Herbal medicines provide regulation against iron overload in cardiovascular diseases: Informing future applications.

ETHNOPHARMACOLOGICAL RELEVANCE: Iron is an essential micronutrient for maintaining physiological activities, especially for highly active cardiomyocytes. Inappropriate iron overload or deficiency has a significant impact on the incidence and severity of cardiovascular diseases (CVD). Iron overload exerts potentially deleterious effects on doxorubicin (DOX) cardiomyopathy, atherosclerosis, and myocardial ischemia-reperfusion injury (MI/RI) by participating in lipid peroxides production. Notably, iron overload-associated cell death has been defined as a possible mechanism for ferroptosis. At present, some traditional herbal medicines and extracts have been included in the study of regulating iron overload and the subsequent therapeutic effect on CVD. AIM OF THE STUDY: To give an outline of iron metabolism and ferroptosis in cardiomyocytes and to focus on herbal medicines and extracts to prevent iron overload in CVD. MATERIALS AND METHODS: Literature information was systematically collected from ScienceDirect, PubMed, Google Scholar, Web of Science, China National Knowledge Infrastructure, WanFang data, as well as classic books and clinical reports. RESULTS: After understanding the mechanism of iron overload on CVD, this paper reviews the therapeutic function of various herbal medicines in eliminating iron overload in CVD. These include Chinese herbal compound prescriptions (Salvia miltiorrhiza injection, Gegen Qinlian decoction, Tongxinluo, Banxia-Houpu decoction), plant extracts, phenylpropanoids, flavonoids, terpenoids, and polyphenols. Among them, flavonoids are considered to be the most promising compounds because of their prominent iron chelation. Mechanically, these herbal medicines act on the Nrf2 signaling pathway, AMPK signaling pathway, and KAT5/GPX4 signaling pathway, thereby attenuating iron overload and lipid peroxidation in CVD. CONCLUSION: Our review provides up-to-date information on herbal medicines that exert cardiovascular protective effects by modulating iron overload and ferroptosis. These herbal medicines hold promise as a template for preventing iron overload in CVD.

Efficacy of Qingpeng ointment (a Tibetan medicine) for acute gouty arthritis: a multi-center, randomized, double-blind, placebo-controlled trial.

BACKGROUND: This study aims to assess the efficacy and safety of Qingpeng ointment (QPO), a Tibetan medicine for alleviating symptoms in individuals with acute gouty arthritis (AGA). METHODS: This study was a randomized, double-blind, placebo-controlled trial that involved individuals with AGA whose joint pain, as measured on a visual analog scale (VAS) from 0 to 10, was equal to or greater than 3. The participants were randomly assigned to either the QPO or the placebo group and received their respective treatments twice daily for seven consecutive days. In case of intolerable pain, the participants were allowed to use diclofenac sodium sustained-release tablets as a rescue medicine. The primary outcomes measured were joint pain and swelling, while the secondary outcomes included joint mobility, redness, serum uric acid levels, C-reactive protein levels, and the amount of remaining rescue medicine. Any adverse events that occurred during the trial were also recorded. RESULTS: A total of 203 cases were divided into two groups, with balanced baselines: 102 in the QPO group and 101 in the placebo group. For joint pain, differences between the groups were notable in the VAS scores [1.75 (0, 3.00) versus 2.00 (1.00, 3.50); P = 0.038], changes in VAS [5.00 (3.00, 6.00) versus 4.00 (2.00, 6.00); P = 0.036], and disappearance rate [26.47% compared to 15.84%; P = 0.046] after treatment. Concerning joint swelling, significant between-group differences were observed in the VAS scores [1.00 (0, 2.30) versus 2.00 (0.70, 3.00); P = 0.032] and disappearance rate [33.33% compared to 21.78%; P = 0.046] at treatment completion. The QPO group exhibited a statistically significant mobility improvement compared to the placebo group (P = 0.004). No significant differences were found in other secondary outcomes. Five patients, four from the QPO group and one from the other, encountered mild adverse events, primarily skin irritation. All of these cases were resolved after dosage reduction or discontinuation of the medication. CONCLUSIONS: Compared to the placebo, QPO exhibits positive effects on AGA by alleviating pain, reducing swelling, and enhancing joint mobility, without causing significant adverse effects. TRIAL REGISTRATION: ISRCTN34355813. Registered on 25/01/2021.

Lupenone improves type 2 diabetic nephropathy by regulating NF-κB pathway-mediated inflammation and TGF-ß1/Smad/CTGF-associated fibrosis.

BACKGROUND: Type 2 diabetic nephropathy is a common diabetic complication and the main cause of death in patients with diabetes. Research has aimed to find an ideal drug with minimal side effects for treating this disease. Banana peel has been shown to be anti-diabetic, with lupenone isolated from banana peel exhibiting antidiabetic and anti-inflammatory activities; However, the effects of lupenone on type 2 diabetic nephropathy are largely unknown. PURPOSE: This study aimed to investigate the ameliorative effect of lupenone on type 2 diabetic nephropathy, and its mechanism from both anti-inflammatory and anti-fibrotic perspectives. METHODS: Spontaneous type 2 diabetic nephropathy db/db mouse models were given three levels of lupenone (24 or 12 or 6 mg/kg/d) via intragastric administration for six weeks, and irbesartan treatment was used for the positive control group. We explored the effects and mechanism of lupenone action using enzyme-linked immunosorbent assay, automatic biochemical analyzer, hematoxylin-eosin and Masson staining, real time-PCR, and western blotting. Concurrently, a high-sugar and high-fat diet combined with a low-dose streptozotocin-induced type 2 diabetic nephropathy rat model was used for confirmatory research. RESULTS: Lupenone administration maintained the fasting blood glucose; reduced glycosylated hemoglobin, insulin, and 24 h proteinuria levels; and markedly regulated changes in biochemical indicators associated with kidney injury in serum and urine (including 24 h proteinuria, micro-albumin, N-acetyl-ß-d-glucosaminidase, α1-micro-globulin, creatinine, urea nitrogen, uric acid, total protein, and albumin) of type 2 diabetic nephropathy mice and rats. Hematoxylin-eosin and Masson staining as well as molecular biology tests revealed that inflammation and fibrosis are the two key processes affected by lupenone treatment. Lupenone protected type 2 diabetic nephropathy kidneys by regulating the NF-κB-mediated inflammatory response and TGF-ß1/Smad/CTGF pathway-associated fibrosis. CONCLUSION: Lupenone has potential as an innovative drug for preventing and treating diabetic nephropathy. Additionally, it has great value for the utilization of banana peel resources.

Di'ao Xinxuekang Capsule Improves the Anti-Atherosclerotic Effect of Atorvastatin by Downregulating the SREBP2/PCSK9 Signalling Pathway.

Statins are the first choice for lowering low-density lipoprotein cholesterol (LDL-C) and preventing atherosclerotic cardiovascular disease (ASCVD). However, statins can also upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9), which in turn might limits the cholesterol-lowering effect of statins through the degradation of LDL receptors (LDLR). Di'ao Xinxuekang (DXXK) capsule, as a well-known traditional Chinese herbal medicine for the prevention and treatment of coronary heart disease, can alleviate lipid disorders and ameliorate atherosclerosis in atherosclerosis model mice and downregulate the expression of PCSK9. In this study, we further explored whether DXXK has a synergistic effect with atorvastatin (ATO) and its underlying molecular mechanism. The results showed that both ATO monotherapy (1.3 mg/kg) and ATO combined with DXXK therapy significantly lowered serum lipid levels and reduced the formation of atherosclerotic plaques and the liver lipid accumulation. Moreover, compared with ATO monotherapy, the addition of DXXK (160 mg/kg) to the combination therapy further lowered LDL-C by 15.55% and further reduced the atherosclerotic plaque area by 25.98%. In addition, the expression of SREBP2, PCSK9 and IDOL showed a significant increase in the model group, and the expression of LDLR was significantly reduced; however, there were no significant differences between the ATO (1.3 mg/kg) and the model groups. When ATO was combined with DXXK, the expression of LDLR was significantly increased and was higher than that of the model group and the expression of SREBP2 and PCSK9 in the liver was also significantly inhibited. Moreover, it can be seen that the expression of SREBP2 and PCSK9 in the combination treatment group was significantly lower than that in the ATO monotherapy group (1.3 mg/kg). Besides, the expression of IDOL mRNA in each treatment group was not significantly different from that of the model group. Our study suggests that DXXK might have a synergistic effect on the LDL-C lowering and antiatherosclerosis effects of ATO through the SREBP2/PCSK9 pathway. This indicates that a combination of DXXK and ATO may be a new treatment for atherosclerosis.

Pharmacological characterization of a novel metal-based proteasome inhibitor Na-AuPT for cancer treatment.

The ubiquitin-proteasome system (UPS) is essential for maintaining cell homeostasis by orchestrating the protein degradation, but is impaired in various diseases, including cancers. Several proteasome inhibitors, such as bortezomib, are currently used in cancer treatment, but associated toxicity limits their widespread application. Recently metal complex-based drugs have attracted great attention in tumor therapy; however, their application is hindered by low water-solubility and poor absorbency. Herein, we synthesized a new type of gold (I) complex named Na-AuPT, and further characterized its anticancer activity. Na-AuPT is highly water-soluble (6 mg/mL), and it was able to potently inhibit growth of a panel of 11 cancer cell lines (A549, SMMC7721, H460, HepG2, BEL7402, LNCap, PC3, MGC-803, SGC-7901, U266, and K562). In A549 and SMMC7721 cells, Na-AuPT (in a range of 2.5-20 µM) inhibited the UPS function in a dose-dependent fashion by targeting and inhibiting both 20 S proteasomal proteolytic peptidases and 19 S proteasomal deubiquitinases. Furthermore, Na-AuPT induced caspase-dependent apoptosis in A549 and SMMC7721 cells, which was prevented by the metal chelator EDTA. Administration of Na-AuPT (40 mg · kg-1 · d-1, ip) in nude mice bearing A549 or SMMC7721 xenografts significantly inhibited the tumor growth in vivo, accompanied by increased levels of total ubiquitinated proteins, cleaved caspase 3 and Bax protein in tumor tissue. Moreover, Na-AuPT induced cell death of primary mononuclear cells from 5 patients with acute myeloid leukemia ex vivo with an average IC50 value of 2.46 µM. We conclude that Na-AuPT is a novel metal-based proteasome inhibitor that may hold great potential for cancer therapy.

Protective effect of Di'ao Xinxuekang capsule against doxorubicin-induced chronic cardiotoxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: Di'ao Xinxuekang capsule (DXXK) extracted from Dioscorea nipponica Makino is a well-known traditional Chinese herbal medicinal product widely used in the treatment of cardiovascular disease, such as myocardial ischemia and arrhythmia. The active ingredients of DXXK were also traditionally utilized for treating cardiovascular disease in the former Soviet Union after the 1960s. As a specific type of cardiovascular disease, doxorubicin (DOX)-induced cardiotoxicity is characterized by arrhythmia, myocardial ischemia, and heart failure. AIM OF THE STUDY: This study aimed to investigate the potential protective effect of DXXK against chronic cardiotoxicity induced by DOX. MATERIALS AND METHODS: A mouse model of chronic cardiotoxicity induced by DOX and an in vitro model of DOX-induced myocardial damage were created to assess the protective effect of DXXK. Cardiac functional parameters, serum levels of CK-MB and LDH and cardiac histopathological indicators were determined in the mouse model. Moreover, cell viability was measured by the MTT method, and the effect of DXXK on the anticancer activity of DOX was also investigated by utilizing 4T1, HepG2, and H460 cell lines. Furthermore, the levels of markers of oxidative stress indexes (SOD, GSH, MDA) and inflammation (TNF-α, IL-1α) were measured using biochemical and Elisa kits, respectively. The level of ROS in H9c2 cardiomyocyte was determined by flow cytometry. The protein expression levels of HIF-1α and NF-κB p65 were measured by western blotting. Finally, molecular docking was performed to visualize the patterns of interactions between the effective molecule and targeted protein. RESULTS: DXXK alleviated DOX-induced chronic cardiotoxicity as shown by the reversal of changes in levels of myocardial enzymes and left ventricular function and structure. DXXK exhibits antioxidant and anti-inflammatory activities. We also observed that DXXK might increase the protein expression level of HIF-1α and decrease the protein expression level of NF-κB p65. Further results of in vitro experiments showed that DXXK could protect cardiomyocyte against DOX-induced production of ROS, but DXXK had no effect on the anticancer activity of DOX. The results of molecular docking showed that dioscin and pseudoprotodioscin were the top two compounds of DXXK, which had high affinity with HIF-1α and NF-κB p65. CONCLUSIONS: Our results indicated that DXXK could protect against cardiotoxicity induced by DOX and alleviate oxidative stress and inflammation in vivo and in vitro via the regulation of HIF-1α and down NF-κB p65.

Dioscin and diosgenin: Insights into their potential protective effects in cardiac diseases.

BACKGROUND AND ETHNOPHARMACOLOGICAL RELEVANCE: Dioscin and diosgenin derived from plants of the genus Dioscoreaceae such as D. nipponica and D. panthaica Prain et Burk. Were utilized as the main active ingredients of traditional herbal medicinal products for coronary heart disease in the former Soviet Union and China since 1960s. A growing number of research showed that dioscin and diosgenin have a wide range of pharmacological activities in heart diseases. AIM OF THE STUDY: To summarize the evidence of the effectiveness of dioscin and diosgenin in cardiac diseases, and to provide a basis and reference for future research into their clinical applications and drug development in the field of cardiac disease. METHODS: Literatures in this review were searched in PubMed, ScienceDirect, Google Scholar, China National Knowledge Infrastructure (CNKI) and Web of Science. All eligible studies are analyzed and summarized in this review. RESULTS: The pharmacological activities and therapeutic potentials of dioscin and diosgenin in cardiac diseases are similar, can effectively improve hypertrophic cardiomyopathy, arrhythmia, myocardial I/R injury and cardiotoxicity caused by doxorubicin. But the bioavailability of dioscin and diosgenin may be too low as a result of poor absorption and slow metabolism, which hinders their development and utilization. CONCLUSION: Dioscin and diosgenin need further in-depth experimental research, clinical transformation and structural modification or research of new preparations before they can be expected to be developed into new therapeutic drugs in the field of cardiac disease.

4-Aryl Pyrrolidines as a Novel Class of Orally Efficacious Antimalarial Agents. Part 1: Evaluation of 4-Aryl- N-benzylpyrrolidine-3-carboxamides.

Identification of novel chemotypes with antimalarial efficacy is imperative to combat the rise of Plasmodium species resistant to current antimalarial drugs. We have used a hybrid target-phenotype approach to identify and evaluate novel chemotypes for malaria. In our search for drug-like aspartic protease inhibitors in publicly available phenotypic antimalarial databases, we identified GNF-Pf-4691, a 4-aryl- N-benzylpyrrolidine-3-carboxamide, as having a structure reminiscent of known inhibitors of aspartic proteases. Extensive profiling of the two terminal aryl rings revealed a structure-activity relationship in which relatively few substituents are tolerated at the benzylic position, but the 3-aryl position tolerates a range of hydrophobic groups and some heterocycles. Out of this effort, we identified (+)-54b (CWHM-1008) as a lead compound. 54b has EC50 values of 46 and 21 nM against drug-sensitive Plasmodium falciparum 3D7 and drug-resistant Dd2 strains, respectively. Furthermore, 54b has a long half-life in mice (4.4 h) and is orally efficacious in a mouse model of malaria (qd; ED99 ∼ 30 mg/kg/day). Thus, the 4-aryl- N-benzylpyrrolidine-3-carboxamide chemotype is a promising novel chemotype for malaria drug discovery.

Practice of traditional Chinese medicine for psycho-behavioral intervention improves quality of life in cancer patients: A systematic review and meta-analysis.

BACKGROUND: Cancer patients suffer from diverse symptoms, including depression, anxiety, pain, and fatigue and lower quality of life (QoL) during disease progression. This study aimed to evaluate the benefits of Traditional Chinese Medicine psycho-behavioral interventions (TCM PBIs) on improving QoL by meta-analysis. RESULTS: The six TCM PBIs analyzed were acupuncture, Chinese massage, Traditional Chinese Medicine five elements musical intervention (TCM FEMI), Traditional Chinese Medicine dietary supplement (TCM DS), Qigong and Tai Chi. Although both TCM PBIs and non-TCM PBIs reduced functional impairments in cancer patients and led to pain relief, depression remission, reduced time to flatulence following surgery and sleep improvement, TCM PBIs showed more beneficial effects as assessed by reducing both fatigue and gastrointestinal distress. In particular, acupuncture relieved fatigue, reduced diarrhea and decreased time to flatulence after surgery in cancer patients, while therapeutic Chinese massage reduced time to flatulence and time to peristaltic sound. METHODS: Electronic literature databases (PubMed, CNKI, VIP, and Wanfang) were searched for randomized, controlled trials conducted in China. The primary intervention was TCM PBIs. The main outcome was health-related QoL (HR QoL) post-treatment. We applied standard meta analytic techniques to analyze data from papers that reached acceptable criteria. CONCLUSION: These findings demonstrate the efficacy of TCM PBIs in improving QoL in cancer patients and establish that TCM PBIs represent beneficial adjunctive therapies for cancer patients.

The accuracy of computed tomography in the pretreatment staging of colorectal cancer.

Colorectal cancer (CRC) is one of the most frequent cancers around the world. Multimodality therapies are used for CRC including surgery, chemotherapy, radiotherapy and targeted therapy. Correct treatment plan depends greatly on the accurate pretreatment staging. Computed tomography (CT) is a widely used detection and staging modality for CRC patients in clinical practice. The role of CT in assessing the patients with CRC has been well established, but the accuracy of pretreatment staging by CT varies in different reports. With the development of CT techniques, some reformations such as multi-detector CT (MDCT), CT with water enema or air insufflations, multiple planner reconstruction (MPR) help to give us higher resolution images in shorter time. The accuracy of CT for N staging was still not so ideal, but CT played an important role in chest and liver staging. Magnetic resonance imaging (MRI) and endorectal ultrasound (ERUS) may provide more precise images and evaluation of local T and N staging for rectal cancer. And positron emission tomography (PET) or PET/CT is recommended as a complement of CT, only for cases suspected of residual or recurrent colorectal carcinoma or before metastasectomy, not for routine use.

Surgical resection of advanced gastric cancer following trastuzumab/oxaliplatin/capecitabine combination therapy.

Late-stage gastric adenocarcinoma patients have a poor prognosis because of high recurrence rates. To improve long-term outcomes, perioperative chemotherapies are combined with surgery. Human epidermal growth factor receptor 2 (HER2) overexpression had been noted in gastric cancer; therefore, trastuzumab has been used occasionally in this setting. A 63-year-old male Chinese patient, who was diagnosed with adenocarcinoma in the gastric antrum, as well as lymph node metastases along the left gastric and hepatic artery, and left adrenal area, was admitted to our hospital. HER2 expression was positive, and cluster amplification was detected in a fluorescence in situ hybridization assay. The patient received three cycles of a neoadjuvant trastuzumab/oxaliplatin /capecitabine regimen. He subsequently underwent distal gastrectomy, D2+ lymphadenectomy, left adrenalectomy, cholecystectomy and Billroth II anastomosis. Treatment was continued with another five postoperative cycles of the same medication and trastuzumab application for 1 year. No recurrence has been observed 18 mo after the operation. Trastuzumab as perioperative and adjuvant medication, in combination with oxaliplatin and capecitabine for a HER2-overexpressing advanced gastric adenocarcinoma, led to recurrence-free survival of at least 18 mo after surgery.

Anacardic acid induces cell apoptosis associated with induction of ATF4-dependent endoplasmic reticulum stress.

Anacardic acid (6-pentadecylsalicylic acid, AA), a natural compound isolated from the traditional medicine Amphipterygium adstringens, has been reported to possess antitumor activities. However, its molecular targets have not been thoroughly studied. Here, we report that AA is a potent inducer of endoplasmic reticulum (ER) stress, leading to apoptosis in hepatoma HepG2 and myeloma U266 cells. Induction of ER stress by AA was supported by a dose- and time-dependent increase in expression of the ER signaling downstream molecules, such as GRP78/BiP, phosphorylated eIF2α, ATF4 and CHOP in both HepG2 and U266 cell lines. Blockage of ATF4 expression by siRNA partially inhibited, while knockdown of CHOP expression by siRNA slightly increased AA-induced cell death in these cells. In addition, AA suppressed HepG2 xenograft tumor growth, associated with increased ER stress in vivo. These results suggest that AA induces tumor cell apoptosis associated with ATF4-dependent ER stress.

Depside salts from Salvia miltiorrhiza improve myocardial microperfusion in rats using laser Doppler flowmetry.

AIM: To investigate the effects of depside salts from Salvia miltiorrhiza on myocardial microperfusion and systemic hemodynamics in open-chest anaesthetized Sprague-Dawley rats. METHODS: Myocardial microperfusion was measured by laser Doppler flowmetry with a needle probe; cardiac output (CO) was determined using ultrasonic Doppler flowmetry. Other hemodynamic parameters, including femoral artery blood pressure, cardiac inotropy, and systemic vascular resistance (SVR) were simultaneously recorded by the PowerLab system. RESULTS: Intravenous administration of S miltiorrhiza depside salts resulted in a significant immediate increase in CO and cardiac inotropy, but a fall in SVR. S miltiorrhiza depside salts (30 mg/kg and 60 mg/kg) promoted cardiac index (CI) by 12.2%+/-6.3% (P<0.01 vs baseline) and 20.1%+/-3.5% (P<0.01), respectively. Myocardial microperfusion maximally increased by 6.3%+/-2.9% (P<0.01) and 9.6%+/-4.0% (P<0.01) for 30 mg/kg and 60 mg/kg S miltiorrhiza depside salts, respectively. CONCLUSION: These results indicated that S miltiorrhiza depside salts improved myocardial micro-perfusion, as well as CO.

Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as high affinity and selective A2B adenosine receptor antagonists.

A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as A(2B)-AdoR antagonists have been synthesized and evaluated for their binding affinities for the A(2B), A(1), A(2A), and A(3)-AdoRs. 8-(1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione (4) displayed high affinity (K(i)=1 nM) and selectivity for the A(2B)-AdoR versus A(1), A(2A), and A(3)-AdoRs (A(1)/A(2B), A(2A)/A(2B), and A(3)/A(2B) selectivity ratios of 370, 1100, and 480, respectively). The synthesis and SAR of this novel class of compounds are presented herein.