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Background: Osteoporosis, a skeletal disease, that leads to increased fracture risk, features an enhanced osteoclast formation and bone resorption. Identification of agents that modulate aberrant osteoclast formation and function is important for the treatment of osteoporosis. Objective: The current study describes for the first time that Pila globosa snail extract inhibits osteoclastogenesis in vitro and thus suppresses bone loss in ovariectomy-induced rat model. Materials and Methods: Ovariectomized (Ovx) rats were treated with P. globosa snail extract and compared with sham, Ovx, and Ovx treated with zoledronate groups. Serum levels of C-terminal crosslinking telopeptides of type-1 collagen (CTX-1), TRAP5b, and antioxidant markers were determined. mRNA expressions of cathepsin K (CTSK), TRAP, calcitonin receptor (CTR), and matrix metalloproteinase 9 (MMP-9) were also assessed. Immunoblots of nuclear factor of activated T-cells c1 (NFATc1), c-Fos, TNF receptor-associated factor 6, c-Jun, and nuclear factor κB (NFκB) proteins were analyzed. Results and Discussion: P. globosa snail extract induced a decrease in the activation of NFκB, c-Fos, and NFATc1, which resulted in the downregulation of target genes, CTSK, TRAP, CTR, and MMP-9. P. globosa snail extract decreased the serum markers of bone resorption, C-terminal telopeptides of type-1 collagen (CTX-1), and tartrate-resistant acid phosphatase 5b (TRAP5b), reflecting the reduced number and activity of osteoclasts. Moreover, the results also suggested that the protective effect of P. globosa snail extract against osteoporosis is associated with the reduction of oxidative stress as evidenced by decreased malondialdehyde and increased serum antioxidant markers, superoxide dismutase, catalase, and glutathione. Conclusion: The upshot of the study suggests that the P. globosa snail extract represents a potential treatment option against osteolytic bone disease. [ABSTRACT FROM AUTHOR]

Abstract: Background: Oxidative stress is implicated in oral carcinogenesis and has been found to be aggravated during radiotherapy. A great deal of attention has been focused on the possible therapeutic implications of selenium as a potent antioxidant. We determined whether selenium supplementation to radiation treated oral cancer patients render improvement in the antioxidant status against oxidative stress. Method: Blood samples were collected from stage (III) oral cancer patients before initiating radiotherapy (Group B) (n =63) and this group is bifurcated into Group C—patients given radiotherapy alone (n =27) and Group D—patients given radiotherapy and supplemented with selenium (400 μg/day for 6 months) (n =36). Both Group C and D were followed up for 6 months. We evaluated the plasma selenium concentration, non-enzymatic system including GSH, vitamins E, C, A and ceruloplasmin and enzymatic antioxidant system including superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase. Results: The concentrations of selenium, all non-enzymatic antioxidants and the activities of enzymatic antioxidants were found to be lowered in oral cancer patients (Group B), compared to normal (Group A) (p <0.05). Similar decrease in the concentration of selenium and antioxidants status was observed in radiotherapy group (Group C) (p <0.05). On the contrary, selenium group (Group D) showed marked increase in the concentrations of selenium and antioxidant status at 6 months compared to radiation group (Group C) (p <0.05). Conclusion: The observed result represents the antioxidant property of selenium through the improvement of antioxidant defense system. Selenium supplementation could be of great interest in protecting cells against oxidative stress. [Copyright &y& Elsevier]

Abstract: A body of evidence has accumulated implicating free radical generation and reaction of arsenic with protein thiols in the biochemical and molecular mechanisms of arsenic toxicity. Brain readily undergoes oxidative damage, so it is important to determine whether arsenic-induced changes in rat brain may be associated with oxidative events. An increase in oxidative stress may contribute to the development of protein damage in rat brain. Present experiments were performed to study the effect of arsenic (sodium arsenite, 100ppm mixed in drinking water) on protein oxidation and further to demonstrate the potential of dl-α-lipoic acid (70mg/kg body weight) against arsenic-induced changes in different anatomic regions (cortex, striatum, cerebellum, hypothalamus and hippocampus) of the brain of male Wistar rats. We report here that arsenic treated rats had a significantly higher level of oxidised protein as assessed by increased carbonyl residues and decreased protein thiols (protein sulfhydryls) as compared to control rats in all five regions studied, with the most notable changes occurring in the cortex, striatum and hippocampus. Coadministration of lipoic acid along with arsenic resulted in reversal of the arsenic induced trends in carbonyl and sulfhydryl concentrations. The results of the study showed, lipoic acid treatment reduces oxidative protein damage in arsenic intoxicated rat brain regions, which is associated with its antioxidant activity that combines free radical scavenging and metal chelating properties. [Copyright &y& Elsevier]

The purpose of this study was to evaluate the anticancer efficacy of interferon β in combination with low dose of cisplatin on human cervical cancer progression, as well as its principal action mechanism. The combination treatment synergistically potentiated the effect of interferon β on cell growth inhibition and DNA damage on HeLa cells by repressing NF-κB/p-Akt signaling. Synergistic targeting of these pathways has a therapeutic potential. Further, the combination treatment ameliorated the expression of pro-apoptotic Bax, and decreased the expression of anti-apoptotic protein Bcl-2. Additionally, the expression of active PARP was significantly increased and MMP-9 level was decreased in combination group as compared to the expression seen for the treatment with interferon β or cisplatin alone. Results demonstrate that the synergistic inhibitory effects of interferon β and low dose of cisplatin on human cervical cancer cells and also suggest that the inhibition of NF-κB/p-Akt signaling pathway plays a critical role in the anticancer effects of combination treatment along with the induction of PARP. Therefore, the combination of interferon β and cisplatin may be a useful treatment for human cervical cancer, with a greater effectiveness than other treatments. [ABSTRACT FROM AUTHOR]

Conventional chemotherapy fails to cure metastatic hepatoma mainly due to its high hepatotoxicity. Currently, doxorubicin is the most widely used drug against liver cancer either as single agent or in combination with other chemotherapeutics such as cisplatin. It is limited due to their severe toxicity on normal hepatocytes. Therefore, alternative therapeutic agents without or with low hepatotoxicity are highly desirable. Interferons are a family of cytokines that potently demonstrate antiviral, immunomodulatory, and antiproliferative activities. It also exerts direct cytotoxic effects on tumor cells. The purpose of this study was to examine the in vitro cytotoxicity of interferon-β on Hep G2 cells. We revealed the presence of binding receptor of interferon-β in Hep G2 cells. The dose-dependent inhibition on cell proliferation was observed. We demonstrated that IFN-β exhibited significant cytotoxicity in Hep G2 cells mainly through phosphorylation of signal transducers and activators of transcription 2. The activation of Akt was suppressed. The stimulation of pro-apoptotic protein expression of Bax, inhibition of anti-apoptotic protein expression of Bcl-2, activation of cleaved caspases 9 and 3 was found at increasing concentrations. In conclusion, our results suggest that interferon-β has potential to inhibit cell proliferation dose dependently. Increased concentrations of interferon-β influenced apoptosis via mitochondrial pathway through inhibition of p- Akt. [ABSTRACT FROM AUTHOR]

In this study we intended to perform in silico and in vitro analysis of naturally derived flavonoid, hesperetin as a promising mammalian target of rapamycin inhibitor. This study features in silico screening of natural compound hesperetin against mammalian target of rapamycin FK506 binding proteins 12 domain by using Schrodinger glide based virtual screening and further molecular dynamics simulation was done to infer the stability of complex formation. Mammalian target of rapamycin co-crystallized with P2X (a known inhibitor of mTOR) (Protein Data Bank ID: 4JT5) was used for reference guided docking protocol. Then in vitro analysis applying hesperetin for cell viability followed by protein expressions in ovarian PA-1 and MCF-7 breast cancer cell lines were performed dose dependently. In silico molecular docking and dynamic studies with mammalian target of rapamycin protein revealed that hesperetin was found to be a potent compound that could inhibit the FK506 binding proteins 12 domain of mammalian target of rapamycin. The in vitro studies with hesperetin on PA-1 and MCF-7 breast cancer cell lines, found that hesperetin in a dose dependent manner significantly reduced the phosphorylation of mammalian target of rapamycin on Serine 2448 a marker for mammalian target of rapamycin complex 1 activity, as well as phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 and Ribosomal protein S6 kinase beta-1 which are downstream molecules of mammalian target of rapamycin was also significantly inhibited. To the best of our knowledge this is the first study that brings up the scientific evidence for the efficacy of hesperetin in inhibiting mammalian target of rapamycin with a similar docking score to the native ligand and also in a dose dependent manner in PA-1 human ovarian cancer cells and MCF-7 breast cancer cells, as an anticancer agent with further studies in near future. [ABSTRACT FROM AUTHOR]

Background: During radiotherapy, trauma and burns tissue responses to injury and homeostasis is lost. By leaving behind the scar tissue, the injured tissue results in angiogenesis, epithelization, and granulation tissue formation. The objective of the present study is to isolate, characterize, and differentiate bone marrow stem cells (BMSCs) from dermal precursors. Therefore, it can be utilized to retain tissue homeostasis. Materials and Methods: Two Wistar albino rats weighing 80 g were used for BMSCs isolation using the gradient centrifuging method. Isolated BMSCs were characterized and differentiated to dermal precursors. Immunocytochemistry was performed with 4',6-diamidino-2-phenylindole (DAPI) staining. Results: Isolated BMSCs were characterized by spindle-shaped morphology and plastic adherence property. BMSCs on flow cytometry exhibit positive CD90 and negative CD34 cells. About 70-80% confluence second passage cells were added with “bone morphogenetic protein-4" and keratinocyte growth supplement media for dermal differentiation. Dermal precursors were stained with DAPI immunostaining. Conclusion: Dermal precursors may serve as an important identity to the bone marrow population. This therapeutic potential of differentiated dermal precursors can assist dermatologists and surgeons to accelerate wound closure and decrease healing time. [ABSTRACT FROM AUTHOR]

Context:Alzheimer’s disease (AD) is the most common form of dementia affecting the aged population and neuroinflammation is one of the most observed AD pathologies. NF-κB is the central regulator of inflammation and inhibitor κB kinase (IKK) is the converging point in NF-κB activation. Celastrol is a natural triterpene used as a treatment for inflammatory conditions. Objective:This study determines the neuroprotective and inhibitory effect of celastrol on amyloid beta1-42(Aβ1-42) induced cytotoxicity and IKKβ activity, respectively. Materials and methods:Retinoic acid differentiated IMR-32 cells were treated with celastrol (1 μM) before treatment with Aβ1-42(IC3010 μM) for 24 h. The cytotoxicity and IKK phosphorylation were measured by MTT and western blotting analysis, respectively. We screened 36 celastrol analogues for the IKKβ inhibition by molecular docking and evaluated their drug like properties to delineate the neuroprotective effects. Results:Celastrol (1 μM) inhibited Aβ1-42(10 μM) induced IκBα phosphorylation and protected IMR-32 cells from cell death. Celastrol and 25 analogues showed strong binding affinity with IKKβ as evidenced by strong hydrogen-bonding interactions with critical active site residues. All the 25 analogues displayed strong anti-inflammatory properties but only 11 analogues showed drug-likeness. Collectively, molecule 15 has highest binding affinity, CNS activity and more drug likeness than parent compound celastrol. Discussion and conclusion:The decreased expression of pIκBα in celastrol pretreated cells affirms the functional representation of inhibited IKKβ activity in these cells. The neuroprotective potentials of celastrol and its analogues may be related to IKK inhibition. [ABSTRACT FROM AUTHOR]

BACE1, a βp secretase candidate enzyme, initiates the Alzheimer's disease (AD) pathogenesis via amyloid β (Aβ) peptide production serving as a potential therapeutic target. Previous experimental evidence suggested that ginsenosides, a key component of Panax ginseng, are effective against AD. In this study, we implemented a molecular modeling method to reveal the inhibitory action of ginsenosides on BACE1 activity. We selected 12 ginsenosides and performed molecular docking studies to evaluate its interaction with the BACE1 active site, which is essential for inhibition. Further ADMET filtration was applied to find drug-like molecules with a specific ability to cross blood brain barrier (BBB), and to determine toxicity. The BACE1-ginsenosides complex was further subjected to a molecular dynamics simulation to study the stability of the complex and its hydrogen bond interactions. In summary, our findings show ginsenosides CK, F1, Rh1 and Rh2 are potential BACE1 inhibitors from Panax ginseng. [ABSTRACT FROM AUTHOR]

Gene expression is often altered by epigenetic modifications that can significantly influence the growth ability and progression of cancers. SAHA (Suberoylanilide hydroxamic acid, also known as Vorinostat), a well-known Histone deacetylase (HDAC) inhibitor, can stop cancer growth and metastatic processes through epigenetic alterations. On the other hand, Letrozole is an aromatase inhibitor that can elicit strong anti-cancer effects on breast cancer through direct and indirect mechanisms. A newly developed inhibitor, RG7388 specific for an oncogene-derived protein called MDM2, is in clinical trials for the treatment of various cancers. In this paper, we performed assays to measure the effects of cell cycle arrest resulting from individual drug treatments or combination treatments with SAHA + letrozole and SAHA + RG7388, using the MCF-7 breast cancer cells. When SAHA was used individually, or in combination treatments with RG7388, a significant increase in the cytotoxic effect was obtained. Induction of cell cycle arrest by SAHA in cancer cells was evidenced by elevated p21 protein levels. In addition, SAHA treatment in MCF-7 cells showed significant up-regulation in phospho-RIP3 and MLKL levels. Our results confirmed that cell death caused by SAHA treatment was primarily through the induction of necroptosis. On the other hand, the RG7388 treatment was able to induce apoptosis by elevating BAX levels. It appears that, during combination treatments, with SAHA and RG7388, two parallel pathways might be induced simultaneously, that could lead to increased cancer cell death. SAHA appears to induce cell necroptosis in a p21-dependent manner, and RG7388 seems to induce apoptosis in a p21-independent manner, outlining differential mechanisms of cell death induction. However, further studies are needed to fully understand the intracellular mechanisms that are triggered by these two anti-cancer agents. [ABSTRACT FROM AUTHOR]