PMID: 

Nutrients. 2019 Aug 22 ;11(9). Epub 2019 Aug 22. PMID: 31443565

Abstract Title: 

Bitter Orange (Citrus aurantium Linné) Improves Obesity by Regulating Adipogenesis and Thermogenesis through AMPK Activation.

Abstract: 

Obesity is a global health threat. Herein, we evaluated the underlying mechanism of anti-obese features of bitter orange (Linné, CA). Eight-week-administration of CA in high fat diet-induced obese C57BL/6 mice resulted in a significant decrease of body weight, adipose tissue weight and serum cholesterol. In further in vitro studies, we observed decreased lipid droplets in CA-treated 3T3-L1 adipocytes. Suppressed peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein alpha indicated CA-inhibited adipogenesis. Moreover, CA-treated primary cultured brown adipocytes displayed increased differentiation associated with elevation of thermogenic factors including uncoupling protein 1 and PPARγ coactivator 1 alpha as well. The effects of CA in both adipocytes were abolished in AMP-activated protein kinase alpha (AMPKα)-suppressed environments, suggesting the anti-adipogenic and pro-thermogenic actions of CA were dependent on AMPKα pathway. In conclusion, our results suggest CA as a potential anti-obese agent which regulates adipogenesis and thermogenesis via AMPKα.

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PMID: 

J Gastrointest Cancer. 2019 Aug 29. Epub 2019 Aug 29. PMID: 31463888

Abstract Title: 

The Anticancer Efficiency of Citrullus colocynthis Toward the Colorectal Cancer Therapy.

Abstract: 

BACKGROUND: Colorectal cancer (CRC) remains a major cause of death worldwide. Chemotherapy is associated with some side effects during CRC treatment. Hence, proper employment of lower toxic and approaches exerting lowest side effects are essential. The Citrullus colocynthis (C. colocynthis) seems a potential anticancerous herbal medicine (HM) against CRC mostly via various efficient compounds.METHODS: We performed a literature review regarding the anticancer traits of C. colocynthis against CRC. The possible active compounds, mechanisms, and combination therapies in vitro and in vivo or clinical trials have been also stated where found.RESULTS AND CONCLUSION: The anticancerous effects of C. colocynthis has been via a variety of pathways including apoptotic pathways (increase in caspase-3 and inhibiting STAT3 function), antioxidant and anti-inflammatory (TNF-α, nitric oxide, and pro-inflammatory cytokines such as IL-6, IL-8, and IL-1α) traits, inhibition of Wnt/β-catenin signaling pathway, and antiangiogenesis and antimetastatic effects. Future studies will be promising regarding proper application of C. colocynthis compounds following their extraction.

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PMID: 

Biomolecules. 2019 Aug 27 ;9(9). Epub 2019 Aug 27. PMID: 31461995

Abstract Title: 

Orientin Induces G0/G1 Cell Cycle Arrest and Mitochondria Mediated Intrinsic Apoptosis in Human Colorectal Carcinoma HT29 Cells.

Abstract: 

Colorectal carcinoma is one of the utmost diagnosed cancer with a steep increase in mortality rate. The incidence has been increasing in developing countries like India due to a westernization life style. Flavonoids have been explored widely for its various pharmacological activity including antitumor activity. Orientin, an analogue of luteolin (citrus flavonoid) isolated from rooibos and tulsi leaves is also expected to deliver significant antitumor activity similar to that of luteolin. The present study anticipates exploring the antitumor activity of orientin against colorectal carcinoma cells (HT29). Orientin exhibited remarkable cytotoxicity and antiproliferative activity against HT29 cells, which is clearly evident from tetrazolium based cytotoxicity and lactate dehydrogenase release assays. Orientin induce G0/G1 cell cycle arrest and regulates cyclin and cyclin-dependent protein kinases in order to prevent the entry of the cell cycle to the S phase. Annexin V-FITC (V-Fluorescein Isothiocyanate) dual staining reveals the apoptotic induction ability of orientin. The Bcl-2 family proteins along with the inhibitor of apoptotic proteins were regulated and the tumor suppressor p-53 expression have been decreased. In conclusion, our results proposed that orientin could be a potent chemotherapeutic agent against colorectal cancer after ascertaining their molecular mechanisms.

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PMID: 

Food Funct. 2019 Aug 27. Epub 2019 Aug 27. PMID: 31454000

Abstract Title: 

The dietary freeze-dried fruit powder of Actinidia arguta ameliorates dextran sulphate sodium-induced ulcerative colitis in mice by inhibiting the activation of MAPKs.

Abstract: 

In this study, we aimed at investigating the antiinflammatory activity of the freeze-dried fruit powder of Actinidia arguta (FAA) on dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) in mice and the effect of its extract on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. For pharmacodynamic studies, the oral administration of FAA (300 or 600 mg kg-1) could decrease the disease activity index (DAI), reduce the incidence of colon and spleen edemas (caused by inflammation), and alleviate the pathological changes in UC. For research involving biochemical indicators, FAA could decrease the expression of inflammatory markers (such as myeloperoxidase (MPO)) and attenuate the oxidative stress levels. ELISA results revealed that the expressions of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) were downregulated by FAA. Furthermore, the expression levels of the inflammation-induced activation of p38, JNK, and ERK were decreased by FAA. Hence, it was concluded that FAA could alleviate the UC symptoms in mice and the inflammatory response of macrophages via the MAPK signal pathway. Overall, FAA might have the potential to treat UC when used as a dietary supplement.

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PMID: 

Med Sci Monit. 2019 Aug 11 ;25:5986-5991. Epub 2019 Aug 11. PMID: 31401645

Abstract Title: 

Protective Effects of Naringenin in a Rat Model of Sepsis-Triggered Acute Kidney Injury via Activation of Antioxidant Enzymes and Reduction in Urinary Angiotensinogen.

Abstract: 

BACKGROUND Sepsis is a devastating medical condition. In the USA, about 745 000 people are diagnosed with sepsis annually. Although many anti-inflammatory drugs have been used to manage sepsis, the treatment success rate is very low. This study was undertaken to examine the protective effects of naringenin on sepsis-induced kidney injury in rats. MATERIAL AND METHODS Sepsis was induced in Wistar albino rats by cecal ligation and puncture methods. Histological analysis was performed with hematoxylin and eosin (HE) staining. Reactive oxygen species (ROS) levels were determined by flow cytometery. TUNEL assay was used to demonstrate apoptosis. Sandwich ELISA method was used for the determination of urinary angiotensinogen, and protein expression was determined by Western blot analysis. RESULTS We found that naringenin decreased atrophy in the glomerulus and enabled maintenance of the capsule area and normal tubular cavity of the septic rats. Admistration of naringenin at the dosage of 10 and 20 mg/kg to sepsis rats caused significant reduction in the sepsis-induced apoptosis of kidney cells, accompanied by decrease in Bax and increase in Bcl-2 expression. Moreover, naringenin also decreased the ROS levels in septic rats and downregulated the expression of SOD, CAT, and APX. The effects of naringenin were also examined on the levels of urinary angiotensinogen in sepsis rats. We found that naringenin caused a significant decrease in urinary angiotensinogen levels of septic rats. CONCLUSIONS Naringenin appears to have potential in the treatment of sepsis.

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PMID: 

Eur J Pharmacol. 2019 Aug 15 ;857:172456. Epub 2019 Jun 17. PMID: 31220438

Abstract Title: 

Flavonoids from Citrus aurantium ameliorate TNBS-induced ulcerative colitis through protecting colonic mucus layer integrity.

Abstract: 

Intestinal barrier injury is recognized as the main reason for ulcerative colitis (UC) which is a chronic inflammatory disease and the effective therapeutic methods remain limited. In this study, we explored the protection effects of naringenin, nobiletin and hesperetin from Citrus aurantium on colonic mucus layer integrity. The UC mice model was induced by trinitrobenzenesulfonic acid (TNBS). Forty mg/kg/day of naringenin, nobiletin and hesperetin were administrated orally for 7 and 3 days before and after TNBS treatment. Then body weight, disease activity index (DAI) score and colon length were recorded. Colons were collected for immunofluorescence, RT-PCR and western blot assay. Lipopolysaccharide (LPS)-induced cell-co-culture system of Caco-2 and RAW264.7 cells were used to determine activities on protecting intestinal epithelial monolayers damage. Our results showed that Naringenin, nobiletin and hesperetin alleviated body weight loss and colon shortness, decreased DAI score, and up-regulated claudin-2, occludin and zona occludens-1 (ZO-1) expression significantly. Meanwhile, the flavonoids enhanced trans epithelial electric resistance, decreased the permeability and up-regulated occludin and ZO-1 expression in LPS-damaged epithelial monolayers system. Hence, Naringnien, nobiletin and hesperetin show the regulatory effect on UC by protecting colonic mucosa layer integrity. It is suggested the flavonoids may be new supplements for the treatment of UC.

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PMID: 

Nat Commun. 2019 Aug 28 ;10(1):3923. Epub 2019 Aug 28. PMID: 31462679

Abstract Title: 

Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge.

Abstract: 

Circadian disruption aggravates age-related decline and mortality. However, it remains unclear whether circadian enhancement can retard aging in mammals. We previously reported that the small molecule Nobiletin (NOB) activates ROR (retinoid acid receptor-related orphan receptor) nuclear receptors to potentiate circadian oscillation and protect against metabolic dysfunctions. Here we show that NOB significantly improves metabolic fitness in naturally aged mice fed with a regular diet (RD). Furthermore, NOB enhances healthy aging in mice fed with a high-fat diet (HF). In HF skeletal muscle, the NOB-ROR axis broadly activates genes for mitochondrial respiratory chain complexes (MRCs) and fortifies MRC activity and architecture, including Complex II activation and supercomplex formation. These mechanisms coordinately lead to a dichotomous mitochondrial optimization, namely increased ATP production and reduced ROS levels. Together, our study illustrates a focal mechanism by a clock-targeting pharmacological agent to optimize skeletal muscle mitochondrial respiration and promote healthy aging in metabolically stressed mammals.

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PMID: 

J Nat Med. 2018 Jan ;72(1):274-279. Epub 2017 Nov 17. PMID: 29147836

Abstract Title: 

Effects of saffron and its constituents, crocin-1, crocin-2, and crocetin on α-synuclein fibrils.

Abstract: 

Saffron, the stigma of Crocus sativus Linné (Iridaceae family), has been known to inhibit aggregation of β-amyloid, a nerve tissue protein. α-Synuclein (αS) is a 140-amino acid protein found abundantly in various regions of the brain. Its abnormal aggregation and accumulation in nerve tissue are said to cause neurodegenerative diseasessuch as Parkinson's disease, Lewy body dementia, and multiple-system atrophy. This study (part of this study was presented at the 137th Annual Meeting of the Pharmaceutical Society of Japan) examined the effects of saffron, its constituents (crocin-1, crocin-2, crocetin, and safranal), and crocetinstructural analogs (hexadecanedioic acid, norbixin, and trans, trans-muconic acid) on αS aggregation, and αS fibril dissociation. Saffron dose-dependently inhibited αS aggregation and dissociated αS fibrils by thioflavin T fluorescence assay. These effects were observed by transmission electronmicroscopy, which showed reduced and shortened αS fibrils. Crocin-1, crocin-2, and crocetin showed anti-aggregation and fibril dissociation effects, with crocetin being the most potent. The effects of norbixin were weaker than those of crocetin, and the other crocetin structural analogs showed no effects. These results show that saffron and its constituents (crocin-1, crocin-2, and crocetin) can be effective in preventing and treating diseases caused by abnormal αS aggregation.

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PMID: 

Curr Drug Deliv. 2018 ;15(5):698-704. PMID: 29189153

Abstract Title: 

Antiviral Effects of Saffron and its Major Ingredients.

Abstract: 

BACKGROUND: The lack of an effective vaccine against viral infections, toxicity of the synthetic anti-viral drugs and the generation of resistant viral strains led to discover novel inhibitors. Recently, saffron and its compounds were used to treat different pathological conditions.METHOD: In this study, we tested the anti-HSV-1 and anti-HIV-1 activities of Iranian saffron extract and its major ingredients including crocin and picrocrocin as well as cytotoxicity in vitro. The data showed that the aqueous saffron extract was not active against HIV-1 and HSV-1 virions at certain doses (i.e., a mild activity), but crocin and picrocrocin indicated significant anti-HSV-1 and also anti-HIV-1 activities. Crocin inhibited the HSV replication at before and after entry of virions into Vero cells. Indeed, crocin carotenoid suppressed HSV penetration in the target cells as well as disturbed virus replication after entry into the cells. Picrocrocin was also effective for inhibiting virus entry and also its replication.RESULTS: This monoterpen aldehyde showed higher anti-HSV effects after virus penetrating in the cells. Generally, these sugar-containing compounds extracted from saffron showed to be effective antiherpetic drug candidates.CONCLUSION: The recent study is the first report suggesting antiviral activities for saffron extract and its major ingredients. Crocin and picrocrocin could be a promising anti-HSV and anti-HIV agent for herbal therapy against viral infections.

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PMID: 

J Biomed Res. 2017 11 1. Epub 2017 Nov 1. PMID: 29219852

Abstract Title: 

Dietary Crocin Reverses Melanoma Metastasis.

Abstract: 

Crocus sativus and its bioactive constituent crocin are well known for anti-tumor potential in different models. However, the efficacy of crocin on in-vivo melanoma metastasis is not yet reported. In this study, melanoma metastatic model was developed by tail vein injection of B16F-10 cells in to C57BL/6 mice. Metastatic mice treated with two different doses of crocin (250 and 500µg/kg of bodyweight) for 10 days and parameters such as lung metastasis inhibition, mean survival time, lung hydroxyproline, uronic acid and hexosamine levels were analyzed after 21 days of treatment. Then blood was collected and serum gamma glutamyl transpeptidase (g-GGT), sialic acid, tumor necrosis factor alpha (TNF-a), interleukin 10 (IL-10), IL-6, IL-2, and TIMP-1 levels were measured. Further, a lung histological examination was done in crocin treated metastatic mice. Subsequently hallmark metastatic parameters such as matrix metalloproteases (MMPs), extracellular regulated kinase 2 (ERK2), vascular endothelial growth factor (VEGF), and K-ras gene expression were investigated in the lungs of crocin treated metastatic mice. Further, in-vitro adhesion, invasion and migration of B16F-10 cells were examined after 24 h of crocin (5 and 10 µg/mL) treatment. Administration of crocin totumor bearing C57BL/6 mice reduced the lung metastasis by 85%. Elevated levels of hydroxyproline, uronic acid, hexosamine, serum sialic acid andg-GGT in metastatic control were found to be significantly reduced in crocin treated mice. Crocin also inhibited expression of MMP-2, MMP-9, ERK-2, K-ras, and VEGF. Crocin reduced the ability of B16F-10 cells invasion (p

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