PMID: 

Biochem Biophys Res Commun. 2019 Dec 10 ;520(3):580-585. Epub 2019 Oct 14. PMID: 31623833

Abstract Title: 

Sodium Tanshinone IIA sulfonate improves post-ischemic angiogenesis in hyperglycemia.

Abstract: 

BACKGROUND: Diabetes is a strong risk factor of peripheral arterial disease (PAD), and also leads to impaired perfusion recovery in the ischemic limb, which eventually results in poor outcomes in PAD patients. Sodium Tanshinone IIA Sulfonate (STS), a monomer from herbs, has been shown to improve the outcomes in a variety of ischemic disease including myocardial infarction. However, the effects of STS treatment in PAD is not known.METHODS AND RESULTS: Unilateral femoral artery was ligated in mice as experimental PAD models, STS treatment improved perfusion recovery, increased capillary densities, decreased reactive oxygen species (ROS) level and microRNA-133a (miR-133a) expression in the ischemic hindlimb in diabetic mice; however, STS did not change perfusion recovery in non-diabetic C57BL/6 mice. Ischemic muscle tissue from diabetic mice was harvested 7 days after femoral ligation for biochemical test, STS resulted in reduced malondialdehyde (MDA), and increased GTP cyclohydrolase 1 (GCH1) and cyclic guanine monophosphate (cGMP) levels. In addition, STS treatment increased miR-133a expression in endothelial cells isolated from ischemic muscle tissue of diabetic mice. In endothelial cells cultured in high glucose medium, STS increased tube formation and nitric oxide (NO) production, and reduced cellular ROS level and miR-133a expression under simulated ischemic condition. In addition, GCH1 inhibitor or miR-133a overexpression using exogenous microRNA mimic blunted STS-induced angiogenic effects and ROS neutralization in cultured endothelial cells under hyperglycemic and hypoxic conditions.CONCLUSION: These findings demonstrate STS improves angiogenesis via inhibiting miR-133a expression and increasing GCH-1 protein levels in experimental PAD with diabetes.

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PMID: 

Biochem Biophys Res Commun. 2020 Jan 29 ;522(1):157-163. Epub 2019 Nov 19. PMID: 31757424

Abstract Title: 

TanshinoneⅡA inhibits homocysteine-induced proliferation of vascular smooth muscle cells via miR-145/CD40 signaling.

Abstract: 

Tanshinone IIA (Tan IIA), isolated from the traditional Chinese herb Danshen, exhibits broad cardiovascular protective effects. However, the effect of Tan IIA on Homocysteine (Hcy)-induced proliferation of vascular smooth muscle cells (VSMCs) remains unknown. We herein determined whether Tan IIA exerted anti-proliferative effect in Hcy-treating VSMCs, and further investigated the underlying mechanism (miR-145/CD40 signaling). The results showed that Tan IIA significantly inhibited VSMCs proliferation induced by Hcy in a dose-dependent manner, and reversed the VSMCs injury as indicated by decreased KLF4 and increased Calponin expression. In view of the key role of miR-145 in VSMCs, we further explored the role of miR-145 on the protective effect of Tan IIA against Hcy-induced VSMCs proliferation. The miR-145 expression was down-regulated and its targeted gene CD40 was up-regulated in Hcy-treating VSMCs, while the Tan IIA reversed the effect of Hcy, suggesting the miR-145/CD40 may be involve in the protective effect of Tan IIA. To determine the speculation, miR-145 inhibitor was used to inhibit miR-145 expression. The results indicated that miR-145 inhibitor can suppress the protective effects of Tan IIA against Hcy-induced VSMCs proliferation. Collectively, present study demonstrates that Tan IIA inhibits Hcy-induced proliferation of VSMCs via miR-145/CD40 signaling.

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PMID: 

Int J Mol Sci. 2019 Dec 30 ;21(1). Epub 2019 Dec 30. PMID: 31905926

Abstract Title: 

Role of Metastasis-Related Genes in Cisplatin Chemoresistance in Gastric Cancer.

Abstract: 

The role of metastasis-related genes in cisplatin (CDDP) chemoresistance in gastric cancer is poorly understood. Here, we examined the expression of four metastasis-related genes (namely,,,,) in 39 cases of gastric cancer treated with neoadjuvant therapy with CDDP or CDDP+5-fluorouracil and evaluated its association with CDDP responsiveness. Comparison of CDDP-sensitive cases with CDDP-resistant cases, the expression of c-met, HMGB1, and PCDHB9 was correlated with CDDP resistance. Among them, the expression of HMGB1 showed the most significant correlation with CDDP resistance in multivariate analysis. Treatment of TMK-1 and MKN74 human gastric cancer cell lines with ethyl pyruvate (EP) or tanshinone IIA (TAN), which are reported to inhibit HMGB1 signaling, showed a 4-5-fold increase in inhibition by CDDP. Treatment with EP or TAN also suppressed the expression of TLR4 and MyD88 in the HMGB1 signal transduction pathway and suppressed the activity of NFκB in both cell lines. These results suggest that the expression of these cancer metastasis-related genes is also related to anticancer drug resistance and that suppression of HMGB1 may be particularly useful for CDDP sensitization.

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PMID: 

Onco Targets Ther. 2019 ;12:9725-9734. Epub 2019 Nov 14. PMID: 32009805

Abstract Title: 

Tanshinone IIA Reverses Oxaliplatin Resistance In Human Colorectal Cancer Via Inhibition Of ERK/Akt Signaling Pathway.

Abstract: 

Background: Oxaliplatin (OXA)-based chemotherapy is generally used to treat human cancers, whereas OXA resistance is a main obstacle for the treatment of colorectal cancer (CRC). Evidence has shown that tanshinone IIA (Tan IIA) could induce apoptosis in CRC cells. However, the role of combination of OXA and Tan IIA on OXA-resistance CRC cells remains unknown. Thus, this study aimed to investigate the effects of Tan IIA in combination with OXA on OXA-resistance CRC cells.Methods: MTT assay, Ki67 immunofluorescence staining and flow cytometry were used to detect viability, proliferation and apoptosis in OXA-resistant cell line SW480/OXA, respectively. The expressions of Bcl-2, Bax, active caspase 3, p-Akt and p-ERK in SW480/OXA cells were detected with Western blot. In vivo animal study was performed finally.Results: In this study, the inhibitory effects of OXA on the proliferation and invasion of SW480/OXA cells were significantly enhanced by Tan IIA. In addition, Tan IIA obviously enhanced the anti-apoptosis effects of OXA on SW480/OXA cells via decreasing the levels of Bcl-2, p-Akt and p-ERK, and increasing the levels of Bax and active caspase 3. In vivo experiments confirmed that Tan IIA enhanced OXA sensitivity in SW480/OXA xenograft model.Conclusion: We found that Tan IIA could reverse OXA resistance in OXA-resistance CRC cells. Therefore, OXA combined with Tan IIA might be considered as a therapeutic approach for the treatment of OXA-resistant CRC.

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PMID: 

Neuroscience. 2020 Jan 31. Epub 2020 Jan 31. PMID: 32014436

Abstract Title: 

Tanshinone IIA Improves Depression-like Behavior in Mice by Activating the ERK-CREB-BDNF Signaling Pathway.

Abstract: 

Depression is a serious global affective disorder and one of the most common neurological diseases. Tanshinone IIA (TSA) is the mainly active constituent of Salvia miltiorrhiza and has diverse biological effects, including anti-inflammatory and antioxidant effects and significant neuroprotective effects against cerebral ischemia and Alzheimer's disease. However, whether TSA has an antidepressant effect remains unknown. The present study attempted to explore the antidepressant effects and the mechanism of TSA by examining the brain-derived neurotrophic factor (BDNF) expression in the hippocampus of depressive mice. The tail suspension test (TST) and forced swim test (FST) showed that TSA can significantly reduce the immobility time of depressed mice. Chronic administration of TSA increased p-ERK and p-CREB, BDNF proteins in mice hippocampus. We further explored the potential mechanism of TSA' antidepressant effect. TSA significantly increased the expression of p-ERK, p-CREB and BDNF proteins in dexamethasone-treated PC12 cells, and this enhancement was suppressed by pretreatment with the extracellular signal-regulated kinase (ERK) inhibitor SL327. Moreover, we observed that SL327 treatment markedly suppressed the increased levels of p-ERK, p-CREB and BDNF in mice hippocampus induced by TSA, preventing the antidepressant effects of TSA. Taken together, our results suggest that the antidepressant-like effects of TSA were mediated by ERK-CREB-BDNF pathway in mice hippocampus.

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PMID: 

J Cachexia Sarcopenia Muscle. 2020 Jan 31. Epub 2020 Jan 31. PMID: 32003547

Abstract Title: 

Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway.

Abstract: 

BACKGROUND: Skeletal muscle is mainly responsible for insulin-stimulated glucose disposal. Dysfunction in skeletal muscle metabolism especially during obesity contributes to the insulin resistance. Astaxanthin (AX), a natural antioxidant, has been shown to ameliorate hepatic insulin resistance in obese mice. However, its effects in skeletal muscle are poorly understood. The current study aimed to investigate the molecular target of AX in ameliorating skeletal muscle insulin resistance.METHODS: We fed 6-week-old male C57BL/6J mice with normal chow (NC) or NC supplemented with AX (NC+AX) and high-fat-diet (HFD) or HFD supplemented with AX for 24 weeks. We determined the effect of AX on various parameters including insulin sensitivity, glucose uptake, inflammation, kinase signaling, gene expression, and mitochondrial function in muscle. We also determined energy metabolism in intact C2C12 cells treated with AX using the Seahorse XFe96 Extracellular Flux Analyzer and assessed the effect of AX on mitochondrial oxidative phosphorylation and mitochondrial biogenesis.RESULTS: AX-treated HFD mice showed improved metabolic status with significant reduction in blood glucose, serum total triglycerides, and cholesterol (p

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PMID: 

Pharmacol Rep. 2020 Feb ;72(1):104-114. Epub 2019 Dec 19. PMID: 32016833

Abstract Title: 

Astaxanthin attenuates oxidative stress and inflammatory responses in complete Freund-adjuvant-induced arthritis in rats.

Abstract: 

BACKGROUND: Astaxanthin (ATX), a natural xanthophyll carotenoid, has shown to exert significant protective effects against various diseases via its antioxidant and anti-inflammatory properties. However, its potential role in arthritis is still not reported. Therefore, the aim of the present study was to investigate the potential anti-arthritic properties of ATX against complete Freund's adjuvant (CFA)-induced arthritis rats.METHODS: Adjuvant arthritis was induced by single intraplantar injection of complete Freund's adjuvant (CFA) in the left hind paw of adult female Wistar rats. ATX (25, 50 and 100 mg/kg) and indomethacin (5 mg/kg) were given orally from days 14 to 28. The anti-arthritic activity was evaluated through various nociceptive behavioral tests (mechanical allodynia, mechanical hyperalgesia, cold allodynia, and thermal hyperalgesia), paw edema assessment, and arthritis scores. Serum tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and cyclic citrullinated peptide (CCP) antibody levels were assessed. Moreover, malondialdehyde (MDA), nitrite, glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels were also evaluated.RESULTS: Oral administration of ATX (50 and 100 mg/kg) exhibited significant anti-arthritic activity via enhancing the nociceptive threshold, reducing paw edema and improving arthritis scores. Moreover, ATX treatment also markedly suppressed inflammatory and oxidative mediators in adjuvant-administered rats.CONCLUSIONS: Our findings suggest that ATX possesses potential anti-arthritic activity, which could be attributed to its anti-inflammatory and antioxidant properties.

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PMID: 

J Mol Endocrinol. 2019 Jul 1 ;63(1):1-9. PMID: 30978698

Abstract Title: 

Humulus japonicus stimulates thermogenesis and ameliorates oxidative stress in mouse adipocytes.

Abstract: 

An aqueous extract of Humulus japonicus (AH) has been documented to ameliorate hypertension and non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effects of an aqueous extract of AH on thermogenesis and palmitate-induced oxidative stress in adipocytes. To verify the effect of AH on browning, we measured the expression levels of specific markers in 3T3-L1 adipocytes using qPCR and Western blotting, respectively. To assess the role of oxidative stress, cells were stained with DCFDA and observed by fluorescence microscopy. AH increased the expression of brown adipose tissue-specific markers. Additionally, it induced fatty acid oxidation and lipolysis and suppressed both lipogenic markers and lipid accumulation. Furthermore, AH ameliorated hydrogen peroxide-induced oxidative stress. Enhanced expression of these markers contributed to fat browning, fatty acid oxidation and lipolysis of 3T3-L1 adipocytes via the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor delta (PPARδ) signaling pathways. Moreover, AMPK and PPARδ resulting in protective effects of AH against oxidative stress. In sum, AH could promote the browning, lipolysis and thermogenesis in 3T3-L1 adipocytes and would suppress the hydrogen peroxide-induced oxidative stress and lipogenesis during differentiation. We therefore suggest that AH could be used as a potential candidate for treating obesity and related metabolic disorders.

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PMID: 

Int J Mol Med. 2020 Feb ;45(2):417-428. Epub 2019 Dec 3. PMID: 31894253

Abstract Title: 

Humulus japonicus extract ameliorates collagen‑induced arthritis in mice through regulation of overall articular inflammation.

Abstract: 

Humulus japonicus (HJ) is a widely used herbal medicine in Asia with anti‑oxidative, anti‑microbial, and anti‑inflammatory effects. We investigated the potential therapeutic effects of HJ in rheumatoid arthritis (RA) using a mouse model of collagen‑induced arthritis (CIA) and a lipopolysaccharide‑stimulated murine macrophage cell line (RAW 264.7). The CIA micewere administered 300 mg/kg HJ orally starting 3 days prior to second immunization. The clinical and histopathological findings were assessed in the paw of CIA mice. The levels of autoantibodies and inflammatory markers were determined in the plasma and cell culture supernatant, respectively. Theexpression at mRNA and protein levels was analyzed by reverse transcription quantitative‑PCR and western blot analysis, respectively. HJ significantly decreased the gross arthritic scores and paw swelling in CIA mice. Furthermore, synovial inflammation, cartilage destruction, and bone erosion were markedly reduced by HJ. It also decreased the expression of inflammatory enzymes in both the paw of mice and RAW 264.7 cells. Moreover, the expression of genes related to all macrophages and pro‑inflammatory M1 macrophage were significantly decreased, whereas the expression of anti‑inflammatory M2 macrophage marker was markedly increased in the paw of HJ‑treated CIA mice. In addition, HJ suppressed the levels of plasma anti‑type II collagen antibody following the decreased expression of T helper type 1 (Th1) and Th2 cell‑associated surface markers and cytokines in the paw. HJ alsosignificantly inhibited the expression of IL‑6 both in vitro and in vivo, followed by reduced STAT3 phosphorylation and expression in the paw of CIA mice. Finally, the expression of osteoclast‑related genes was decreased in the paw of HJ‑treated CIA mice. These findings suggest that HJ canplay a role in suppressing the development of CIA by overall regulation of articular inflammation. This study should provide new insights into the use of HJ as a therapeutically effective natural product against RA.

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A study finds that Curcuma longa, more popularly known as turmeric, can alleviate certain symptoms of Type 2 diabetes, namely arterial stiffness and endothelial dysfunction