameliorated oxidative stress, and downregulated IL-1ß expression in the hippocampus and cerebrospinal fluid (P < 0.05). Moreover, HLJDD enhanced BDNF, ATG7, and LC3 protein expression and significantly inhibited the expression of P62, NLRP3, cleaved caspase-1, and mature IL-1ß in the hippocampal CA1 region (P < 0.05). Immunofluorescence results further confirmed that the fluorescence intensity of NLRP3 and P62 in the hippocampus decreased after HLJDD intervention (P < 0.05). CONCLUSIONS: HLJDD ameliorated cognitive dysfunction in T2DM rats. The neuroprotective effect is exerted via the modulation of glucose and lipid metabolism, upregulation of autophagy, and inhibition of NLRP3 inflammasome signaling pathway.

Cisplatin resistance of NSCLC cells involves upregulation of visfatin through activation of its transcription and stabilization of mRNA.

Non-small cell lung cancer (NSCLC) is one of the prevalent and deadly cancers worldwide. Cisplatin (CDDP) has been used as a standard adjuvant therapy for advanced NSCLC patients, while chemoresistance is one of the most challenging problems to limit its clinical application. Our data showed that the expression of visfatin was significantly increased in CDDP resistant NSCLC cells as compared with that in their parental cells, while knockdown of visfatin or its neutralization antibody can restore the CDDP sensitivity of resistant NSCLC cells. The upregulation of visfatin in CDDP resistant NSCLC cells was due to the increased mRNA stability and promoter activity. Further, we found that signal transducer and activator of transcription 3 (STAT3), which was increased in chemoresistant cells, can increase the transcription of visfatin. While tristetraprolin (TTP), which can decease mRNA stability of visfatin, was decreased in chemoresistant cells. Inhibition of STAT3 or over expression of TTP can restore CDDP sensitivity of resistant NSCLC cells. Collectively, our data showed that STAT3 and TTP-regulated expression of visfatin was involved in CDDP resistance of NSCLC cells. It indicated that targeted inhibition of visfatin should be a potential approach to overcome CDDP resistance of NSCLC treatment.

Targeting foam cell formation and macrophage polarization in atherosclerosis: The Therapeutic potential of rhubarb.

Atherosclerosis, a chronic inflammatory disease associated with high morbidity and mortality, is characterized by the accumulation of foam cells in the arterial wall. It has long been acknowledged that the formation of foam cells is caused by excess lipid uptake and abnormal cholesterol metabolism function. And increasing evidence shows that inhibiting foam cell formation is a promising way to suppress the development of atherosclerotic lesions. In addition to excess foam cells accumulation, inflammation is another major contributor of atherosclerotic lesions. Recently, macrophage polarization has been demonstrated to play a vital role in the regulation of inflammatory response. Generally, macrophages mainly polarized into two phenotypes: either classically activated pro-inflammatory M1 or alternatively activated anti-inflammatory M2. And targeting macrophage polarization has been considered as a feasible approach to prevent the development of atherosclerosis. At present, the anti-atherosclerosis drugs mainly classified into two types: lipid-lowering drugs and anti-inflammatory drugs. A large part of those drugs belong to western medicine, and various side effects are unavoidable. Interestingly, in recent years, Traditional Chinese medicine has attracted growing attention because of its good efficacy and low negative effects. Rhubarb (called Da Huang in Chinese) is a famous folk medicine with a wide spectrum of pharmacological effects, such as lipid-lowering and anti-inflammatory effects. In this review, we summarized current findings about the regulatory effects of Rhubarb on foam cell formation and macrophage polarization, with emphasis on the molecular mechanisms of action that have been revealed during the past two decades, to better understand its pivotal role in the treatment and prevention of atherosclerosis.

Apoptosis Exerts a Vital Role in the Treatment of Colitis-Associated Cancer by Herbal Medicine.

Colitis-associated cancer (CAC) is known as inflammatory bowel disease (IBD)-developed colorectal cancer, the pathogenesis of which involves the occurrence of apoptosis. Western drugs clinically applied to CAC are often single-targeted and exert many adverse reactions after long-term administration, so it is urgent to develop new drugs for the treatment of CAC. Herbal medicines commonly have multiple components with multiple targets, and most of them are low-toxicity. Some herbal medicines have been reported to ameliorate CAC through inducing apoptosis, but there is still a lack of systematic review. In this work, we reviewed articles published in Sci Finder, Web of Science, PubMed, Google Scholar, CNKI, and other databases in recent years by setting the keywords as apoptosis in combination with colitis-associated cancer. We summarized the herbal medicine extracts or their compounds that can prevent CAC by modulating apoptosis and analyzed the mechanism of action. The results show the following. (1) Herbal medicines regulate both the mitochondrial apoptosis pathway and death receptor apoptosis pathway. (2) Herbal medicines modulate the above two apoptotic pathways by affecting signal transductions of IL-6/STAT3, MAPK/NF-κ B, Oxidative stress, Non-canonical TGF-ß1, WNT/ß-catenin, and Cell cycle, thereby ameliorating CAC. We conclude that following. (1) Studies on the role of herbal medicine in regulating apoptosis through the Ras/Raf/ERK, WNT/ß-catenin, and Cell cycle pathways have not yet been carried out in sufficient depth. (2) The active constituents of reported anti-CAC herbal medicine mainly include polyphenols, terpenoids, and saccharide. Also, we identified other herbal medicines with the constituents mentioned above as their main components, aiming to provide a reference for the clinical use of herbal medicine in the treatment of CAC. (3) New dosage forms can be utilized to elevate the targeting and reduce the toxicity of herbal medicine.

Tianzhi granule improves cognition and BPSD of vascular dementia: a randomized controlled trial.

BACKGROUND AND PURPOSE: Tianzhi granule (TZ) is usually used for patients with vascular dementia (VaD) in China. The aim was to assess the effect of TZ by a randomized clinical trial (RCT). METHODS: A 24-week RCT was conducted in 16 centres. Participants were grouped into TZ, donepezil or placebo. The co-primary outcomes were the Vascular Dementia Assessment Scale-cognitive subscale (VADAS-cog) and Clinician's Interview-based Impression of Change-plus caregiver information (CIBIC-plus). RESULTS: A total of 543 patients with mild to moderate VaD were enrolled, of whom 242 took TZ granules, 241 took donepezil, and 60 took placebo. The least-squares mean changes from baseline and 95% CI were 6.20 (5.31, 7.09) (TZ group), 6.53 (5.63, 7.42) (donepezil group) and 3.47 (1.76, 5.19) (placebo group), both TZ and donepezil showed small but significantly improvement compared with placebo group. The percent of improvement on the global impression which was measured by CIBIC-plus was 73.71% in TZ and 58.18% in placebo, there was significant different between TZ and placebo group (P = 0.004). No significant differences were observed between TZ and donepezil. No significant differences of adverse events were found. CONCLUSIONS: TZ and donepezil could bring symptomatic benefit for mild to moderate VaD. Trial registration The protocol had retrospectively registered at clinical trial.gov, Unique identifier: NCT02453932, date of registration: May 27, 2015; https://www.clinicaltrials.gov/ct2/show/NCT02453932?term=NCT02453932&rank=1.

[Design of modulating intermediate frequency electrotherapy system based on microcontroller unit].

This article is devoted to the design of a system for modulating intermediate frequency electrotherapy waveform output. Prescriptions with different output waveform combinations were produced using microcontroller unit (MCU). The rich output waveforms effectively improve tolerance of human adaptability and achieve a therapeutic effect.

[Clinical study of effect of tianzhi granule on senile vascular demetia].

OBJECTIVE: To investigate the clinical effect of Tianzhi Granule (TZK) on senile vascular dementia (VaD), which is classified as sthenia of liver-yang. METHOD: Two hundred VaD patients were treated with TZK (0.5 g/bag), which was taken one bag each, three times a day. The treatment course was one month and they were treated for rwo courses. RESULT: TZK could remarkably increase gnosia and activity, with no striking difference from that of positive control group (P > 0.05). Simultaneously, TZK could significantly improve the clinical syndrome of traditional Chinese medicine and viability. It could also drastically reduce the whole blood and plasma viscosity and improve erythrodegeneration and abnormality of aggregation index in the abnormal blood viscosity patients. CONCLUSION: TMC has certain effects on senile VaD.