Study protocol: phase II study to evaluate the effect of cetuximab monotherapy after immunotherapy with PD-1 inhibitors in patients with head and neck squamous cell cancer.

Background: Immunotherapy with programmed death receptor-1 (PD-1) inhibitors, as a single agent or in combination with chemotherapy, is the standard first-line treatment for recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC). Unfortunately, there is no established second-line treatment for the many patients who fail immunotherapy. Cetuximab is the only targeted therapy approved in HNSCC but historically has a low response rate of 13%.

Redox integration of signaling and metabolism in a head and neck cancer model of radiation resistance using COSM.

Redox metabolism is increasingly investigated in cancer as driving regulator of tumor progression, response to therapies and long-term patients' quality of life. Well-established cancer therapies, such as radiotherapy, either directly impact redox metabolism or have redox-dependent mechanisms of action defining their clinical efficacy. However, the ability to integrate redox information across signaling and metabolic networks to facilitate discovery and broader investigation of redox-regulated pathways in cancer remains a key unmet need limiting the advancement of new cancer therapies.

Early [18]FDG PET/CT scan predicts tumor response in head and neck squamous cell cancer patients treated with erlotinib adjusted per smoking status.

Translational Relevance: Evaluation of targeted therapies is urgently needed for the majority of patients with metastatic/recurrent head and neck squamous cell carcinoma (HNSCC) who progress after immunochemotherapy. Erlotinib, a targeted inhibitor of epidermal growth factor receptor pathway, lacks FDA approval in HNSCC due to inadequate tumor response. This study identifies two potential avenues to improve tumor response to erlotinib among patients with HNSCC.

[F]Fluoro-DCP, a first generation PET radiotracer for monitoring protein sulfenylation in vivo.

Redox metabolism plays essential functions in the pathology of cancer and many other diseases. While several radiotracers for imaging redox metabolism have been developed, there are no reports of radiotracers for in vivo imaging of protein oxidation. Here we take the first step towards this goal and describe the synthesis and kinetic properties of a new positron emission tomography (PET) [F]Fluoro-DCP radiotracer for in vivo imaging of protein sulfenylation.

Discovery of Spilanthol Endoperoxide as a Redox Natural Compound Active against Mammalian Prx3 and Infection.

(Ct) is a bacterial intracellular pathogen responsible for a plethora of diseases ranging from blindness to pelvic inflammatory diseases and cervical cancer. Although this disease is effectively treated with antibiotics, concerns for development of resistance prompt the need for new low-cost treatments. Here we report the activity of spilanthol (SPL), a natural compound with demonstrated anti-inflammatory properties, against Ct infections.

MTHFD2 Blockade Enhances the Efficacy of β-Lapachone Chemotherapy With Ionizing Radiation in Head and Neck Squamous Cell Cancer.

Head and Neck Squamous Cell Cancer (HNSCC) presents with multiple treatment challenges limiting overall survival rates and affecting patients' quality of life. Amongst these, resistance to radiation therapy constitutes a major clinical problem in HNSCC patients compounded by origin, location, and tumor grade that limit tumor control. While cisplatin is considered the standard radiosensitizing agent for definitive or adjuvant radiotherapy, in recurrent tumors or for palliative care other chemotherapeutics such as the antifolates methotrexate or pemetrexed are also being utilized as radiosensitizers.

Aldose reductase regulates hyperglycemia-induced HUVEC death via SIRT1/AMPK-α1/mTOR pathway.

Although hyperglycemia-mediated death and dysfunction of endothelial cells have been reported to be a major cause of diabetes associated vascular complications, the mechanisms through which hyperglycemia cause endothelial dysfunction is not well understood. We have recently demonstrated that aldose reductase (AR, AKR1B1) is an obligatory mediator of oxidative and inflammatory signals induced by growth factors, cytokines and hyperglycemia. However, the molecular mechanisms by which AR regulates hyperglycemia-induced endothelial dysfunction is not well known.

Didymin by suppressing NF-κB activation prevents VEGF-induced angiogenesis in vitro and in vivo.

Although didymin, a dietary flavonoid glycoside from citrus fruits, known to be a potent antioxidant with anti-cancer activities, its role in angiogenesis is not known. In this study, we examined the effect of didymin on VEGF-induced angiogenesis in vitro and in vivo models. Our results suggest that treatment of human umbilical vein endothelial cell (HUVECs) with didymin significantly prevented the VEGF-induced cell proliferation, migration, and invasion.

Sulforaphane promotes chlamydial infection by suppressing mitochondrial protein oxidation and activation of complement C3.

Sulforaphane (SFN), a phytochemical found in broccoli and other cruciferous vegetables, is a potent antioxidant and anti-inflammatory agent with reported effects in cancer chemoprevention and suppression of infection with intracellular pathogens. Here we report on the impact of SFN on infection with Chlamydia trachomatis (Ct), a common sexually transmitted pathogen responsible for 131 million new cases annually worldwide. Astoundingly, we find that SFN as well as broccoli sprouts extract (BSE) promote Ct infection of human host cells.

Mitochondria-targeted Probes for Imaging Protein Sulfenylation.

Mitochondrial reactive oxygen species (ROS) are essential regulators of cellular signaling, metabolism and epigenetics underlying the pathophysiology of numerous diseases. Despite the critical function of redox regulation in mitochondria, currently there are limited methods available to monitor protein oxidation in this key subcellular organelle. Here, we describe compounds for imaging sulfenylated proteins in mitochondria: DCP-NEt-Coumarin (DCP-NEtC) and rhodamine-based DCP-Rho1.

Didymin prevents hyperglycemia-induced human umbilical endothelial cells dysfunction and death.

Although didymin, a flavonoid-O-glycosides compound naturally found in the citrus fruits, has been reported to be a potent anticancer agent in the prevention of various cancers, its role in the prevention of cardiovascular complications is unclear. Most importantly, its effect in the prevention of endothelial dysfunction, a pathological process involved in the atherogenesis, is unknown. We have examined the efficacy of didymin in preventing the high glucose (HG; 25 mM)-induced human umbilical vein endothelial cells (HUVECs) dysfunction.

Vialinin A, an Edible Mushroom-Derived p-Terphenyl Antioxidant, Prevents VEGF-Induced Neovascularization In Vitro and In Vivo.

Increased side toxicities and development of drug resistance are the major concern for the cancer chemotherapy using synthetic drugs. Therefore, identification of novel natural antioxidants with potential therapeutic efficacies is important. In the present study, we have examined how the antioxidant and anti-inflammatory activities of vialinin A, a p-terphenyl compound derived from Chinese edible mushroom and , prevents human umbilical vascular endothelial cell (HUVEC) neovascularization in vitro and in vivo models.

Aldose reductase inhibitor, fidarestat prevents doxorubicin-induced endothelial cell death and dysfunction.

Despite doxorubicin (Dox) being one of the most widely used chemotherapy agents for breast, blood and lung cancers, its use in colon cancer is limited due to increased drug resistance and severe cardiotoxic side effects that increase mortality associated with its use at high doses. Therefore, better adjuvant therapies are warranted to improve the chemotherapeutic efficacy and to decrease cardiotoxicity. We have recently shown that aldose reductase inhibitor, fidarestat, increases the Dox-induced colon cancer cell death and reduces cardiomyopathy.

Aldose reductase inhibitor, fidarestat regulates mitochondrial biogenesis via Nrf2/HO-1/AMPK pathway in colon cancer cells.

Although we have shown earlier that aldose reductase (AR) inhibitors prevent colorectal cancer cell (CRC) growth in culture as well as in nude mice xenografts, the mechanism(s) is not well understood. In this study, we have investigated how AR inhibition prevents CRC growth by regulating the mitochondrial biogenesis via Nrf2/HO-1 pathway. Incubation of CRC cells such as SW-480, HT29, and HCT116 with AR inhibitor, fidarestat that non-covalently binds to the enzyme, increases the expression of Nrf2.

Aldose Reductase Mediates NLRP3 Inflammasome-Initiated Innate Immune Response in Hyperglycemia-Induced Thp1 Monocytes and Male Mice.

Despite recent studies that show oxidative stress-generated reactive oxygen species (ROS) regulate NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated innate immune response in various diabetic complications, the mechanism by which ROS activate innate immune response is not well understood. We have shown previously that aldose reductase (AR), besides reducing glucose, reduces lipid aldehydes and their glutathione conjugates and participates in various oxidative stress-induced inflammatory pathways. To understand the role of AR in ROS-induced innate immune response, we have investigated the mechanism(s) by which AR activates hyperglycemia-induced NLRP3 inflammsome-initiated innate immune response in Thp1 monocytes and in streptozotocin (STZ)-induced diabetic mice.

Aldose Reductase Inhibitor Protects against Hyperglycemic Stress by Activating Nrf2-Dependent Antioxidant Proteins.

We have shown earlier that pretreatment of cultured cells with aldose reductase (AR) inhibitors prevents hyperglycemia-induced mitogenic and proinflammatory responses. However, the effects of AR inhibitors on Nrf2-mediated anti-inflammatory responses have not been elucidated yet. We have investigated how AR inhibitor fidarestat protects high glucose- (HG-) induced cell viability changes by increasing the expression of Nrf2 and its dependent phase II antioxidant enzymes.

Aspalatone Prevents VEGF-Induced Lipid Peroxidation, Migration, Tube Formation, and Dysfunction of Human Aortic Endothelial Cells.

Although aspalatone (acetylsalicylic acid maltol ester) is recognized as an antithrombotic agent with antioxidative and antiplatelet potential; its efficacy in preventing endothelial dysfunction is not known. In this study, we examined the antiangiogenic, antioxidative, and anti-inflammatory effect of aspalatone in human aortic endothelial cells (HAECs). Specifically, the effect of aspalatone on VEGF-induced HAECs growth, migration, tube formation, and levels of lipid peroxidation-derived malondialdehyde (MDA) was examined.

Current Scenario of Prevalence of Vitamin D Deficiency in Ostensibly Healthy Indian Population: A Hospital Based Retrospective Study.

25-hydroxy vitamin D [25(OH) vit D] deficiency is a serious public health problem, particularly in the Indian sub-continent. The objective of the present study was to study the prevalence of 25(OH) vit D in different age groups. The data of 25(OH) vit D assay of 26,346 ostensibly healthy individuals, enrolled under executive health checkup at Medanta The Medicity, Gurgaon, over a period of 3 years, were extracted from the hospital information system and reviewed extensively.

Antihypercholesterolemic and antioxidant effect of sterol rich methanol extract of stem of Musa sapientum (banana) in cholesterol fed wistar rats.

Musa sapientum Linn. (English 'Banana' family Musaceae), is a plant with nutritive, as well as medicinal value. Antihypercholesterolemic and antioxidant effect of methanolic extract of stem of this plant was investigated in hypercholesterolemic rats.

Hypolipidemic and antioxidant activity of aqueous extract of fruit of Withania coagulans (Stocks) Dunal in cholesterol-fed hyperlipidemic rabbit model.

Withania coagulans (family: Solanaceae, English: Indian Cheese Maker, Hindi: Doda Paneer) fruit is known for its ethanopharmacological significance in health care system of India. Diet rich in high-fat is an important risk factor for diabetes, atherosclerosis and macro and microvascular complications. Treatment with aqueous extract of fruit of W.

Association of biomarkers of inflammation and oxidative stress with the risk of chronic kidney disease in Type 2 diabetes mellitus in North Indian population.

Chronic kidney disease (CKD) is a major cause of morbidity and mortality worldwide. It results from diverse etiologies, diabetes being a frontrunner amongst them. Type 2 diabetes mellitus (DM) is being increasingly recognized as a proinflammatory state with increased oxidative stress which enormously increases the risk of micro and macro vascular diseases.

The aqueous extract of Withania coagulans fruit partially reverses nicotinamide/streptozotocin-induced diabetes mellitus in rats.

Withania coagulans fruit has been shown to possess antihyperglycemic properties and is used in the traditional Indian system of medicine. However, there has no systematic study of its mechanism of action. In a rat model diabetes mellitus (DM) was induced by intraperitoneal injection of nicotinamide (230 mg/kg of body weight) followed by streptozotocin at 55 mg/kg of body weight.

Ameliorative effect of Withania coagulans on dyslipidemia and oxidative stress in nicotinamide-streptozotocin induced diabetes mellitus.

Present study aims to evaluate the effect of Withania coagulans fruit (aqWC) on diabetic-dyslipidemia and antioxidant/oxidant status in DM. Diabetic animals were treated with aqWC at a dose of 250 mg/kg bw for 30 days. Lipid profile, MDA, GSH, SOD, FRAP, HMG CoA reductase and acetyl CoA carboxylase activities were estimated in blood and tissues.

Antidiabetic and antihyperlipidemic effects of the stem of Musa sapientum Linn. in streptozotocin-induced diabetic rats.

Background: Musa sapientum Linn. is a herbaceous plant of the Musaceae family. It has been used in India for the treatment of gastric ulcer, hypertension, diarrhea, dysentery, and diabetes.

Hepatoprotective effect of stem of Musa sapientum Linn in rats intoxicated with carbon tetrachloride.

Methods: The study was designed to evaluate the hepatoprotective activity of aqueous extract of central stem of Musa sapientum (AqMS) against carbon tetrachloride induced hepatotoxicity in rats. Animals were divided into six groups. Group I served as normal control.