Shakti Prasad Pattanayak

Phytoestrogens in postmenopausal indications: A theoretical perspective.

This review discusses plant-derived compounds with estrogenic activity. The authors rightly emphasize the need for the intake of foods containing phytoestrogens in view of their positive effects on postmenopausal indications. This is particularly significant in the light of the current wave of enthusiasm for vegetarian food, in general, and phytoestrogens, in particular. Phytoestrogens are plant-derived hormone-like diphenolic compounds of dietary origin. These compounds are weakly estrogenic and could play a role in the prevention of other estrogen-related conditions, namely, cardiovascular diseases, menopausal symptoms, postmenopausal osteoporosis, neuroprotective effects, and hormone-dependent cancers (breast and endometrium cancer).

mTOR Activation Promotes Plasma Cell Differentiation and Bypasses XBP-1 for Immunoglobulin Secretion

ABSTRACT Plasma cells (PCs) are responsible for the secretion of antibodies. The development of fully functional PCs relies on the activation of the inositol-requiring enzyme 1/X-box binding protein 1 (IRE1/XBP-1) arm of the unfolded protein response (UPR). XBP-1-deficient PCs secrete antibodies poorly and exhibit distensions of the endoplasmic reticulum (ER). The kinase mammalian target of rapamycin (mTOR) promotes anabolic activities and is negatively regulated by the tuberous sclerosis complex (TSC). Deletion of TSC1 renders mTOR hyperactive. To explore the relationship between mTOR and the UPR in PC development and function, mice with conditional deletions of XBP-1 and/or TSC1 in their B cell lineage were generated. Deletion of TSC1 enhanced Ig synthesis and promoted differentiation into PCs independently of XBP-1, as evidenced by comparison of TSC1/XBP-1 double-knockout (DKO) PCs to XBP-1 knockout (KO) PCs. The typical morphological abnormalities of the ER in XBP-1 KO PCs were alleviated in the DKO PCs. Expression profiling identified the glycoprotein Ly6C as an mTOR target. Ly6C expression contributed to the enhanced Ig secretion from DKO PCs. Our data reveal a functional overlap between mTOR and the UPR in promoting PC development. In addition to the classical mTOR role in promoting protein synthesis, the mechanism entails transcription regulation of accessory molecules, such as Ly6C.

Effect of Dendrophthoe falcata (L.f.) Ettingsh on female reproductive system in Wistar rats: a focus on antifertility efficacy ☆

BACKGROUND This study was designed to assess the effect of one traditionally used antifertility plant, Dendrophthoe falcata (L.f.) Ettingsh (Loranthaceae), on female reproductive system, fertility and safety, by oral administration to adult female Wistar rats. STUDY DESIGN After the oral acute toxicity study, the hydroalcoholic extract of the aerial parts was administered at three doses. Treatment started at weaning and continued until Day 0 postpartum. RESULTS The LD(50) value was found to be 4.55 g/kg body weight. Vaginal opening occurred earlier in treated females when compared with controls. Analysis of vaginal smears revealed that all animals were cycling, although the length of the diestrus was longer in treated groups. In postcoital testing, the extract was found to be more effective in causing significant anti-implantation activity and reduction in the number of litters born. The extract also exhibited weak estrogenic activity when given alone, and when given along with ethinyl estradiol, it exhibited slight antiestrogenic activity in immature ovariectomized rats. CONCLUSION All observations suggest that the extract has antifertility effect and is safe at effective doses employed in the study.

A review on Cressa cretica Linn.: A halophytic plant

Herbal medicine is used by up to 80% of the population in developing countries. Cressa cretica L. is a popular holophytic plant and is used in folklore medicine for ailments including diabetes, ulcers, asthma, anthelmintic, stomachic, tonic and aphrodisiac purposes, enriches the blood, and is useful in constipation, leprosy, and urinary discharges. The plant is traditionally used in Bahrain as expectorant and antibilious agent. Scientific evidence suggests its versatile biological functions such as its antibacterial, antifungal, antitussive, anticancer with some other plants, anti-inflammatory, and improving testicular function in rats. In this article, a comprehensive account of the morphology, phytochemical constituents, ethnobotany, and biological activities are included in view of the recent findings of importance on the plant, C. cretica.

Daphnetin inhibits TNF-α and VEGF-induced angiogenesis through inhibition of the IKKs/IκBα/NF-κB, Src/FAK/ERK1/2 and Akt signalling pathways.

Coumarins, identified as plant secondary metabolites possess diverse biological activities including anti‐angiogenic properties. Daphnetin (DAP), a plant derived dihydroxylated derivative of coumarin has shown significant pharmacological properties such as anticancer, anti‐arthritic and anti‐inflammatory. The present study was performed to investigate the anti‐angiogenic potential of DAP, focusing on the mechanism of action. The in vivo anti‐angiogenic potential of DAP was evaluated by vascular endothelial growth factor (VEGF)‐induced rat aortic ring (RAR) assay and chick chorioallantoic membrane (CAM) assay. For in vitro evaluation, wounding migration, transwell invasion, tube formation and apoptosis assays were performed on VEGF (8 ng/mL)‐induced human umbilical vein endothelial cells (HUVECs). The cellular mechanism of DAP was examined on TNFα (10 ng/mL) and VEGF‐induced HUVECs by extracting the mRNA and protein levels using RT‐qPCR and western blotting. Our data demonstrated that DAP inhibited the in vivo angiogenesis in the RAR and CAM assay. DAP also inhibited the different steps of angiogenesis, such as migration, invasion, and tube formation in HUVECs. DAP inhibited nuclear factor‐κB signalling together including TNF‐α induced IκBα degradation; phosphorylation of IκB kinase (IKKα/β) and translocation of the NF‐κB‐p65 protein. Furthermore, western blotting revealed that DAP significantly down‐regulated the VEGF‐induced signalling such as c‐Src, FAK, ERK1/2 and the related phosphorylation of protein kinase B (Akt) and VEGFR2 expressions. DAP reduced the elevated mRNA expression of iNOS, MMP2 and also, induced apoptosis in VEGF‐stimulated HUVECs by the caspase‐3 dependent pathway. Taken together, this study reveals that DAP may have novel prospective as a new multi‐targeted medication for the anti‐angiogenesis and cancer therapy.

Daphnetin ameliorates 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis through Nrf-2-Keap1 and NF-κB pathways

Cancer is a faction of disorders that conjugated primarily with oxidative imbalance. In mammary carcinoma, oxidative stress secondarily changes various gene expressions and signalling pathways that bring genomic instability and mutagenic alterations that fascinating carcinogenesis. Several coumarin compounds are active against various malignancies. Among them, daphnetin (DAP) exhibits valuable safety and bioactivity profile that contributes towards its efficacy against cancer. In this study, the antioxidative and chemotherapeutic potential of DAP against 7,12-dimethylbenz(a)anthracene (DMBA)- induced mammary carcinogenesis was evaluated in female Sprague-Dawley rats. Besides this, we have determined the effect of DAP on Keap1-Nrf-2, associated HO-1 and NF-κB expressions behind the antioxidative and anti-proliferating activity. In our findings, a protective effect of DAP was established against lipid peroxidation, enzymic (Total SOD, MnSOD, CuZnSOD, CAT, GPx) and non-enzymic (GSH) antioxidative markers in serum, liver, kidney and breast tissue of both control and experimental groups. An up-regulation of protective Nrf-2 & HO-1 with a synchronized suppression in Keap1 & NF-κB mRNA and protein expressions were observed. DAP revealed the inhibition of p-AKT which accountable for decrease in NF-κB expressions but shown to be ineffective on p-ERK1/2. This study revealed that DAP inhibits mammary carcinogenesis through multiple mechanisms. Dual efficacy of DAP on Nrf-2-Keap1 pathway and NF-κB expressions propose it as a potential chemotherapeutic agent in mammary cancer management.

Bronchodilatory and mast cell stabilising activity of Cressa cretica L. : Evaluation through in vivo and in vitro experimental models

OBJECTIVE To evaluate the effect of ethylacetate fraction (Fr-Et) and methanolic fraction (Fr-Me) obtained from Cressa cretica L.(C. cretica) L. on experimental models for bronchodilatory activity and mast cell stabilising activity. METHODS The effect of Fr-Et and Fr-Me were studied on acetylcholine and histamine aerosol-induced broncospasm using guinea pigs as experimental animals. Also, the effects of these fractions were evaluated on the isolated guinea pig tracheal preparations. Besides this mast cell degranulation effect was assessed using egg albumin and compound 48/80 on rat peritoneal mast cells. RESULTS Significant increase in preconvulsion time was observed due to pretreatment with the fractions when guinea pigs were exposed to histamine and acetylcholine aerosol. Fr-Et and Fr-Me significantly increased the preconvulsion in a dose depended manner that suggestive of bronchodilating activity. Fr-Et and Fr-Me exhibited a significant concentration dependant relaxant effect on guinea pig trachea pre-contracted with CCh, K(+) and histamine. The results revealed that Fr-Et to be more potent than Fr-Me in relaxing histamine and K(+) and calcium induced contraction than CCh induced contractions. Studies on the fractions in protecting mast cell degranulation, which were elicited by the egg albumin as well as synthetic compound 48/80 revealed both the fractions significantly protect the mast cell degranulation, which release mediators such as histamine and proinflammatory cytokines through various stimuli in a dose depended manner. CONCLUSIONS Thus our study established the bronchodilator activity, and mast cell stabilizing activity which are important mediators that provoke or sustain in asthma.

Wound healing activity of silibinin in mice

Background: Silibinin is a semi-purified fraction of silymarin contained in milk thistle (Silybum marianum Asteraceae). Primarily known for its hepatoprotective actions, silymarin may also stimulate epithelialization and reduce inflammation in excision wound. Previous studies show antioxidant, anti-inflammatory, and antimicrobial actions of silibinin. However, wound healing property of silibinin is not well studied. Objective: This study investigates wound healing activity of silibinin topical formulation. Materials and Methods: Wound healing activity of 0.2% silibinin gel was assessed by incision and excision wound models in mice. Animals were divided into gel base, silibinin gel, and Mega Heal gel® treated groups with six animals in each group. Wound contraction, wound tissue tensile strength, and hydroxyproline content were measured, and histopathological evaluation of wound tissue of all the above treatment groups was carried out. Results: Application of 0.2% silibinin hydrogel for 8 days led to 56.3% wound contraction compared to 64.6% using standard Mega Heal gel with a subsequent increase in hydroxyproline content, which was significantly higher (P < 0.001) over control animals showing 33.2% contraction. After 14 days, percentage of contraction reached 96.1%, 97.6%, and 86.7%, respectively. Wound tissue tensile strength with silibinin (223.55 ± 3.82 g) and standard (241.38 ± 2.49 g) was significantly higher (P < 0.001) than control (174.06 ± 5.75 g). Histopathology of silibinin and standard gel treated wound tissue showed more fibroblasts, fewer macrophage infiltration, and well-formed collagen fibers. Conclusion: Here, we show potent wound healing activity of silibinin hydrogel formulation.

Silibinin Inhibits the Hepatocellular Carcinoma in NDEA-Induced Rodent Carcinogenesis Model: An Evaluation through Biochemical and Bio-Structural Parameters

The present study was aimed to investigate the chemopreventive potential of Silibinin (SIB) against N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinoma (HCC) in wistar rats. Thirty experimental animals were subjected to partial hepatectomy (PH) and after 24 hours of stabilization period a single dose of NDEA (100 mg/kg b.w., i.p) was administered to each animal followed by CCl4 (1 ml/kg b.w., s.c.). The effect of SIB (25 and 50 mg/kg/day, i.p.) on NDEA-induced HCC was determined after 2 weeks of treatment (6th to 8th week after PH, in the promotional stage of tumor development). NDEA treatment to rats resulted in significant decrease in body weight and increase in liver weight along with levels of transaminases, γ-glutamyl transferase, lipoprotein, glycoproteins. Hepatic and serum malondialdehyde content, enzymatic and non-enzymatic antioxidant levels were also altered in HCC bearing animals without treatment. Bio-structural components (such as amide bands of proteins, symmetric phosphate stretching of nucleic acids, methylene chains in membrane lipids, methyl to methylene ratio of carbohydrates and proteins etc.) were marked in NDEA-treated groups of animals by analysing changes in the position and intensities of the peaks in Fourier transform infrared spectroscopy (FTIR). Immunohistochemical staining of Ki67 and histopathological analysis were also carried out in order to support the study. SIB treatment could attenuate NDEA-induced hepatocarcinogenesis by improving the biochemical and bio-structural changes of the hepatic tissue near normal levels in a dose dependent manner. Taken together, this study reveals that SIB may have potential as a multi-functional drug candidate for cancer therapy.

mTORC1 activation in B cells confers impairment of marginal zone microarchitecture by exaggerating cathepsin activity

Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell metabolism and lymphocyte proliferation. It is inhibited by the tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2. Deletion of either gene results in robust activation of mTORC1. Mature B cells reside in the spleen at two major anatomical locations, the marginal zone (MZ) and follicles. The MZ constitutes the first line of humoral response against blood‐borne pathogens and undergoes atrophy in chronic inflammation. In previous work, we showed that mice deleted for TSC1 in their B cells (TSC1BKO) have almost no MZ B cells, whereas follicular B cells are minimally affected. To explore potential underlying mechanisms for MZ B‐cell loss, we have analysed the spleen MZ architecture of TSC1BKO mice and found it to be severely impaired. Examination of lymphotoxins (LTα and LTβ) and lymphotoxin receptor (LTβR) expression indicated that LTβR levels in spleen stroma were reduced by TSC1 deletion in the B cells. Furthermore, LTα transcripts in B cells were reduced. Because LTβR is sensitive to proteolysis, we analysed cathepsin activity in TSC1BKO. A higher cathepsin activity, particularly of cathepsin B, was observed, which was reduced by mTORC1 inhibition with rapamycin in vivo. Remarkably, in vivo administration of a pan‐cathepsin inhibitor restored LTβR expression, LTα mRNA levels and the MZ architecture. Our data identify a novel connection, although not elucidated at the molecular level, between mTORC1 and cathepsin activity in a manner relevant to MZ dynamics.