Morin Hydrate Sensitizes Hepatoma Cells and Xenograft Tumor towards Cisplatin by Downregulating PARP-1-HMGB1 Mediated Autophagy.

The cross-talk between apoptosis and autophagy influences anticancer drug sensitivity and cellular death in various cancer cell lines. However, the fundamental mechanisms behind this phenomenon are still unidentified. We demonstrated anti-cancerous role of cisplatin (CP) and morin hydrate (Mh) as an individual and/or in combination (CP-Mh) in hepatoma cells and tumor model. Exposure of CP resulted in the production of intracellular reactive oxygen species (ROS)-mediated cellular vacuolization, expansion of mitochondria membrane and activation of endoplasmic reticulum (ER)-stress. Consequently, Cyt c translocation led to the increase of Bax/Bcl-2 ratio, which simultaneously triggered caspase-mediated cellular apoptosis. In addition, CP-induced PARP-1 activation led to ADP-ribosylation of HMGB1, which consequently developed autophagy as evident by the LC3I/II ratio. Chemically-induced inhibition of autophagy marked by increased cell death signified a protective role of autophagy against CP treatment. CP-Mh abrogates the PARP-1 expression and significantly reduced HMGB1-cytoplasmic translocation with subsequent inhibition of the HMGB1-Beclin1 complex formation. In the absence of PARP-1, a reduced HMGB1 mediated autophagy was observed followed by induced caspase-dependent apoptosis. To confirm the role of PARP-1-HMGB1 signaling in autophagy, we used the PARP-1 inhibitor, 4-amino-1,8-naphthalimide (ANI), HMGB1 inhibitor, ethyl pyruvate (EP), autophagy inhibitors, 3-methyl adenine (3-MA) and bafilomycin (baf) and small interfering RNAs (siRNA) to target Atg5 in combination of CP and Mh. Exposure to these inhibitors enhanced the sensitivity of HepG2 cells to CP. Collectively, our findings indicate that CP-Mh in combination served as a prominent regulator of autophagy and significant inducer of apoptosis that maintains a homeostatic balance towards HepG2 cells and the subcutaneous tumor model.

Supramolecular insulin assembly II for a sustained treatment of type 1 diabetes mellitus.

Diabetes is a chronic disease requiring continuous medical supervision and patient education to prevent acute secondary complications. In this study, we have harnessed the inherent property of insulin to aggregate into an oligomeric intermediate on the pathway to amyloid formation, to generate a form that exhibits controlled and sustained release for extended periods. Administration of a single dose of the insulin oligomer, defined here as the supramolecular insulin assembly II (SIA-II), to experimental animals rendered diabetic by streptozotocin or alloxan, released the hormone capable of maintaining physiologic glucose levels for >120 days for bovine and >140 days for recombinant human insulin without fasting hypoglycemia. Moreover, the novel SIA-II described here not only improved the glycemic control, but also reduced the extent of secondary diabetic complications.

Distribution and determinants of submandibular gland involvement in oral cavity squamous cell carcinoma.

INTRODUCTION: Though the submandibular gland (SMG) is routinely sacrificed for several reasons during neck dissection in patients undergoing curative surgery for oral cavity cancers, it might be an innocent bystander and should be considered for preservation. This study aimed to identify the incidence, different patterns of invasion, and risk factors of SMG involvement in oral cavity squamous cell carcinoma (SCC). METHODS: This was a retrospective study of the patients who underwent upfront curative surgery for a biopsy-proven oral cavity SCC. A consistent protocol-based treatment strategy was followed during the study period. Data about clinical profile including demographics, clinical and histology details, and treatment profile were extracted and analysed. RESULTS: A total of 303 patients underwent unilateral and bilateral neck dissections contributing 79.2% (n = 240) and 20.8% (n = 63) of patients respectively. The common primary sites were buccal mucosa (n = 129, 42.5%), tongue (n = 100, 33.0%) and alveolar gingiva (n = 52, 17.2%). A total of four SMGs showed tumor involvement resulting in a prevalence of 1.09% per neck dissection (n = 366) and 1.32% per patient (n = 303). Of these four cases of SMG involvement, one patient with alveolar cancer had direct tumor invasion while the other three (alveolar cancer - two, tongue cancer - one) patients had neck node metastasis. CONCLUSION: The present study confirms a very low incidence of SMG involvement in patients with oral cavity cancer who undergo neck dissection. It is often observed in patients with high neck node burden (≥N2 disease and the presence of extracapsular spread) or direct invasion by the primary tumor.

Effect of immunosenescence on the induction of cardiovascular disease pathogenesis: role of peripheral blood mononuclear cells.

It is well established that the immune potential declines with age. However, there is a great paucity of information regarding role of monocytes in elderly suffering from cerebrovascular accident. This present study was undertaken to investigate if the functions of peripheral blood mononuclear cells have any correlation to the manifestation of an age-associated cerebrovascular disorders: myocardial infraction, cerebrovascular (infract & hemorrhage). An age-associated inhibition in the production of interleukin-1 (IL-1) by monocytes was observed while the production of nitric oxide (NO) remained unaltered in the response of monocytes, obtained from normal elderly donors, to Lipopolysaccharide (LPS) treatment in vitro. Cerebrovascular pathologies were found to be associated with an augmentation of IL-1 production by monocyte, while NO production was augmented in case of CVA (hemorrhage) and MI. Trace element copper was found to be lower in the serum of patients suffering from CVA, while concentration of zinc was found to be elevated in serum compared to these trace elements in normal adults. Thus these factors are likely to play a role in the pathogenesis of age-related cerebrovascular disorders.