MicroRNA signature of stromal-epithelial interactions in prostate and breast cancers.

Stromal-epithelial communication is an absolute necessity when it comes to the morphogenesis and pathogenesis of solid tissues, including the prostate and breast. So far, signalling pathways of several growth factors have been investigated. Besides such chemical factors, non-coding RNAs such as miRNAs have recently gained much interest because of their variety and complexity of action. Prostate and breast tissues being highly responsive to steroid hormones such as androgen and estrogen, respectively, it is not surprising that a huge set of available literature critically investigated the interplay between such hormones and miRNAs, especially in carcinogenesis. This review showcases our effort to highlight hormonally-related miRNAs that also somehow perturb the regular stromal-epithelial interactions during carcinogenesis in the prostate and breast. In future, we look forward to exploring how hormonal changes in the tissue microenvironment bring about miRNA-mediated changes in stromal-epithelial interactome in carcinogenesis and cancer progression.

Naringenin-Zinc Oxide Nanocomposites Amalgamated Polymeric Gel Augmented Drug Delivery and Attenuated Experimental Cutaneous Candidiasis in Balb/c Mice: In Vitro and In Vivo Studies.

Naringenin (NRG) inhibits the fungal 17ß-hydroxysteroid dehydrogenase accountable for ergosterol synthesis in Candida albicans (C. albicans), a causative agent for cutaneous candidiasis. In present research, NRG was complexed with ZnO nanomaterial (NRG-Zn2+) to synthesize NRG-Zn2+ nanocomposites. The particle size and ζ-potential of NRG-Zn2+ nanocomposites were respectively estimated to be 180.33 ± 1.22-nm and - 3.92 ± 0.35-mV. In silico data predicted the greater affinity of NRG-Zn2+ nanocomposite for 14α-demethylase and ceramide in comparison to NRG alone. Later, NRG-Zn2+ nanocomposites solution was transformed in to naringenin-zinc oxide nanocomposites loaded chitosan gel (NRG-Zn-CS-Gel) with viscosity and firmness of 854806.7 ± 52386.43 cP and 698.27 ± 10.35 g, respectively. The ex-vivo skin permeation demonstrated 70.49 ± 5.22% skin retention, significantly greater (P < 0.05) than 44.48 ± 3.06% of naringenin loaded chitosan gel (NRG-CS-Gel) and 31.24 ± 3.28% of naringenin solution (NRG Solution). NRG-Zn-CS-Gel demonstrated 6.71 ± 0.84% permeation of NRG with a flux value of 0.046 ± 0.01-µg/cm2/h. The MIC50 of NRG-Zn-CS-Gel against C. albicans was estimated to be 0.156-µg/mL with FICI (fractional inhibitory concentration index) of 0.018 that consequently exhibited synergistic efficacy. Further, NRG-Zn-CS-Gel demonstrated superior antifungal efficacy in C. albicans induced cutaneous candidiasis infection in Balb/c mice. The fungal burden in NRG-Zn-CS-Gel treated group was 109 ± 25 CFU/mL, significantly lower (P < 0.05) than positive control (2260 ± 446 CFU/mL), naringenin loaded chitosan gel (NRG-CS-Gel; 928 ± 127 CFU/mL) and chitosan gel (CS-Gel; 2116 ± 186 CFU/mL) treated mice. Further, histopathology examination and cytokine profiling of TNF-α, IL-1ß and IL-10 revealed the healing of skin and inflammation associated with cutaneous candidiasis infection. In conclusion, NRG-Zn-CS-Gel may be a potential candidate for translating in to a clinical viable topical nanotherapeutic.

Multistrain probiotic rescinds quinpirole-induced obsessive-compulsive disorder phenotypes by reshaping of microbiota gut-brain axis in rats.

Obsessive-compulsive disorder (OCD) is a disabling mental condition that poses recurring bothersome intrusive thoughts, obsessions, and compulsions. Considering the positive impact of probiotics on neuropsychiatric disorders, herein, we investigated the effect of multistrain probiotic (Bifidobacterium lactis UBBLa-70, Bacillus coagulans Unique IS-2, Lactobacillus rhamnosus UBLR-58, Lactobacillus plantarum UBLP-40, Bifidobacterium infantis UBBI-01, Bifidobacterium breve UBBr-01, and glutamine) in the management of OCD-like phenotype in rats. Rats injected with quinpirole for 5 weeks showed an increased number of marble burying and self-grooming episodes. Quinpirole-injected animals also did less head dipping in the hole board test and avoided exploration of open spaces in the elevated-plus maze. These repetitive, compulsive, self-directed, and anxiety-like phenotypes were abolished after 8-week of multistrain probiotic treatment. The probiotic formulation also prevented the elevated mRNA expression of interleukin-6, tumor-necrosis factor-α, and C-reactive protein in the amygdala and dysregulated levels of 5-hydroxytryptamine, dopamine, and noradrenaline in the frontal cortex of quinpirole-injected rats. The level of brain-derived neurotrophic factor in the frontal cortex remained unaffected across the groups. The altered levels of goblet cells and crypt-to-villi ratio in quinpirole rats were prevented by multistrain probiotic treatment. The results of 16S-rRNA gene-sequencing of gut microbiota from feces contents revealed an elevation in the abundance of Allobaculum and Bifidobacterium species (specifically Bifidobacterium animalis), while the presence of Lactobacillus species (including Lactobacillus reuteri and Lactobacillus vaginalis) exhibited a decline in quinpirole-induced rats. These results imply that modifying the gut-brain axis may be a possible mechanism by which selective multistrain probiotic therapy prevents OCD-like behaviors.

Multistrain Probiotics with Fructooligosaccharides Improve Middle Cerebral Artery Occlusion-Driven Neurological Deficits by Revamping Microbiota-Gut-Brain Axis.

Recent burgeoning literature unveils the importance of gut microbiota in the neuropathology of post-stroke brain injury and recovery. Indeed, ingestion of prebiotics/probiotics imparts positive effects on post-stroke brain injury, neuroinflammation, gut dysbiosis, and intestinal integrity. However, information on the disease-specific preference of selective prebiotics/probiotics/synbiotics and their underlying mechanism is yet elusive. Herein, we examined the effect of a new synbiotic formulation containing multistrain probiotics (Lactobacillus reuteri UBLRu-87, Lactobacillus plantarum UBLP-40, Lactobacillus rhamnosus UBLR-58, Lactobacillus salivarius UBLS-22, and Bifidobacterium breve UBBr-01), and prebiotic fructooligosaccharides using a middle cerebral artery occlusion (MCAO) model of cerebral ischemia in female and male rats. Three weeks pre-MCAO administration of synbiotic rescinded the MCAO-induced sensorimotor and motor deficits on day 3 post-stroke in rotarod, foot-fault, adhesive removal, and paw whisker test. We also observed a decrease in infarct volume and neuronal death in the ipsilateral hemisphere of synbiotic-treated MCAO rats. The synbiotic treatment also reversed the elevated levels/mRNA expression of the glial fibrillary acidic protein (GFAP), NeuN, IL-1ß, TNF-α, IL-6, matrix metalloproteinase-9, and caspase-3 and decreased levels of occludin and zonula occludens-1 in MCAO rats. 16S rRNA gene-sequencing data of intestinal contents indicated an increase in genus/species of Prevotella (Prevotella copri), Lactobacillus (Lactobacillus reuteri), Roseburia, Allobaculum, and Faecalibacterium prausnitzii, and decreased abundance of Helicobacter, Desulfovibrio, and Akkermansia (Akkermansia muciniphila) in synbiotic-treated rats compared to the MCAO surgery group. These findings confer the potential benefits of our novel synbiotic preparation for MCAO-induced neurological dysfunctions by reshaping the gut-brain-axis mediators in rats.

Synthesis and Biological Evaluation of 2-(Halophenyl)benzoxazole-5-Carboxylic Acids as Potential Anti-Inflammatory and Cytotoxic Agent with Molecular Docking Studies.

2-Halogenatedphenyl benzoxazole-5-carboxylic acids with mono-halogen (chloro, bromo and fluoro) substituted at ortho-, meta- and para-positions on the phenyl ring were designed and synthesized based on significance of presence of halogen in increasing number of marketed halogenated drugs and importance of benzoxazoles. These 2-alogenatedphenylbenzoxazole-5-carboxylic acids and their methyl esters were screened for anti-inflammatory activity, and cytotoxicity. 2-(3-Chlorophenyl)benzoxaole-5-carboxylic acid (6b) exhibited significant anti-inflammatory activity with IC50 values of 0.103 mM almost equivalent to the standard drug ibuprofen (0.101 mM). 2-(4-Chlorophenyl)benzoxaole-5-carboxylic acid (6c) showed excellent cytotoxic activity against 22Rv1 cells (human prostate carcinoma epithelial cell lines) with IC50 value of 1.54 µM better than that of standard drug doxorubicin having IC50 value of 2.32 µM. More importantly, the selectivity index of this potential molecule was found to be 57.74. Molecular docking analysis resulted in good binding interactions of these compounds with their respective biochemical targets viz. Cyclooxygenase-2 and aldo-keto reductase IC3.

Synthesis of indolo/pyrroloazepinone-oxindoles as potential cytotoxic, DNA-intercalating and Topo I inhibitors.

A series of 17 indolo/pyrroloazepinone-oxindole conjugates was synthesized and evaluated for their antiproliferative activity against a panel of selected human cancer cell lines including A549 (lung cancer), HCT116 (colon cancer), MCF7 (breast cancer), and SK-MEL-28 (melanoma). Among the synthesized molecules (14a-m and 15a-d), compound 14d displayed remarkable activity against A549, HCT116 and SK-MEL-28 cells with IC50 values < 4 µM with the best cytotoxicity and a 13-fold selectivity towards lung cancer cells (IC50 value of 2.33 µM) over the normal rat kidney cells (NRK). Further, 14d-mediated apoptosis affected the cellular and nuclear morphology of the cancer cells in a dose-dependent manner. Wound healing and clonogenic assays inferred the inhibition of cell growth and migration. Target-based studies of compound 14d corroborated its DNA-intercalative capability and Topo I inhibitory activity which have been fortified by molecular modeling studies. Finally, the drug-likeness of the potent compound was determined by performing in silico ADME/T prediction studies.

Role of dietary flavonoids in amelioration of sugar induced cataractogenesis.

Sugar induced cataractogenesis and visual impairment is more prominent ophthalmic problem in humans suffering from diabetes. Flavonoids have been identified as one of the therapeutically important class of phytochemicals possessing myriad of biological activities. Analyzing the anti-cataract effects of flavonoids from natural sources is an important aspect owing to their bioavailability in variety of dietary sources. In the present study a panel of ten dietary flavonoids like 3, 6-dihydroxy flavone, 3, 7-dihydroxy flavone, chrysin, 3-hydroxy-7-methoxy flavone, apigenin, genistein, baicalein, galangin, Biochanin-A, and diosmin were evaluated for their anti-cataract effects in sugar induced lens model studies. Series of parameters like role of flavonoids in glycation induced lens opacity, protein aggregation measurements, carbonyl group formation: a biochemical marker of glycation reaction, non-tryptophan fluorescence: a marker of formation of advanced glycation end products (AGEs) and assessment of (experimental and in silico) aldose reductase inhibition: a key enzyme of polyol pathway involved in cataractogenesis. The results of the study clearly demonstrated the impressive anti-cataract activity of chrysin followed by significant activity by apigenin, baicalein and genistein. The results of the present study may find applications in formulation of functional foods and neutraceuticals for the management of diabetic cataract.

Comprehensive analyses of genomes, transcriptomes and metabolites of neem tree.

Neem (Azadirachta indica A. Juss) is one of the most versatile tropical evergreen tree species known in India since the Vedic period (1500 BC-600 BC). Neem tree is a rich source of limonoids, having a wide spectrum of activity against insect pests and microbial pathogens. Complex tetranortriterpenoids such as azadirachtin, salanin and nimbin are the major active principles isolated from neem seed. Absolutely nothing is known about the biochemical pathways of these metabolites in neem tree. To identify genes and pathways in neem, we sequenced neem genomes and transcriptomes using next generation sequencing technologies. Assembly of Illumina and 454 sequencing reads resulted in 267 Mb, which accounts for 70% of estimated size of neem genome. We predicted 44,495 genes in the neem genome, of which 32,278 genes were expressed in neem tissues. Neem genome consists about 32.5% (87 Mb) of repetitive DNA elements. Neem tree is phylogenetically related to citrus, Citrus sinensis. Comparative analysis anchored 62% (161 Mb) of assembled neem genomic contigs onto citrus chromomes. Ultrahigh performance liquid chromatography-mass spectrometry-selected reaction monitoring (UHPLC-MS/SRM) method was used to quantify azadirachtin, nimbin, and salanin from neem tissues. Weighted Correlation Network Analysis (WCGNA) of expressed genes and metabolites resulted in identification of possible candidate genes involved in azadirachtin biosynthesis pathway. This study provides genomic, transcriptomic and quantity of top three neem metabolites resource, which will accelerate basic research in neem to understand biochemical pathways.

De novo Transcriptome Sequencing and Development of Abscission Zone-Specific Microarray as a New Molecular Tool for Analysis of Tomato Organ Abscission.

Abscission of flower pedicels and leaf petioles of tomato (Solanum lycopersicum) can be induced by flower removal or leaf deblading, respectively, which leads to auxin depletion, resulting in increased sensitivity of the abscission zone (AZ) to ethylene. However, the molecular mechanisms that drive the acquisition of abscission competence and its modulation by auxin gradients are not yet known. We used RNA-Sequencing (RNA-Seq) to obtain a comprehensive transcriptome of tomato flower AZ (FAZ) and leaf AZ (LAZ) during abscission. RNA-Seq was performed on a pool of total RNA extracted from tomato FAZ and LAZ, at different abscission stages, followed by de novo assembly. The assembled clusters contained transcripts that are already known in the Solanaceae (SOL) genomics and NCBI databases, and over 8823 identified novel tomato transcripts of varying sizes. An AZ-specific microarray, encompassing the novel transcripts identified in this study and all known transcripts from the SOL genomics and NCBI databases, was constructed to study the abscission process. Multiple probes for longer genes and key AZ-specific genes, including antisense probes for all transcripts, make this array a unique tool for studying abscission with a comprehensive set of transcripts, and for mining for naturally occurring antisense transcripts. We focused on comparing the global transcriptomes generated from the FAZ and the LAZ to establish the divergences and similarities in their transcriptional networks, and particularly to characterize the processes and transcriptional regulators enriched in gene clusters that are differentially regulated in these two AZs. This study is the first attempt to analyze the global gene expression in different AZs in tomato by combining the RNA-Seq technique with oligonucleotide microarrays. Our AZ-specific microarray chip provides a cost-effective approach for expression profiling and robust analysis of multiple samples in a rapid succession.

Incidence of metabolic syndrome and its characteristics of patients attending a diabetic outpatient clinic in a tertiary care hospital.

OBJECTIVE: We sought to evaluate the incidence of metabolic syndrome and non-metabolic syndrome among type 2 diabetic patients attending the diabetic outpatient clinic at tertiary care hospital, Warangal. MATERIALS AND METHODS: A cross-sectional study was conducted in a period of 6 months from January 2011 to June 2011. The study group consisted of 75 type 2 diabetic patients. They were screened for hypertension, hyperlipidemia, obesity, and clinical characteristics, and other co-morbidities were recorded. Metabolic syndrome diagnosis was made as per ATP III guidelines. RESULTS: The prevalence of metabolic syndrome was significant in men (54.8%) compared to women (45.2%). Incidence of metabolic syndrome was found to be more in normal weight patients (43.56%). Low high density lipoprotein (HDL) levels were observed in both rural (90.63%) and urban (95.65%) patients with metabolic syndrome, followed by increase in waist circumference. The mean HDL level was found to be 23.77 mg/dl. Patients in the age group 51-60 years were found to be more affected with metabolic syndrome. Sedentary household female patients (58.3%) and illiterates (41.8%) were suffering from metabolic syndrome. Patients with metabolic syndrome had been suffering with diabetes (duration of diabetes) from 1 to 5 years. In summary, this cross-sectional study characterizes the metabolic and non-metabolic syndromes of type 2 diabetes patients living in Telangana regions, using ATP III guidelines, and generates a biological resource that enables further investigation of numerous hypotheses related to genetic exposure of both in a population. CONCLUSION: These results suggest that higher prevalence of metabolic syndrome was observed in non-obese male patients and was significantly associated with aging. Nevertheless, further studies are required to confirm the metabolic syndrome in larger population.

Synthesis of novel carbazole chalcones as radical scavenger, antimicrobial and cancer chemopreventive agents.

A series of novel carbazole chalcones has been synthesised and evaluated for radical scavenging activity, cytotoxicity and antimicrobial activities. Compounds 12m, 12o and 12c exhibited good 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, compounds 12e, 12m and 12d were excellent hydroxyl radical scavengers and compounds 12a, 12e, 12g, 12n and 12m have shown inhibition of oxidative DNA damage induced by 2,2'-azobis (2-amidinopropane hydrochloride). Compounds 12j, 12i, 12n, 12c, 12m and 12e were most active against the selected cancer cell lines. Compounds 12a, 12e and 12m showed good antibacterial activity and compounds 12h and 12m have shown good antifungal activity. All the compounds were subjected for absorption, distribution, metabolism and excretion (ADME) predictions by computational method and found that these molecules could be considered as potential candidates for oral drug development.

Microcapsules with a pH responsive polymer: influence of the encapsulated oil on the capsule morphology.

Microcapsules were prepared by microsieve membrane cross flow emulsification of Eudragit FS 30D/dichloromethane/edible oil mixtures in water, and subsequent phase separation induced by extraction of the dichloromethane through an aqueous phase. For long-chain triglycerides and jojoba oil, core-shell particles were obtained with the oil as core, surrounded by a shell of Eudragit. Medium chain triglyceride (MCT oil) was encapsulated as relatively small droplets in the Eudragit matrix. The morphology of the formed capsules was investigated with optical and SEM microscopy. Extraction of the oil from the core-shell capsules with hexane resulted in hollow Eudragit capsules with porous shells. It was shown that the differences are related to the compatibility of the oils with the shell-forming Eudragit. An oil with poor compatibility yields microcapsules with a dense Eudragit shell on a single oil droplet as the core; oils having better compatibility yield porous Eudragit spheres with several oil droplets trapped inside.

Porous microcapsule formation with microsieve emulsification.

A simple route is presented to prepare core-shell Eudragit microcapsules through a solvent extraction method with the use of microsieve emulsification. Droplets from a solution of Eudragit FS 30D (a commercial copolymer of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1) and hexadecane in dichloromethane are dispersed into water, using a micro-engineered membrane with well-defined pores, in a cross-flow setting. The dichloromethane is extracted from the droplets, which induces demixing in the droplets, leading to a hexadecane-rich core, and an Eudragit-rich shell. The obtained microcapsules have a narrow size distribution due to the microsieve emulsification process. The capsules have a porous shell as shown by SEM and AFM measurements. Their porosity and pore size is dependent on the ratios of Eudragit and hexadecane in the dispersed phase. At pH 7.1 and above Eudragit (FS 30D) dissolves in water; this pH change is used to release the contents of the microcapsule.

Anaesthetic considerations in a patient with right heart thrombi-in-transit.

This is a case report of a patient with underlying pulmonary thromboembolism who was diagnosed as having a large, mobile right heart thrombi while undergoing treatment with low-molecular weight heparin. She underwent emergency embolectomy with exploration of the right heart under a cardiopulmonary bypass (CPB). Soon after induction of anaesthesia, the patient had an episode of severe hypotension, which responded to inotropes. Large, serpiginous thrombi were found in the right atrium extending into the right ventricle and pulmonary arteries, which were evacuated. She was weaned off CPB on inotropic support and was extubated uneventfully on the 4th POD. Postoperatively, she was started on anticoagulant therapy and also underwent placement of a Greenfield inferior vena caval (IVC) filter to prevent further thromboembolic episodes.

Faecal incontinence after lateral internal sphincterotomy is often associated with coexisting occult sphincter defects: a study using endoanal ultrasonography.

BACKGROUND: Troublesome faecal incontinence following a lateral internal sphincterotomy (LIS) is often attributed to faulty surgical techniques: division of excessive amount of internal sphincter or inadvertent injury to the external sphincter. The aim of the present paper was to assess the anatomic and physiological factors that may contribute to faecal incontinence following a technically satisfactory lateral internal sphincterotomy by a group of colorectal specialists. METHODS: Fourteen patients (nine women, five men; median age: 38 years; range: 23-52 years) who developed troublesome postoperative faecal incontinence were evaluated by clinical assessment, endoanal ultrasonography and anorectal physiological studies (manometry, pudendal nerve terminal motor latency) by two independent observers. The Cleveland Clinic continence score (0-20; 0, perfect continence; 20, complete incontinence) was used to quantify the severity of faecal incontinence. Fourteen continent subjects after a LIS (nine female patients, five male patients; median age: 36 years; range: 20-44 years) were also evaluated as 'continent' controls (continence score