Hypoglycemic Potential of Carica papaya in Liver Is Mediated through IRS-2/PI3K/SREBP-1c/GLUT2 Signaling in High-Fat-Diet-Induced Type-2 Diabetic Male Rats.

Regardless of socioeconomic or demographic background, the prevalence of type 2 diabetes mellitus, which affects more than half a billion people worldwide, has been steadily increasing over time. The health, emotional, sociological, and economic well-being of people would suffer if this number is not successfully handled. The liver is one of the key organs accountable for sustaining metabolic balance. Elevated levels of reactive oxygen species inhibit the recruitment and activation of IRS-1, IRS-2, and PI3K-Akt downstream signaling cascade. These signaling mechanisms reduce hepatic glucose absorption and glycogenesis while increasing hepatic glucose output and glycogenolysis. In our work, an analysis of the molecular mechanism of Carica papaya in mitigating hepatic insulin resistance in vivo and in silico was carried out. The gluconeogenic enzymes, glycolytic enzymes, hepatic glycogen tissue concentration, oxidative stress markers, enzymatic antioxidants, protein expression of IRS-2, PI3K, SREBP-1C, and GLUT-2 were evaluated in the liver tissues of high-fat-diet streptozotocin-induced type 2 diabetic rats using q-RT-PCR as well as immunohistochemistry and histopathology. Upon treatment, C. papaya restored the protein and gene expression in the liver. In the docking analysis, quercetin, kaempferol, caffeic acid, and p-coumaric acid present in the extract were found to have high binding affinities against IRS-2, PI3K, SREBP-1c, and GLUT-2, which may have contributed much to the antidiabetic property of C. papaya. Thus, C. papaya was capable of restoring the altered levels in the hepatic tissues of T2DM rats, reversing hepatic insulin resistance.

Carica Papaya Reduces High Fat Diet and Streptozotocin-Induced Development of Inflammation in Adipocyte via IL-1ß/IL-6/TNF-α Mediated Signaling Mechanisms in Type-2 Diabetic Rats.

The prevalence of obesity in contemporary society has brought attention to how serious it is all around the world. Obesity, a proinflammatory condition defined by hypertrophied adipocytes and immune cells that reside in adipose tissue, is characterized by elevated circulating levels of proinflammatory cytokines. The pro-inflammatory mediators trigger a number of inflammatory pathways and affect the phosphorylation of a number of insulin-signaling pathways in peripheral tissues. In this work, we pointed the outcome of the leaves of Carica papaya (C. papaya) on the inflammatory molecules by in vivo and in silico analysis in order to prove its mechanisms of action. Adipocytokines, antioxidant enzymes, gene and protein expression of pro-inflammatory signaling molecules (mTOR, TNF-α, IL-1ß, IL-6 and IKKß) by q-RT-PCR and immunohistochemistry, as well as histopathological analysis, in adipose tissues were carried out. C. papaya reinstated the levels of adipocytokines, antioxidant enzymes and mRNA levels of mTOR, TNF-α, IL-1ß, IL-6 and IKKß in the adipose tissues of type 2 diabetic rats. Molecular docking and dynamics simulation studies revealed that caffeic acid, transferulic acid and quercetin had the top hit rates against IKKß, TNF-α, IL-6, IL-1ß, and mTOR. This study concludes that C. papaya put back the altered effects in fatty tissue of type 2 diabetic rats by restoring the adipocytokines and the gene expression.

Effect of Carica papaya on IRS-1/Akt Signaling Mechanisms in High-Fat-Diet-Streptozotocin-Induced Type 2 Diabetic Experimental Rats: A Mechanistic Approach.

Despite rigorous endeavors, existing attempts to handle type 2 diabetes (T2DM) are still a long way off, as a substantial number of patients do not meet therapeutic targets. Insulin resistance in skeletal muscle is discerned as a forerunner in the pathogenesis of T2DM and can be detected years before its progress. Studies have revealed the antidiabetic properties of Carica papaya (C. papaya), but its molecular mechanism on insulin receptor substrate-1 (IRS-1)/Akt signaling mechanisms is not yet known. The present study aimed to evaluate the role of C. papaya on IRS1 and Akt in high-fat-diet-streptozotocin-induced type 2 diabetic rats and also to analyze the bioactive compounds of C. papaya against IRS-1 and Akt via in silico analysis. Ethanolic extract of the leaves of C. papaya (600 mg/kg of body weight) was given daily for 45 days postinduction of T2DM up to the end of the study. Gluconeogenic enzymes, glycolytic enzymes, gene expression, and immunohistochemical analysis of IRS-1 and Akt in skeletal muscle were evaluated. C. papaya treatment regulated the levels of gluconeogenic and glycolytic enzymes and the levels of IRS-1 and Akt in skeletal muscle of type 2 diabetic animals. In silico studies showed that trans-ferulic acid had the greatest hit rate against the protein targets IRS-1 and Akt. C. papaya restored the normoglycemic effect in diabetic skeletal muscle by accelerating the expression of IRS-1 and Akt.

Carica papaya Reduces Muscle Insulin Resistance via IR/GLUT4 Mediated Signaling Mechanisms in High Fat Diet and Streptozotocin-Induced Type-2 Diabetic Rats.

In the management of type 2 diabetes, oral antidiabetic drugs have several side effects, which in turn have led the pharmaceutical industry to search for good therapeutic, non-toxic and reliable drugs. Carica papaya (C. papaya) is one of several plants in nature that have been found to possess anti-diabetic properties. Despite studies being focused on the antidiabetic activity of C. papaya, the molecular mechanism against high fat diet induced insulin resistance is yet to be identified. The role of C. papaya was evaluated on insulin signaling molecules, such as the insulin receptor (IR) and glucose transporter-4 (GLUT4) in high fat, diet-streptozotocin induced type 2 diabetic rats, and analyzed the bioactive compounds of C. papaya against IR and GLUT4 via molecular docking and dynamics. The ethanolic extract of C. papaya leaves (600 mg/kg of body weight) was given daily to male wistar rats for 45 days and we observed the various biochemical parameters, gene expression analysis and histopathology of skeletal muscle. Molecular docking and dynamics were undertaken to understand the bioactive compounds with the greatest hit rate. C. papaya treatment was able to control blood glucose levels, the lipid profile and serum insulin, but it facilitated tissue antioxidant enzymes and IR and GLUT4 levels. The in-silico study showed that kaempferol, quercitin and transferulic acid were the top three ligands with the greatest hit rate against the protein targets. Our preliminary findings, for the first time, showed that C. papaya reinstates the glycemic effect in the diabetic skeletal muscle by accelerating the expression of IR and GLUT4.

A comprehensive study of mesoappendix and arterial pattern of appendix.

Objectives: The length and the attachment of the mesoappendix is important in the degree of inflammation, spread of tumor and during surgical resection of the appendix. The presence of accessory appendicular artery along with varied origin of appendicular artery may cause intra- as well as post-operative complications. Hence, the study of length of mesoappendix and the origin and branching pattern of arterial supply to the appendix was undertaken. Material and Methods: Sixty formalin fixed appendix specimens were resected along with the intact mesopappendix and were dissected to analyze the extent of attachment, origin of appendicular arteries and the accessory branches as well. Results: The whole length mesoappendix was seen in 76% and the half length mesoappendix was not found. The main appendicular artery originated from the ileocolic artery in 80%, and accessory appendicular artery was seen in 13% of the study specimens. Conclusion: The mesoappendix and the branching pattern of the appendicular artery varies from person to person, and this awareness will be of use during surgeries on appendix.

Chlorpyrifos and its metabolite modulates angiogenesis in the chorioallantoic membrane of chick embryo.

Background Chlorpyrifos (CPF) is an organophosphate insecticide, acaricide, and miticide used primarily to control foliage and soilborne insect pests on a variety of food and feed crops. Since trace amounts of these compounds are found in water and food products, they easily enter into the organ system unnoticed. In the same way, the compound or its metabolite gets transmitted from the parent to the embryo mainly through blood vessels. Since blood vessels form the major route of transport, it is pertinent to study the effect of these compounds during angiogenesis. The effect of CPF and 3,5,6-trichloro-2-pyridinol (TCPy) on the angiogenesis of chick embryo was evaluated in the chorioallantoic membrane (CAM) using an ex vivo model. Methods Nine-day-old incubated eggs where inoculated with various doses of CPF and TCPy. After 48 h of incubation, the CAM layers were retrieved and analyzed using angiogenesis software to obtain the density of blood vessels. Histomorphometric studies were performed to measure the thickness of vessel walls. The expression of VEGF, VEGFR2, and N-cadherin genes responsible for angiogenesis were analyzed. Results The exposure to the parent compound CPF and its metabolite TCPy promoted angiogenesis in groups administered with lower concentration of the pesticide and its metabolite, whereas a decline in angiogenesis was observed at higher concentrations. These observations were made by analyzing the density, histomorphometry results, and semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) results. The density, thickness, and lumen size of blood vessels in the groups with low concentration of CPF and TCPy were 28.34, 9 µm, and 30 µm, respectively, whereas in the groups with higher CPF and TCPy concentrations, they were 12, 3 µm, and 9 µm, respectively. Conclusions Hence, CPF and its metabolites interfere with angiogenesis in the CAM of chick embryos. Because of their estrogen-mimicking ability, pesticides are the prime etiological suspects of increasing alteration in blood vessel formation. These results may be of help in future studies on the effect of CPF in embryonic growth, wound healing, diabetes, and tumors.

Nimesulide induced histopathological changes in the vas deferens of mice.

AIM: Nimesulide, a preferential COX-2 inhibitor has 20 times more selectivity towards COX-2 than that of COX-1. COX-2 selective inhibitors cause frequent nephrotoxicity and hepatotoxicity following their usage. This proposes a physiological role of COX-2 in kidney and liver. Not much attention has been focused on the role of COX-2 with respect to reproduction especially in male reproduction, and the available information is scanty. AIMs and Objectives: The present study aims to investigate the adverse effects of nimesulide in the vas deferens thereby indirectly assess the role of COX-2 in male reproductive tract. MATERIAL AND METHODS: Nimesulide was administered orally and the animals were maintained for different time periods prior to sacrifice. RESULTS: The vas deferens of nimesulide treated mice showed extensive histopathological changes such as vacoulation and exfoliation of cells in the epithelial layer. CONCLUSION: Nimesulide administration leads to cytotoxic effects suggestive of apoptosis in the vas deferens of mice.

Variations in the posterior division branches of the mandibular nerve in human cadavers

<p><b>INTRODUCTION</b>The lingual, inferior alveolar and auriculotemporal nerves, being branches of the posterior division of the mandibular nerve, mainly innervate the mandibular teeth and all the major salivary glands. Anomalous communications among these branches are widely reported due to their significance to various treatment procedures undertaken in the region. This study was performed as detailed exploration of the functional perspectives of such communicating branches would further enhance the scope of these procedures.</p><p><b>METHODS</b>A total of 36 specimens were dissected to examine the infratemporal region. The branches from the posterior division of the mandibular nerve--namely the lingual, inferior alveolar and auriculotemporal nerves--were carefully dissected, and their branches were studied and analysed for abnormal course.</p><p><b>RESULTS</b>Communication between branches of the posterior division of the mandibular nerve was observed in four specimens. In two of the four specimens, communication between the mylohyoid and lingual nerves was observed. A rare and seldom reported type of communication between the auriculotemporal and inferior alveolar nerves is described in this study. This communicating nerve split into two to form a buttonhole for the passage of the mylohyoid nerve.</p><p><b>CONCLUSION</b>Such communicating branches between nerves found in this study are developmental in origin and thought to maintain functional integrity through an alternative route.</p>

Sternalis "mystery" muscle and its clinical implications.

Sternalis is an anomalous muscle found occasionally in the anterior part of the thorax. During routine dissection sternalis muscle was found in a male cadaver. This rare anatomic variant is reported in 8% of the population. In the present case, the muscle was found bilaterally, placed obliquely on either side of the sternum. It originated by tendinous fibres from the lower costal cartilages and inserted to the manubriosternal junction. The right side muscle was well developed whereas the left one was reduced in size. The pectoralis major and minor were normal. The knowledge of sternalis is important for radiologists and surgeons.

Suppression of constitutively expressed cyclooxygenase-2 in the epididymis of mice by nimesulide decreases sperm motility.

Significant levels of constitutive cyclooxygenase-2 (COX-2) are present in the male reproductive organs of rodents, especially in the vas deferens and epididymis. In the epididymis, the sperm storehouse, COX-2 is thought to play a vital role in altering the membrane lipids of sperm. The present study aims at localizing COX-2 in the epididymis and analyzing the effects of the preferential COX-2 inhibitor nimesulide. COX-2 protein activity was nearly equal to that of COX-1 in the cauda epididymis. Immunohistochemical studies showed an intense staining for COX-2 in the cauda epididymis but not in the caput epididymis. Nimesulide administration induced a significant reduction in both COX-2 staining intensity and protein activity, followed by an initial decline in total prostaglandin levels but a reversible increase upon sustained COX-2 suppression. Sperm numbers and vitality showed no significant change, but motility decreased and total and free serum testosterone levels mildly increased.

Localization of cyclooxygenase-2 in mice testis and assessment of its possible role through suppressing its expression using nimesulide: a preferential cyclooxygenase-2 inhibitor.

Present generation non-steroidal anti-inflammatory drugs (NSAID) are potent inhibitors of the enzyme cyclooxygenase-2 (COX-2). Even though they exhibit reduced incidence of gastrotoxicity, severe nephrotoxicity and other side effects have been widely reported with respect to usage of these drugs. Since COX-2 levels are not only upregulated by inflammation but also by other stimuli such as cytokines, growth factors, mitogens and steroid hormones, we investigated the localization of COX-2 and activity of both COX-1 and COX-2 in mice testis. To correlate the localization of COX-2 with its function we suppressed COX-2 expression with the aid of nimesulide a preferential COX-2 inhibitor. We found COX-2 was constitutively expressed in the Leydig cells of mice testis suggesting a role on testosterone synthesis. Suppression of COX-2 resulted in increased concentration of most of polyunsaturated fatty acids especially arachidonic acid (AA). Prostaglandin (PG) levels which showed an initial decline during nimesulide treatment had a reversible effect during prolonged treatment. These findings state that cyclooxygenase is constitutively expressed in mice testis and continuous inhibition of COX-2 interferes in maturation of sperm.

Localization of cyclooxygenase-2 in mice vas deferens and its effects on fertility upon suppression using nimesulide: a preferential cyclooxygenase-2 inhibitor.

Accumulating evidence on constitutive expression of cyclooxygenase-2 (COX-2), one of the isoforms of enzyme cyclooxygenase (COX) the other isoform being cyclooxygenase-1 (COX-1), questions the safety profile of non-steroidal anti-inflammatory drugs (NSAIDs). This COX-2 isoform which is induced not only during inflammation but also by factors such as cytokines, steroid hormones and mitogenic stimuli is constitutively expressed in brain, kidney and reproductive organs. Present NSAIDs, particularly COX-2 inhibitors is no longer considered safe since suppression of COX-2 in tissues which it is constitutively expressed may lead to adverse effects. Though intense expression of COX-2 in vas deferens is proved, lack of information with respect to its function has attracted a wide scope for research as to whether COX-2 in vas deferens contributes to male fertility. In the present study, the authors investigated the localization of COX-2 as well as COX-1 in mice vas deferens and also assessed the activity of COX-2 and total prostaglandin (PG) levels in vas deferens. Further they suppressed the expression of COX-2 using a preferential COX-2 inhibitor nimesulide and analyzed the sperm from vas deferens for any defects. COX-2 was intensely expressed in the epithelial cells of mice vas deferens and nimesulide was able to effectively suppress most of COX-2 expression. A decrease in PG levels was observed initially but interestingly, the levels tend to rise on sustained suppression of COX-2. The motility of sperm was affected severely after 6h of nimesulide administration that suggested a crucial role of COX-2 towards fertility of mice sperm.