Embryonic lung development requires reciprocal endodermal-mesodermal interactions; mediated by various signaling proteins. Wnt/β-catenin is a signaling protein that exhibits the pivotal role in lung development, injury and repair while aberrant expression of Wnt/β-catenin signaling leads to asthmatic airway remodeling: characterized by hyperplasia and hypertrophy of airway smooth muscle cells, alveolar and vascular damage goblet cells metaplasia, and deposition of extracellular matrix; resulting in decreased lung compliance and increased airway resistance. The substantial evidence suggests that Wnt/β-catenin signaling links embryonic lung development and asthmatic airway remodeling. Here, we summarized the recent advances related to the mechanistic role of Wnt/β-catenin signaling in lung development, consequences of aberrant expression or deletion of Wnt/β-catenin signaling in expansion and progression of asthmatic airway remodeling, and linking early-impaired pulmonary development and airway remodeling later in life. Finally, we emphasized all possible recent potential therapeutic significance and future prospectives, that are adaptable for therapeutic intervention to treat asthmatic airway remodeling.
Polycystic ovarian syndrome is a multidisciplinary endocrinopathy of reproductive-aged women that provokes insulin resistance, hyperandrogenism, cardiovascular problems, obesity, and menstrual complications. The present study was designed to investigate the effectiveness of ethanolic extract of Fagonia indica in letrozole-induced PCOS young adult female rats. HPLC was carried out to find the phenolic and flavonoid content of the ethanolic extract of Fagonia indica. Twenty-five female rats were taken and initially divided into two groups: group I (control group) and group II (PCOS group). PCOS was induced by letrozole given orally by gavage. Body weight was recorded weekly and vaginal cytology was analyzed daily. After induction of disease, the PCOS group is further divided into four groups (n = 5): group II (positive control with PCOS), group III (metformin 20 mg/kg treated group), group IV (ethanolic extract of Fagonia indica 500 mg/kg treated group), and group V (metformin plus Fagonia extract). At the end of experimental period, the blood sample of each rat was collected and serum was separated by centrifugation. Afterwards hormonal analysis, lipid profile and liver functioning tests were performed. Ovaries were removed and preserved for histopathological findings while the liver of each rat was stored for the determination of antioxidant potential assessment. Fagonia indica was found to possess quercetin as one of the major flavonoid phytoconstituents. The plant extract exhibited its beneficial effects by restoring hormonal balance, lipid profile, and liver functioning markers. Treatment with F. indica reduced body weight, resolved ovarian cysts, and showed positive effects on follicular growth. Treatment with plant also increased the levels of antioxidant enzymes. This study validates the potential of Fagonia indica for the amelioration of metabolic, as well as, hormonal disturbances that occurred in PCOS.
Cdc42, a member of Rho family small guanosine triphosphatases (GTPases), is critical for cartilage development. We investigated the roles of Cdc42 in osteoarthritis and explored the potential mechanism underlying Cdc42-mediated articular cartilage degeneration and subchondral bone deterioration. Cdc42 is highly expressed in both articular cartilage and subchondral bone in a mouse osteoarthritis model with surgical destabilization of the medial meniscus (DMM) in the knee joints. Specifically, genetic disruption of Cdc42, knockdown of Cdc42 expression, or inhibition of Cdc42 activity robustly attenuates the DMM-induced destruction, hypertrophy, high expression of matrix metallopeptidase-13 and collagen X, and activation of Stat3 in articular cartilages. Notably, genetic disruption of Cdc42, knockdown of Cdc42 expression or inhibition of Cdc42 activity significantly restored the increased numbers of mesenchymal stem cells, osteoprogenitors, osteoblasts, osteoclasts, and neovascularized vessels, the increased bone mass, and the activated Erk1/2, Smad1/5 and Smad2 in subchondral bone of DMM-operated mice. Mechanistically, Cdc42 mediates interleukin-1β-induced interleukin-6 production and subsequent Jak/Stat3 activation to regulate chondrocytic inflammation, and also lies upstream of Erk/Smads to regulate subchondral bone remodeling during transform growth factor-β1 signaling. Cdc42 is apparently required for both articular cartilage degeneration and subchondral bone deterioration of osteoarthritis, thus, interventions targeting Cdc42 have potential in osteoarthritic therapy. © 2018 American Society for Bone and Mineral Research.
Sonic hedgehog (SHH) is abundantly expressed and critical for morphogenesis in embryonic lungs, however, SHH expression drops to a much lower level in mice from E17.5 and in humans from the 21st gestational week. We find that SHH expression is robustly up-regulated in the airway epithelia of children with asthma or mouse models with allergic airway disease. Specifically, airway-specific SMO loss of function significantly suppresses allergen-induced goblet cell phenotypes, whereas an airway-specific SMO gain of function markedly enhances the goblet cell phenotypes in mouse models with allergic airway disease. Notably, intratracheal administration with SHH- neutralizing antibody or cyclopamine robustly attenuates goblet cell phenotypes in mouse models with allergic airway disease. Finally, we identify that Muc5AC gene encoding MUC5AC mucin serves as a direct target of GLI transcriptional factors in response to SHH, whereas the SAM pointed domain-containing ETS transcription factor and Forkhead box A2, critical transcriptional factors for goblet cell phenotypes, both function as the effectors of GLIs in response to SHH stimulation. Together, the up-regulation of SHH expression in allergic bronchial epithelia contributes to goblet cell metaplasia; thus, blockage of SHH signaling is a rational approach in a therapeutic intervention of epithelial remodeling in chronic airway diseases.
Jasminum sambac (L.) is a South Asian folkloric medicinal plant that has traditionally been used to treat cardiovascular problems. The current investigation was meticulously organized to explore the pharmacological foundation for the medicinal uses of J. sambac pertaining to cardiovascular ailments and to investigate the core mechanisms. Mechanistic investigation revealed that crude leaf extract of J. sambac produced ex-vivo vasorelaxant effects in endotheliumintact aorta ring preparation and hypotensive effect was recorded via pressure and force transducers coupled to the Power Lab Data Acquisition System. Moreover; J. sambac showed cardioprotective effects against adrenaline -induced left ventricular hypertrophy in rabbits observed hemodynamic. CK-MB, LDH, troponin, CRP, ALT, AST, ALP levels were shown to be lower in the myocardial infarction model, as were necrosis, oedema, and inflammatory cell recruitment in comparison to control. J. sambac has shown good antioxidant potential as well as prolonged the noradrenaline induced platelet adhesion. The vasorelaxant and cardioprotective effects in both in vivo and ex vivo experiments, which are enabled by activation of muscarinic receptor and/or releasing the nitric oxide and by reducing the adrenaline, induced oxidative stress, justifying its usage in cardiovascular disorders.
Polycystic ovarian syndrome (PCOS) is an heterogenous, endocrine, metabolic, and multidisciplinary disorder of reproductive-aged females that aggravates insulin resistance, hyperandrogenism, obesity, menstrual irregularities, and infertility. Bitter melon is consumed as vegetable in various parts of the world. The purpose of this study was to provide the rationale for the folkloric uses of bitter melon (Momordica charantia L.) in reproductive abnormalities. HPLC analysis of standardized aqueous methanolic extract of bitter melon revealed the presence of various phytochemicals such as quercetin, gallic acid, benzoic acid, chlorogenic acid, syringic acid, p-coumaric acid, ferulic acid, and cinnamic acid. Twenty-five Swiss albino adult female rats (120–130 g) were acquired and divided into two groups (5 + 20). Letrozole (1 mg/kg p.o.) was used for four weeks to induce PCOS in twenty rats. Disease induction was confirmed by vaginal smear cytology analysis under the microscope. Animals were further divided into four groups, with one group as PCOS group, and the remaining three are treated with standardized extract of bitter melon (500 mg/kg p.o.), bitter melon plus metformin (500 mg/kg p.o.), and metformin alone for the period of next four weeks. After four weeks, the rats were euthanized at diestrus stage. Ovaries of the experimental animals were removed and fixed in 10% buffered formalin, and blood samples were obtained from direct cardiac puncture and stored. Ovaries histopathological analysis showed cystic follicles (9–10) in PCOS group, while, in all the treatment groups, we found developing and mature follicles. Similarly, hormone analysis showed significant ( p < 0.001 ) reduction of LH surge, insulin, and testosterone levels and improvement in FSH levels. Lipid profile and antioxidant enzymes status were also significantly ( p < 0.001 ) improved. In conclusion, the study validates the bitter melon potential as an insulin sensitizer and ovulation enhancer and authenticates its potential in PCOS management.
Lung development is mediated by assorted signaling proteins and orchestrated by complex mesenchymal-epithelial interactions. Notch signaling is an evolutionarily conserved cell-cell communication mechanism that exhibits a pivotal role in lung development. Notably, both aberrant expression and loss of regulation of Notch signaling are critically linked to the pathogenesis of various lung diseases, in particular, pulmonary fibrosis, lung cancer, pulmonary arterial hypertension, and asthmatic airway remodeling; implying that precise regulation of intensity and duration of Notch signaling is imperative for appropriate lung development. Moreover, evidence suggests that Notch signaling links embryonic lung development and asthmatic airway remodeling. Herein, we summarized all-recent advances associated with the mechanistic role of Notch signaling in lung development, consequences of aberrant expression or deletion of Notch signaling in linking early-impaired lung development and asthmatic airway remodeling, and all recently investigated potential therapeutic strategies to treat asthmatic airway remodeling.
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