Profitability and risk-return comparison across health care industries, evidence from publicly traded companies 2010-2019.

We conducted the first profitability comparison study across health care industries in the United States, using the DuPont Analysis framework. The combination of Return on Equity (ROE) and ROE volatility was used to provide a comprehensive "risk-return" approach for profitability comparison. Based on the 2010-2019 financial disclosures of 1,231 publicly traded health care companies in the U.S. that reported positive assets and equity, we estimated the industry-specific fixed effects on ROE and its three components-profit margin, asset utilization, and financial leverage-for ten industries in the health care sector, classified by the Global Industry Classification Standard (GICS). For each industry, we also estimated its fixed effects on ROE volatility. We found that the pharmaceuticals industry and biotechnology industry have lower ROE-mainly driven by their relatively low profit margin and low assets utilization-and higher ROE volatility than other health care industries. We also found that the health care facilities industry relies most on debt financing. This study demonstrates a holistic approach for profitability comparison across industries.

Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target.

We investigated biomarker CEACAM6, a highly abundant cell surface adhesion receptor that modulates the extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) RNA-Seq data from PDA patients were analyzed for CEACAM6 expression and evaluated for overall survival, association, enrichment and correlations. A CRISPR/Cas9 Knockout (KO) of CEACAM6 in PDA cell line for quantitative proteomics, mitochondrial bioenergetics and tumor growth in mice were conducted. We found CEACAM6 is over-expressed in primary and metastatic basal and classical PDA subtypes. Highest levels are in classical activated stroma subtype. CEACAM6 over-expression is universally a poor prognostic marker in KRAS mutant and wild type PDA. High CEACAM6 expression is associated with low cytolytic T-cell activity in both basal and classical PDA subtypes and correlates with low levels of T-REG markers. In HPAF-II cells knockout of CEACAM6 alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport and autophagy. CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity. HPAF-II CEACAM6-/- cells are growth suppressed by >65% vs. wild type in mice bearing tumors. CEACAM6, a key regulator affects several hallmarks of PDA including the fibrotic reaction, immune regulation, energy metabolism and is a novel therapeutic target in PDA.

Hypoxia-mediated alteration in cholesterol oxidation and raft dynamics regulates BDNF signalling and neurodegeneration in hippocampus.

Brain-derived neurotrophic factor (BDNF) which is primarily associated with neuronal survivability, differentiation and synaptic plasticity has been reported to mediate neurodegeneration in hypoxia through its p75 Neurotrophin receptors (p75NTR). The molecular events promoting BDNF-mediated pro-death signalling in hypoxia, however, still remain an enigma. This study attempts towards deciphering the signalling cascades involved in alteration of BDNF isoforms and its cognate receptor subtypes leading to neurodegeneration in hypoxia. Adult Sprague-Dawley rats were exposed to global hypobaric hypoxia simulating an altitude of 7620 m at standard temperature and humidity. Chronic hypoxic exposure for 7 days resulted in higher expression of pro-BDNF and alteration in N-linked glycosylation in hippocampus along with increased expression of endoplasmic reticulum stress markers viz., glucose-regulated protein (Grp78), calnexin and changes in the endoplasmic reticulum morphology. Our findings reveal enriched expression of p75NTR in lipid rafts and higher expression of tyrosine receptor kinase ß (Trkß) in non-raft regions following hypoxic exposure. Further investigations on membrane properties revealed decline in membrane fluidity along with increased cholesterol oxidation resulting in reduced translocation of Trkß from non-raft to raft regions. Supplementation of vitamin E during hypoxic exposure on the other hand reduced cholesterol oxidation and increased translocation of Trkß from non-raft to raft regions and promoted neuronal survival. Hence, our findings suggest a novel mechanism of cholesterol oxidation-induced alteration in raft dynamics which is promotes p75 receptor-mediated death signalling in hippocampal neurons during chronic hypoxia.

MKK3 influences mitophagy and is involved in cigarette smoke-induced inflammation.

Cigarette smoking is the primary risk factor for COPD which is characterized by excessive inflammation and airflow obstruction of the lung. While inflammation is causally related to initiation and progression of COPD, the mitochondrial mechanisms that underlie the associated inflammatory responses are poorly understood. In this context, we have studied the role played by Mitogen activated protein (MAP) kinase kinase 3 (MKK3), a dual-specificity protein kinase, in cigarette smoke induced-inflammation and mitochondrial dysfunction. Serum pro-inflammatory cytokines were significantly elevated in WT but not in MKK3-/- mice exposed to Cigarette smoke (CS) for 2 months. To study the cellular mechanisms of inflammation, bone marrow derived macrophages (BMDMs), wild type (WT) and MKK3-/-, were exposed to cigarette smoke extract (CSE) and inflammatory cytokine production and mitochondrial function assessed. The levels of IL-1ß, IL-6, and TNFα were increased along with higher reactive oxygen species (ROS) and P-NFκB after CSE treatment in WT but not in MKK3-/- BMDMs. CSE treatment adversely affected basal mitochondrial respiration, ATP production, maximum respiratory capacity, and spare respiratory capacity in WT BMDMs only. Mitophagy, clearance of dysfunctional mitochondria, was up regulated in CS exposed WT mice lung tissue and CSE exposed WT BMDMs, respectively. The proteomic analysis of BMDMs by iTRAQ (isobaric tags for relative and absolute quantitation) showed up regulation of mitochondrial dysfunction associated proteins in WT and higher OXPHOS (Oxidative phosphorylation) and IL-10 signaling proteins in MKK3-/- BMDMs after CSE exposure, confirming the critical role of mitochondrial homeostasis. Interestingly, we found increased levels of p-MKK3 by immunohistochemistry in COPD patient lung tissues that could be responsible for insufficient mitophagy and disease progression. This study identifies MKK3 as a negative regulator of mitochondrial function and inflammatory responses to CS and suggests that MKK3 could be a therapeutic target.

Prevention of hexachlorocyclohexane-induced neuronal oxidative stress by natural antioxidants.

OBJECTIVE: Decalepis hamiltonii roots are traditionally consumed as general vitalizer and used in ayurvedic medicine preparations. We have isolated/characterized potent antioxidants from the aqueous extract of the root of this plant. In this study, we examined the antioxidant potential of the aqueous extract of the roots of D. hamiltonii (DHAE) against hexachlorocyclohexane (HCH)-induced oxidative stress in four major regions of the rat brain. METHODS: The antioxidant activity of the standardized DHAE with known antioxidant constituents was tested against HCH-induced oxidative stress in the major brain regions of 60-day-old adult male Wistar rats. RESULTS: Pretreatment of rats with multiple doses of DHAE, 50 and 100 mg/kg body weight (b.w.), for 7 consecutive days significantly prevented the HCH-induced (single dose -500 mg/kg b.w.) increase in lipid peroxidation, reduction in glutathione, and altered antioxidant enzyme activities viz. superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase in major rat brain regions viz. cortex, cerebellum, midbrain, and brain stem. DHAE, per se, elevated the antioxidant status of the rat brain. DISCUSSION: DHAE shows protective action against HCH-induced oxidative stress in rat brain regions. The protective effect of DHAE could be ascribed to the isolated/characterized antioxidant compounds which could be prospective novel nutraceuticals.

2,4,8-trihydroxybicyclo [3.2.1]octan-3-one scavenges free radicals and protects against xenobiotic-induced cytotoxicity.

Currently, there is a great deal of interest in the study of natural compounds with free-radical-scavenging activity because of their potential role in maintaining human health and preventing diseases. In this paper, we report the antioxidant and cytoprotective properties of 2,4,8-trihydroxybicyclo [3.2.1]octan-3-one (TBO) isolated from the aqueous extract of Decalepis hamiltonii roots. Our results show that TBO is a potent scavenger of superoxide (O(2)·-), hydroxyl (·OH), nitric oxide (·NO) and lipid peroxide (LOO·) - physiologically relevant free radicals with IC(50) values in nmolar (42-281) range. TBO also exhibited concentration-dependent secondary antioxidant activities such as reducing power, metal-chelating activity and inhibition of protein carbonylation. Further, TBO at nmolar concentration prevented CuSO(4)-induced human LDL oxidation. Apart from the in vitro free-radical-scavenging activity, TBO demonstrated cytoprotective activity in primary hepatocytes and Ehrlich ascites tumour (EAT) cells against oxidative-stress-inducing xenobiotics. The mechanism of cytoprotective action involved maintaining the intracellular glutathione (GSH), scavenging of reactive oxygen species (ROS) and inhibiting lipid peroxidation (LPO). Based on the results, it is suggested that TBO is a novel bioactive molecule with implications in both prevention and amelioration of diseases involving oxidative stress as well as in the general well-being.

14-aminotetradecanoic acid exhibits antioxidant activity and ameliorates xenobiotics-induced cytotoxicity.

Natural compounds with free-radical scavenging activity have potential role in maintaining human health and preventing diseases. In this study, we report the antioxidant and cytoprotective properties of 14-aminotetradecanoic acid (ATDA) isolated from the Decalepis hamiltonii roots. ATDA is a potent scavenger of superoxide (O(2) (•-)), hydroxyl ((•)OH), nitric oxide ((•)NO), and lipid peroxide (LOO(•)) physiologically relevant free radicals with IC(50) values in nM (36-323) range. ATDA also exhibits concentration-dependent secondary antioxidant activities like reducing power, metal-chelating activity, and inhibition of protein carbonylation. Further, ATDA at nM concentration prevented CuSO(4)-induced human LDL oxidation. ATDA demonstrated cytoprotective activity in primary hepatocytes and Ehrlich ascites tumor cells against oxidative stress inducing xenobiotics apart from the in vitro free-radical scavenging activity. The mechanism of cytoprotective action involved maintaining the intracellular glutathione, scavenging of reactive oxygen species, and inhibition of lipid peroxidation. It is suggested that ATDA is a novel bioactive molecule with potential health implications.

Differential cholinesterase inhibition in the rat brain regions by dichlorvos and protective effect of Decalepis hamiltonii roots.

Dichlorvos (DDVP) causes neurotoxicity primarily by inhibiting cholinesterase (ChE) which is the characteristic feature of organophosphate pesticides. In this study, we found for the first time that DDVP shows differential inhibition of ChE (acetylcholinesterase+butyrylcholinesterase) in various rat brain regions. A single dose of DDVP (1/3 LD(50)) after 16 h of treatment elicited ChE inhibition in the brain regions which was highest in striatum and lowest in cerebellum. The inhibition of ChE by DDVP has been shown to be accompanied with induction of oxidative stress. Further, we investigated the protective potential of the aqueous extract of the roots of Decalepis hamiltonii (DHA), having potent antioxidant constituents, against DDVP-induced ChE inhibition in various rat brain regions. Pretreatment of rats with multiple doses of DHA, 50 and 100mg/kg b.w., for 7 consecutive days did not produce any significant change in ChE activity. Pretreatment of rats with DHA, at high dose, significantly protected against DDVP-induced ChE inhibition in all the brain regions except cerebellum. Pretreatment of rats with DHA, at low dose, showed significant protection in striatum, cortex, and pons against DDVP-induced ChE inhibition. The protective activity of DHA can be attributed to the characterized potent antioxidant constituents which could have an important role in preventing ChE inhibition by inducing the DDVP detoxifying enzymes. We strongly believe that these antioxidant constituents are prospective novel nutriceuticals.