Melastoma malabathricum L. Suppresses Neutrophil Extracellular Trap Formation Induced by Synthetic Analog of Viral Double-Stranded RNA Associated with SARS-CoV-2 Infection.

Platelet hyper-reactivity and neutrophil extracellular trap (NET) formation contribute to the development of thromboembolic diseases for patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study investigated the pathophysiological effects of SARS-CoV-2 surface protein components and the viral double-stranded RNA (dsRNA) on platelet aggregation and NET formation. Traditional Chinese medicine (TCM) with anti-viral effects was also delineated. The treatment of human washed platelets with SARS-CoV-2 spike protein S1 or the ectodomain S1 + S2 regions neither caused platelet aggregation nor enhanced agonists-stimulated platelet aggregation. Moreover, NET formation can be induced by polyinosinic-polycytidylic acid (poly(I:C)), a synthetic analog of viral dsRNA, but not by the pseudovirus composed of SARS-CoV-2 spike, envelope, and membrane proteins. To search for TCM with anti-NET activity, the plant Melastoma malabathricum L. which has anticoagulant activity was partially purified by fractionation. One of the fractions inhibited poly(I:C)-induced NET formation in a dose-dependent manner. This study implicates that SARS-CoV-2 structural proteins alone are not sufficient to promote NET and platelet activation. Instead, dsRNA formed during viral replication stimulates NET formation. This study also sheds new insight into using the active components of Melastoma malabathricum L. with anti-NET activity in the battle of thromboembolic diseases associated with SARS-CoV-2 infection.

Biochemical and tissue physiopathological evaluation of the preclinical efficacy of Solanum torvum Swartz leaves for treating oxidative impairment in rats administered a ß-cell-toxicant (STZ).

The current study evaluated the protective role of Solanum torvum Swartz against diabetes-induced oxidative stress and tissue impairment in streptozotocin (STZ)-intoxicated rats. Rats with STZ (40 mg/kg intraperitoneally (i.p.))-induced diabetes were divided into five groups (n = 5) and treated with (i) normal saline, (ii) 150 mg/kg body weight (BW) of the ethanol extract of S. torvum leaf (EESTL), (ii) 300 mg/kg BW EESTL, (iv) 100 mg/kg BW metformin, and (v) 50 m/kg BW metformin + 100 mg/kg BW EESTL orally for 21 days. Our results revealed that the EESTL displayed dose-dependent ferric-reducing antioxidant power (FRAP) activity, scavenged DPPH radicals (IC50) = 13.52 ± 0.45 µg/mL), and inhibited lipid peroxidation in an in vitro models. In addition, the EESTL demonstrated dose-dependent inhibitory activity against α-amylase (IC50 =138.46 ± 3.97 µg/mL) and promoted glucose uptake across plasma membranes of yeast cells in a manner comparable to that of metformin. Interestingly, the extract demonstrated in vivo blood glucose normalization effects with concomitant increased activities of antioxidant parameters (superoxide dismutase (SOD), catalase, and reduced glutathione (GSH)) while decreasing malondialdehyde (MDA) levels when compared to untreated rats. Similarly, serum biochemical alterations, and tissues (liver, kidney, and pancreases) histopathological aberrations in untreated rats with STZ-induced diabetes were attenuated by treatment with the EESTL. Biometabolite characterization of the extract identified gallic acid (45.81 ppm), catechin (1.18 ppm), p-coumaric acid (1.43e-1 ppm), DL-proline 5-oxo-methyl ester (9.16 %, retention time (RT): 8.57 min), salicylic acid (3.26% and 7.61 min), and butylated hydroxytoluene (4.75%, RT: 10.18 min) as the major polyphenolic compounds in the plant extract. In conclusion, our study provides preclinical evidence of the antioxidant properties and oxidative stress-preventing role of S. torvum in STZ-dosed diabetic rats. Taken together, the EESTL represents a reserve of bioactive metabolites for managing diabetes and associated complications.

The Effects of Freshwater Clam (Corbicula fluminea) Extract on Serum Tumor Necrosis Factor-Alpha (TNF-α) in Prediabetic Patients in Taiwan.

Freshwater clam extract (FCE) is a functional food that regulates the immune system and has been demonstrated in numerous studies to display desirable anti-tumor necrosis factor-alpha (TNF-α) responses. In addition, excess TNF-α production is positively associated with type 2 diabetes. However, few longitudinal clinical studies evaluating the efficiency and toxicity of FCE are available. This article reports that patients with prediabetes who received FCE had a desirable outcome of a reduction in serum TNF-α for a long period. This was a double-blind, randomized, parallel clinical trial conducted using FCE intervention and placebo groups, and 36 patients with prediabetes were enrolled. Two grams of FCE or placebo was consumed daily for 180 consecutive days. The serum of the participants was collected at four time points (0M: before the intervention; 3M: after 3 months of intervention; 6M: after 6 months of intervention; 12M: 6 months after cessation of intervention at 6M). A serum TNF-α concentration higher than 4.05 pg/mL was defined as a cut-off value. FCE reduced serum TNF-α in all participants at 6M and 12M. Moreover, FCE significantly suppressed serum TNF-α concentrations at 6M and 12M and inhibited TNF-α release with time series in subjects with elevated TNF-α values. FCE intervention effectively reduced serum TNF-α and persistently sustained the effects for half a year in patients with prediabetes. Gas chromatography-mass spectrometry (GS-MS) analysis revealed that the major components of FCE were phytosterols and fatty acids, which exerted anti-inflammatory and anti-TNF-α abilities. Hence, FCE has the potential to be developed as a natural treatment for prediabetic patients in Taiwan.

Hypoglycemic peptide-enriched hydrolysates of Corbicula fluminea and Chlorella sorokiniana possess synergistic hypoglycemic activity through inhibiting α-glucosidase and dipeptidyl peptidase-4 activity.

BACKGROUND: The prevalence of diabetes mellitus worldwide has increased in recent decades. Maintaining the level of blood glucose is the most basic and important issue for diabetics. This study aimed to investigate the hypoglycemic activity of a combination of hypoglycemic peptide-enriched hydrolysates of Corbicula fluminea (ACH) and Chlorella sorokiniana (PCH). RESULTS: Combined supplementation of ACH and PCH synergistically inhibited α-glucosidase and DPP4 activities in vitro. After 4 weeks of treatment with ACH and/or PCH, the plasma glucose concentration and insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR), total cholesterol (TC) and triglyceride (TG) levels significantly decreased. The hypoglycemic peptides in ACH and PCH were purified and assayed for α-glucosidase and DPP4 activity. The hypoglycemic peptides in ACH and PCH effectively decreased α-glucosidase and DPP4 activities. In silico assays showed that these two peptide types have different docking poses, which determined their inhibitory effect against α-glucosidase and DPP4 activity. CONCLUSION: Combined treatment with hypoglycemic peptide-enriched ACH and PCH could modulate blood glucose by synergistically inhibiting α-glucosidase and DPP4 activities. © 2021 Society of Chemical Industry.

Gamma-mangostin isolated from garcinia mangostana suppresses colon carcinogenesis and stemness by downregulating the GSK3ß/ß-catenin/CDK6 cancer stem pathway.

BACKGROUND: Despite advances in chemotherapies and targeted drugs, colorectal cancer (CRC) remains challenging to treat due to drug resistance. Emerging evidence indicates that cancer-associated fibroblasts (CAFs) facilitate the generation of cancer stem-like cells (CSCs) and drug resistance. Glycogen synthase kinase-3 (GSK) associated signaling pathways have been implicated in the generation of CSCs and represent a target for therapeutics development. HYPOTHESIS: Gamma-mangostin (gMG) isolated from Garcinia mangostana was evaluated for its ability to downregulate GSK3ß-associated signaling in CRC cells and overcome CAF-induced 5-fluorouracil resistance and CSC generation. METHODS: Bioinformatics analysis, in silico molecular docking, in vitro assays, including cell viability tests, colony- and tumor sphere-formation assays, transwell migration assays, ELISA, SDS-PAGE, Western blotting, miR expression, qPCR, and flow cytometry, as well as in vivo mouse xenograft models were used to evaluate the antitumor effects of gMG. RESULTS: Bioinformatics analyses indicated that GSK3ß/CDK6/ß-catenin mRNA signature was significantly higher in colon cancer patients. Additional algorithms predicted a higher miR-26b level was associated with significantly higher survival in CRC patients and GSK3ß and CDK6 as targets of miR-26b-5p. To validate these findings in vitro, we showed that CAF-cocultured CRC cells expressed an increased expression of GSK3ß, ß-catenin, CDK6, and NF-κB. Therapeutically, we demonstrated that gMG treatment suppressed GSK3ß-associated signaling pathways while concomitantly increased the miR-26b-5p level. Using a xenograft mouse model of CAFs cocultured HCT116 tumorspheres, we showed that gMG treatment reduced tumor growth and overcame CAF-induced 5-fluorouracil resistance. CONCLUSIONS: Pharmacological intervention with gMG suppressed CRC carcinogenesis and stemness via downregulating GSK3/ß-catenin/CDK6 and upregulating the miR-26b-5p tumor suppressor. Thus, gMG represents a potential new CRC therapeutic agent and warrants further investigation.

Rhubarb hydroxyanthraquinones act as antiobesity agents to inhibit adipogenesis and enhance lipolysis.

Rhubarb as an herbal medicine has been shown to exhibit antiadipogenic activity. This study evaluated and compared the lipid-lowering activity of five rhubarb hydroxyanthraquinones (HAQs), including chrysophanol, aloe emodin, emodin, physcion, and rhein, aiming to identify candidate compounds for obesity treatment. Examination of the antiobesity effects of HAQs in 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese rats showed that these anthraquinone compounds inhibited lipid accumulation in 3T3-L1 cells before and after differentiation. Emodin and rhein showed greater inhibition than the other compounds; dosage at 50 µM reduced intracellular triglyceride (TG) by about 30% in the differentiated adipocytes. Both compounds also revealed lipolytic effects to increase glycerol release from adipocytes. Adipokine overexpression induced by differentiation was downregulated by emodin and rhein through mitogen-activated protein kinase (MAPK) signaling. Despite their structural similarity, emodin and rhein exhibited different mechanisms on adipogenesis and lipid metabolism. Rhein restrained lipid deposition by controlling adipogenic transcriptional factors and lipolytic lipases during differentiation. The lipid-lowering effects of emodin did not use these pathways but reduced levels of lipogenic enzymes. HFD consumption in rats significantly increased body weight, visceral fat mass and adipocyte size, which were attenuated by intraperitoneal delivery of emodin or rhein. Rhein showed greater amelioration of obesity than emodin, decreasing plasma cholesterol by 29% and 14%, respectively. HAQs also suppressed cytokine upregulation in the liver and adipose tissues of obese rats. Rhein is a potential antiobesity agent through its ability to regulate obesity-associated adipogenesis, lipolysis and inflammation.

Identification of NSP3 (SH2D3C) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from Allium sativum L. as Therapeutic Candidates.

The multi-domain non-structural protein 3 (NSP3) is an oncogenic molecule that has been concomitantly implicated in the progression of coronavirus infection. However, its oncological role in lung cancer and whether it plays a role in modulating the tumor immune microenvironment is not properly understood. In the present in silico study, we demonstrated that NSP3 (SH2D3C) is associated with advanced stage and poor prognoses of lung cancer cohorts. Genetic alterations of NSP3 (SH2D3C) co-occurred inversely with Epidermal Growth Factor Receptor (EGFR) alterations and elicited its pathological role via modulation of various components of the immune and inflammatory pathways in lung cancer. Our correlation analysis suggested that NSP3 (SH2D3C) promotes tumor immune evasion via dysfunctional T-cell phenotypes and T-cell exclusion mechanisms in lung cancer patients. NSP3 (SH2D3C) demonstrated a high predictive value and association with therapy resistance in lung cancer, hence serving as an attractive target for therapy exploration. We evaluated the in silico drug-likeness and NSP3 (SH2D3C) target efficacy of six organosulfur small molecules from Allium sativum using a molecular docking study. We found that the six organosulfur compounds demonstrated selective cytotoxic potential against cancer cell lines and good predictions for ADMET properties, drug-likeness, and safety profile. E-ajoene, alliin, diallyl sulfide, 2-vinyl-4H-1,3-dithiin, allicin, and S-allyl-cysteine docked well into the NSP3 (SH2D3C)-binding cavity with binding affinities ranging from -4.3~-6.70 A and random forest (RF) scores ranging from 4.31~5.26 pKd. However, S-allyl-cysteine interaction with NSP3 (SH2D3C) is unfavorable and hence less susceptible to NSP3 ligandability. In conclusion, our study revealed that NSP3 is an important onco-immunological biomarker encompassing the tumor microenvironment, disease staging and prognosis in lung cancer and could serve as an attractive target for cancer therapy. The organosulfur compounds from A. sativum have molecular properties to efficiently interact with the binding site of NSP3 and are currently under vigorous preclinical study in our laboratory.

Correction of Breech Presentation with Moxibustion and Acupuncture: A Systematic Review and Meta-Analysis.

Acupuncture-type interventions (such as moxibustion and acupuncture) at Bladder 67 (BL67, Zhiyin point) have been proposed to have positive effects on breech presentation. The aim of this systematic review and meta-analysis was to evaluate the effectiveness and safety of moxibustion and acupuncture in correcting breech presentation. We searched PubMed, MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), the Chinese Electronic Periodical Services (CEPS), and databases at ClinicalTrials.gov to identify relevant randomized controlled trials (RCTs). In this study, sixteen RCTs involving 2555 participants were included. Compared to control, moxibustion significantly increased cephalic presentation at birth (RR = 1.39; 95% CI = 1.21-1.58). Moxibustion also seemed to elicit better clinical outcomes in the Asian population (RR = 1.42; 95% CI = 1.21-1.67) than in the non-Asian population (RR = 1.20; 95% CI = 1.01-1.43). The effects of acupuncture on correcting breech presentation after sensitivity analysis were inconsistent relative to control. The effect of moxibustion plus acupuncture was synergistic for correcting breech presentation (RR = 1.53; 95% CI = 1.26-1.86) in one RCT. Our findings suggest that moxibustion therapy has positive effects on correcting breech presentation, especially in the Asian population.

Positive Effects of Laser Acupuncture in Methamphetamine Users Undergoing Group Cognitive Behavioral Therapy: A Pilot Study.

BACKGROUND: Methamphetamine (MA) addiction has become a crucial public health concern because of its adverse consequences to individuals and the society. OBJECTIVE: To investigate the clinical efficacy of laser acupuncture combined with group cognitive behavioral therapy for MA addiction treatment. MATERIALS AND METHODS: MA users who participated in group cognitive behavioral therapy and met the inclusion criteria were referred from psychiatrists to participate. The participants received laser acupuncture treatment once a week for 2 months (total eight treatments) on selected acupoints (PC6, HT7, LI4, ST36, SP6, and LR3). Laboratory assessment included urinalysis for MA and liver function tests aspartate aminotransferase, alanine aminotransferase, and γ-glutamyltransferase (AST, ALT, and γ-GT), whereas the objective assessment included visual analog scale (VAS) for MA craving and refusal and Pittsburgh sleep quality index (PSQI), Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI) questionnaires. All data were collected before and at 1 and 2 months after treatment. Cognitive behavioral therapy completion rate and rate of relapse to MA use were also determined. RESULT: Fifteen participants were enrolled, of whom seven completed the trial. Urinalysis for MA revealed a decrease in drug use from 57.1% to 28.6%. Compared with those before treatment, PSQI scores were significantly lower at 1 and 2 months after treatment (-3.73 and -4.10, respectively; both p < 0.001), and so were BDI scores (-5.64 and -8.17, respectively; p=0.01 and 0.001, respectively). However, no significant difference was observed in the liver function test, VAS of craving and refusal, and BAI results. A slight improvement in the motivation for drug abstinence and anxiety was observed during the treatment course. Participants reported no adverse events. CONCLUSION: Laser acupuncture combined with group cognitive behavioral therapy may improve sleep quality, alleviate depression, and reduce MA use. Additional large-scale studies confirming the effectiveness of this modality are warranted.

The Beneficial Effects of Moxibustion on Overweight Adolescent Girls.

Among adolescent girls, overweight or obesity has both physical and psychological involvement. We conducted a randomized controlled trial of moxibustion using a moxa burner. Fifty-four eligible girls aged 15-18 years with a body mass index (BMI) greater than 25.3 were enrolled in the study. The girls were randomly allocated to the treatment (n = 27) and control (n = 27) groups. The girls underwent treatment three times per week for 8 weeks (24 treatments). Moxibustion was applied to the RN12, RN6, ST25, ST36, and SP6 acupoints. Physical assessments were BMI, waist-to-hip ratio (WHR), and body fat ratio (BFR). Psychological outcomes were measured using the Rosenberg Self-Esteem Scale (RSE). Data were collected at the beginning of the study (baseline), week 4, and week 8. Of the 54 participants, 46 completed the trial. The difference in mean BMI from baseline between the two groups was 0.097 (p=0.655) at week 4 and -0.794 (p=0.001) at week 8. The mean WHR of the treatment group was significantly reduced compared with baseline, with a -0.011 (p=0.017) and -0.035 (p < 0.001) mean change at weeks 4 and 8, respectively. The mean BFR was slightly reduced (-0.253;p=0.474 ) at week 4 compared with baseline in the treatment group. At week 8, it was significantly reduced (-2.068; p < 0.001) from baseline in the treatment group. The mean RSE in the treatment group showed no significant increase from baseline at week 4 (0.155 points, p=0.803), but it improved significantly from baseline at week 8 (1.606 points, p=0.021) compared to that in the control group. No obvious adverse effect was reported during this study. Moxibustion using a moxa burner may be an effective and safe intervention for overweight adolescent girls, having both physical and psychological benefits.

The Chang Gung Research Database: Multi-institutional real-world data source for traditional Chinese medicine in Taiwan.

BACKGROUND: The Chang Gung Research Database (CGRD), the largest multi-institutional electronic medical records collection in Taiwan, has been used to establish real-world evidence related to traditional Chinese medicine (TCM). We aimed to evaluate patient characteristics and representativeness of TCM patients in CGRD. METHODS: We identified a cohort of patients who had TCM records both from CGRD and from Taiwan's National Health Insurance Database (NHIRD) during 2010-2015 to investigate the representativeness of CGRD for TCM uses. The NHIRD was considered as reference because it covers all medical claims from 99.9% of the entire Taiwanese population. We investigated the coverage rates of TCM patients within CGRD compared to NHIRD, and compared the characteristics of patients between CGRD and NHIRD including age, sex, and 15 health conditions. RESULTS: We identified 71 002 average annual patients within the CGRD, which accounted for 1.1% of the patients from the NHIRD. The patients from CGRD were older than those from NHIRD (≥65: 16.6% vs. 9.9% for CGRD vs. NHIRD). The ratios of female over male patients were 1.7 vs. 1.5 for CGRD vs. NHIRD. We found higher patient coverage rates for patients with major comorbidities in CGRD, specifically for neoplasm (9.2%) and mental disorders (6.0%). The most frequently prescribed Chinese herbal medicines in CGRD included Jia-Wei-Xiao-Yao-San, Xiang-Sha-Liu-Jun-Zi-Tang and Gui-Lu-Er-Xian-Jiao. CONCLUSION: Higher patient coverage rates were found in CGRD for TCM patients with major comorbidities. Investigators should note possible selection bias since TCM patient disorders may be more severe in CGRD than in the NHIRD.

Low-fluence laser-facilitated platelet-rich plasma permeation for treating MRSA-infected wound and photoaging of the skin.

Platelet-rich plasma (PRP) is rich in cytokines and growth factors and is a novel approach for tissue regeneration. It can be used for skin rejuvenation but the large molecular size of the actives limits its topical application. In this study, low-fluence laser-facilitated PRP was delivered to evaluate its effect on absorption through the skin, infection-induced wound, and photoaging. The PRP permeation enhancement was compared for two ablative lasers: fractional (CO2) laser and fully-ablative (Er:YAG) laser. In the Franz cell experiment, pig skin was treated with lasers with superficial ablation followed by the application of recombinant cytokines, growth factors, or PRP. The transport of interferon (IFN)-γ and tumor necrosis factor (TNF)-α was negligible in intact skin and stratum corneum (SC)-stripped skin. Both lasers significantly elevated skin deposition of IFN-γ and TNF-α from PRP, and fully-ablative laser showed a higher penetration enhancement. A similar tendency was found for vascular endothelial growth factor and epidermal growth factor. Er:YAG laser-exposed skin displayed 1.8- and 3.9-fold higher skin deposition of platelet-derived growth factor (PDGF)-BB and transforming growth factor (TGF)-ß1 from PRP, respectively. According to the confocal images, both laser interventions led to an extensive and deep distribution of IFN-γ and PDGF-BB in the skin. In the in vivo methicillin-resistant Staphylococcus aureus (MRSA) infection model, CO2 laser- and Er:YAG laser-assisted PRP delivery reduced bacterial load from 1.8 × 106 to 5.9 × 105 and 1.4 × 104 colony-forming units, respectively. The open wound induced by MRSA was closed by the laser-assisted PRP penetration. In the mouse photoaging model, elastin and collagen deposition were fully restored by combined PRP and full-ablative laser but not by PRP alone and PRP combined with fractional laser. Laser-facilitated PRP delivery even with a low fluence setting can be considered a promising strategy for treating some dermatological disorders.

Positive Effects of Ger-Gen-Chyn-Lian-Tang on Cholestatic Liver Fibrosis in Bile Duct Ligation-Challenged Mice.

The purpose of this study was to investigate whether Ger-Gen-Chyn-Lian-Tang (GGCLT) suppresses oxidative stress, inflammation, and angiogenesis during experimental liver fibrosis through the hypoxia-inducible factor-1α (HIF-1α)-mediated pathway. Male C57BL/6 mice were randomly assigned to a sham-control or bile duct ligation (BDL) group with or without treatment with GGCLT at 30, 100, and 300 mg/kg. Plasma alanine aminotransferase (ALT) levels were analyzed using a diagnostic kit. Liver histopathology and hepatic status parameters were measured. Compared to control mice, the BDL mice exhibited an enlargement in liver HIF-1α levels, which was suppressed by 100 and 300 mg/kg GGCLT treatments (control: BDL: BDL + GGCLT-100: BDL + GGCLT-300 = 0.95 ± 0.07: 1.95 ± 0.12: 1.43 ± 0.05: 1.12 ± 0.10 fold; p < 0.05). GGCLT restrained the induction of hepatic hydroxyproline and malondialdehyde levels in the mice challenged with BDL, further increasing the hepatic glutathione levels. Furthermore, in response to increased hepatic inflammation and fibrogenesis, significant levels of ALT, nuclear factor kappa B, transforming growth factor-ß, α-smooth muscle actin, matrix metalloproteinase-2 (MMP-2), MMP-9, and procollagen-III were found in BDL mice, which were attenuated with GGCLT. In addition, GGCLT reduced the induction of angiogenesis in the liver after BDL by inhibiting vascular endothelial growth factor (VEGF) and VEGF receptors 1 and 2. In conclusion, the anti-liver fibrosis effect of GGCLT, which suppresses hepatic oxidative stress and angiogenesis, may be dependent on an HIF-1α-mediated pathway.

The concurrent treatment of Scutellaria baicalensis Georgi enhances the therapeutic efficacy of cisplatin but also attenuates chemotherapy-induced cachexia and acute kidney injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Cisplatin is an important chemotherapy to lung cancer, but it usually induces severe cachexia and acute kidney injury in patients. Scutellaria baicalensis Georgi (SB), commonly known as a skullcap, is a popular Chinese herbal medicine mainly used to treat inflammation, infection, and malignancy. In this study, we report the synergic effect of SB and cisplatin to Lewis lung carcinoma (LLC) cells, and the ameliorative effect of SB to cisplatin-induced cachexia and acute kidney injury. MATERIALS AND METHODS: The extract of SB was applied by water boiling and lyophilization. The MTS assay was used to exam the in-vitro effects of SB and cisplatin on the LLC viability. In the animal experiment, male C57BL/6J mice were inoculated with LLC cells, and then treated by cisplatin intraperitoneally and the SB extract orally. Tumor volume, weights of tumor, murine body, white adipose tissue and gastrocnemius muscle, as well as serum levels of BUN and creatinine were measured during the experiment. Murine kidney sample was observed after the H&E and annexin V staining. RESULTS: SB provided an enhancement of cisplatin action to inhibit tumor growth in vitro and in vivo. In the animal experiment, SB improved the loss of murine body weight and gastrocnemius muscle, the elevating BUN level, and the apoptosis of renal tubular cells in mice receiving cisplatin therapy. Meanwhile, the current treatment of SB did not further interfere with the blood cell counts of mice receiving chemotherapy. CONCLUSION: SB can enhance the anti-cancer effect of cisplatin. It also attenuates cisplatin-induced cachexia and acute kidney injury.

Antrodia cinnamomea Enhances Chemo-Sensitivity of 5-FU and Suppresses Colon Tumorigenesis and Cancer Stemness via Up-Regulation of Tumor Suppressor miR-142-3p.

5-Fluorouracil (5-FU) regimen remains the backbone of the first-line agent to treat colon cancer, but often these patients develop resistance. Cancer stem cells (CSC's) are considered as one of the key contributors in the development of drug resistance and tumor recurrence. We aimed to provide preclinical evidence for Antrodiacinnamomea (AC), as a potential in suppressing colon cancer CSC's to overcome 5-FU drug-resistant. In-vitro assays including cell viability, colony formation, AC + 5-FU drug combination index and tumor sphere generation were applied to determine the inhibitory effect of AC. Mouse xenograft models also incorporated to evaluate in vivo effect of AC. AC treatment significantly inhibited the proliferation, colony formation and tumor sphere generation. AC also inhibited the expression of oncogenic markers (NF-κB, and C-myc), EMT/metastasis markers (vimentin and MMP3) and stemness associated markers (ß-catenin, SOX-2 and Nanog). Sequential treatment of AC and 5-FU synergized and reduces colon cancer viability both in vivo and in vitro. Mechanistically, AC mediated anti-tumor effect was associated with an increased level of tumor suppressor microRNAs especially, miR142-3p. AC can be a potent synergistic adjuvant, down-regulates cancer stemness genes and enhances the antitumor ability of 5-FU by stimulating apoptosis-associated genes, suppressing inflammation and metastasis genes through miR142-3p in colon cancer.

Apoptotic or Antiproliferative Activity of Natural Products against Keratinocytes for the Treatment of Psoriasis.

Natural products or herbs can be used as an effective therapy for treating psoriasis, an autoimmune skin disease that involves keratinocyte overproliferation. It has been demonstrated that phytomedicine, which is used for psoriasis patients, provides some advantages, including natural sources, a lower risk of adverse effects, and the avoidance of dissatisfaction with conventional therapy. The herbal products' structural diversity and multiple mechanisms of action have enabled the synergistic activity to mitigate psoriasis. In recent years, the concept of using natural products as antiproliferative agents in psoriasis treatment has attracted increasing attention in basic and clinical investigations. This review highlights the development of an apoptotic or antiproliferatic strategy for natural-product management in the treatment of psoriasis. We systematically introduce the concepts and molecular mechanisms of keratinocyte-proliferation inhibition by crude extracts or natural compounds that were isolated from natural resources, especially plants. Most of these studies focus on evaluation through an in vitro keratinocyte model and an in vivo psoriasis-like animal model. Topical delivery is the major route for the in vivo or clinical administration of these natural products. The potential use of antiproliferative phytomedicine on hyperproliferative keratinocytes suggests a way forward for generating advances in the field of psoriasis therapy.

The atopic dermatitis-like lesion and the associated MRSA infection and barrier dysfunction can be alleviated by 2,4-dimethoxy-6-methylbenzene-1,3-diol from Antrodia camphorata.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin disease with an associated barrier dysfunction and Staphylococcus aureus infection. The mainstay steroid and calcineurin inhibitor therapy shows some adverse effects. 2,4-Dimethoxy-6-methylbenzene-1,3-diol (DMD) is a benzenoid isolated from Antrodia camphorata. OBJECTIVE: We investigated the inhibitory effect of DMD on methicillin-resistant S. aureus (MRSA), the chemokine production in stimulated keratinocytes, and the AD-like lesion found in ovalbumin (OVA)-sensitized mice. METHODS: The antimicrobial effect and cutaneous barrier function were evaluated using an in vitro culture model and an in vivo mouse model of AD-like skin. RESULTS: DMD exhibited a comparative minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against MRSA with nalidixic acid, a conventional antibiotic. The MIC and MBC for DMD was 78.1 and 156.3 µg/ml, respectively. DMD also showed the ability to eliminate the clinical bacteria isolates with resistance to methicillin and vancomycin. The DNA polymerase and gyrase inhibition evoked by DMD for bacterial lethality was proposed. In the activated keratinocytes, DMD stopped the upregulation of chemokines (CCL5 and CCL17) and increased the expression of differentiation proteins (filaggrin, involucrin, and integrin ß-1). Topical application of DMD facilely penetrated into the skin, with AD-like skin displaying 2.5-fold greater permeation than healthy skin. The in vivo assessment using the mouse model with OVA sensitization and MRSA inoculation revealed a reduction of transepidermal water loss (TEWL) and bacterial burden by DMD by about 2- and 100-fold, respectively. Differentiation proteins were also restored after topical DMD delivery. CONCLUSION: Our data demonstrated an advanced concept of AD treatment by combined barrier repair and bacterial eradication with a sole agent for ameliorating the overall complications.

Cosmetic and Therapeutic Applications of Fish Oil's Fatty Acids on the Skin.

Fish oil has been broadly reported as a potential supplement to ameliorate the severity of some skin disorders such as photoaging, skin cancer, allergy, dermatitis, cutaneous wounds, and melanogenesis. There has been increasing interest in the relationship of fish oil with skin protection and homeostasis, especially with respect to the omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). The other PUFAs, such as α-linolenic acid (ALA) and linoleic acid (LA), also show a beneficial effect on the skin. The major mechanisms of PUFAs for attenuating cutaneous inflammation are the competition with the inflammatory arachidonic acid and the inhibition of proinflammatory eicosanoid production. On the other hand, PUFAs in fish oil can be the regulators that affect the synthesis and activity of cytokines for promoting wound healing. A systemic review was conducted to demonstrate the association between fish oil supplementation and the benefits to the skin. The following describes the different cosmetic and therapeutic approaches using fatty acids derived from fish oil, especially ALA, LA, DHA, and EPA. This review summarizes the cutaneous application of fish oil and the related fatty acids in the cell-based, animal-based, and clinical models. The research data relating to fish oil treatment of skin disorders suggest a way forward for generating advances in cosmetic and dermatological uses.

Therapeutic Effect of Superficial Acupuncture in Treating Myofascial Pain of the Upper Trapezius Muscle: A Randomized Controlled Trial.

The aim of this study was to compare the treatment efficacies of superficial acupuncture and traditional acupuncture on trigger points of the upper trapezius muscle. Forty people were recruited and randomly allocated to the traditional and superficial acupuncture groups. Each subject received two treatments per week in a four-week period. Outcomes were measured by visual analogue scale (VAS), the Northwick Park neck pain questionnaire scores (NPQ), and pressure pain threshold (PPT) assessments of trigger points. Data collected before the interventions were considered as baseline. Assessments were performed after the first treatment and at the end of the second and fourth weeks of treatment. Patients reported significant (p<0.05) and immediate improvements in VAS and PPT for both superficial acupuncture and traditional acupuncture after the first treatment and after two and four weeks. Significant improvements (p<0.05) in NPQ were attained after two weeks of treatments in both groups. Because superficial acupuncture is associated with less pain while producing immediate pain relief, we recommend it for treating myofascial pain syndrome in the upper trapezius muscle.

Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes.

Clinically, serum level of folate has been negatively correlated to the stage and progression of liver cancer. Nevertheless, the functional consequence of folate deficiency (FD) in malignancy has not been fully investigated. Human hepatocellular carcinoma (HCC) cells (as study model) and other cancer types such as lung and glioma were cultured under folate deficient (FD) and folate complete (FD) conditions. Molecular characterization including intracellular ROS/RNS (reactive oxygen/nitrogen species), viability, colony formation, cancer stem-like cell (CSC) phenotype analyses were performed. In vivo tumorigenesis under FD and FC conditions were also examined. FD induced a significant increase in ROS and RNS, suppressing proliferative ability but inducing metastatic potential. Mesenchymal markers such as Snail, ZEB2, and Vimentin were significantly up-regulated while E-cadherin down-regulated. Importantly, CSC markers such as Oct4, ß-catenin, CD133 were induced while PRRX1 decreased under FD condition. Furthermore, FD-conditioned HCC cells showed a decreased miR-22 level, leading to the increased expression of its target genes including HDAC4, ZEB2 and Oct4. Finally, xenograft mouse model demonstrated that FD diet promoted tumorigenesis and metastasis as compared to their FC counterparts. Our data provides rationales for the consideration of folate supplement as a metastasis preventive measure.