Cidofovir in Severe Hypoxemic Adenoviral Pneumonia.

The authors present a 16-mo-old boy with flu like symptoms, not responding to supportive management and progressed to severe hypoxemic pneumonia. Adenovirus was detected in the nasopharyngeal aspirate. He showed rapid improvement after intravenous cidofovir administration.

Transient Receptor Potential (TRP) based polypharmacological combination stimulates energy expending phenotype to reverse HFD-induced obesity in mice.

BACKGROUND & AIM: Obesity is a worldwide epidemic leading to decreased quality of life, higher medical expenses and significant morbidity. Enhancing energy expenditure and substrate utilization in adipose tissues through dietary constituents and polypharmacological approaches is gaining importance for the prevention and therapeutics of obesity. An important factor in this regard is Transient Receptor Potential (TRP) channel modulation and resultant activation of "brite" phenotype. Various dietary TRP channel agonists like capsaicin (TRPV1), cinnamaldehyde (TRPA1), and menthol (TRPM8) have shown anti-obesity effects, individually and in combination. We aimed to determine the therapeutic potential of such combination of sub-effective doses of these agents against diet-induced obesity, and explore the involved cellular processes. KEY FINDINGS: The combination of sub-effective doses of capsaicin, cinnamaldehyde and menthol induced "brite" phenotype in differentiating 3T3-L1 cells and subcutaneous white adipose tissue of HFD-fed obese mice. The intervention prevented adipose tissue hypertrophy and weight gain, enhanced the thermogenic potential, mitochondrial biogenesis and overall activation of brown adipose tissue. These changes observed in vitro as well as in vivo, were linked to increased phosphorylation of kinases, AMPK and ERK. In the liver, the combination treatment enhanced insulin sensitivity, improved gluconeogenic potential and lipolysis, prevented fatty acid accumulation and enhanced glucose utilization. SIGNIFICANCE: We report on the discovery of therapeutic potential of TRP-based dietary triagonist combination against HFD-induced abnormalities in metabolic tissues. Our findings indicate that a common central mechanism may affect multiple peripheral tissues. This study opens up avenues of development of therapeutic functional foods for obesity.

Tubercular Tenosynovitis Mimicking a Large Ganglion Cyst.

Introduction: Tubercular tenosynovitis of the wrist and hand, although rare, presents a diagnostic dilemma primarily due to its non-specific clinical presentation, insidious course, and the large number of differentials that mimic it. When the diagnosis is late or delayed, significant bone and tendon complications occur. Large progressive swelling around the wrist in TB endemic countries should raise an early suspicion of being of tubercular etiology and should be high on the list of differential diagnoses. Case Report: A 48-year-old female presented with a large progressive swelling on the volar aspect of the left wrist and palm for 7 months, associated with increasing pain, stiffness, limited wrist range of movements, and weakened grip strength. Magnetic resonance imaging (MRI) revealed synovitis and fluid within flexor tendon synovial sheaths. The patient underwent an excision of the mass in toto and the cut section revealed an irregularly thickened wall with rice bodies within. Histopathological examination was indicative of a large ganglion cyst. GeneXpert MTB/RIF assay detected Mycobacterium tuberculosis. Despite histopathology being inconclusive, a diagnosis of TTS was considered due to the patient's clinical presentation, MRI, and operative findings. The patient was started on an antitubercular drug regimen for a 1-year duration. The patient regained a complete range of movements of fingers and wrist and normal grip strength at the 3rd month follow-up. Conclusion: TTS is a challenging diagnosis entity. The diagnostic confirmation was achieved either by histopathology or detection of the organism either by culture or GeneXpert MTB/RIF assay. When the diagnosis is unsupported, drug therapy can be initiated empirically on strong suspicion of tuberculosis, especially in TB endemic areas.

E-cig vapor condensate alters proteome and lipid profiles of membrane rafts: impact on inflammatory responses in A549 cells.

Electronic cigarettes (e-cigs) are battery-operated heating devices that aerosolize e-liquid, typically containing nicotine and several other chemicals, which is then inhaled by a user. Over the past decade, e-cigs have gained immense popularity among both smokers and non-smokers. One reason for this is that they are advertised as a safe alternative to conventional cigarettes. However, the recent reports of e-cig use associated lung injury have ignited a considerable debate about the relative harm and benefits of e-cigs. The number of reports about e-cig-induced inflammation and pulmonary health is increasing as researchers seek to better understand the effects of vaping on human health. In line with this, we investigated the molecular events responsible for the e-cig vapor condensate (ECVC)-mediated inflammation in human lung adenocarcinoma type II epithelial cells (A549). In an attempt to limit the variables caused by longer ingredient lists of flavored e-cigs, tobacco-flavored ECVC (TF-ECVC±nicotine) was employed for this study. Interestingly, we observed significant upregulation of cytokines and chemokines (IL-6, IL-8, and MCP-1) in A549 cells following a 48 h TF-ECVC challenge. Furthermore, there was a significant increase in the expression of pattern recognition receptors TLR-4 and NOD-1, lipid raft-associated protein caveolin-1, and transcription factor NF-кB in TF-ECVC with and/or without nicotine-challenged lung epithelial cells. Our results further demonstrate the harboring of TLR-4 and NOD-1 in the caveolae of TF-ECVC-challenged A549 cells. Proteomic and lipidomic analyses of lipid raft fractions from control and challenged cells revealed a distinct protein and lipid profile in TF-ECVC (w/wo nicotine)-exposed A549 cells. Interestingly, the inflammatory effects of TF-ECVC (w/wo nicotine) were inhibited following the caveolin-1 knockdown, thus demonstrating a critical role of caveolae raft-mediated signaling in eliciting inflammatory responses upon TF-ECVC challenge. Graphical Abstract Graphical Abstract.

In vitro study of the role of FOXO transcription factors in regulating cigarette smoke extract-induced autophagy.

Cigarette smoking is the chief etiological factor for chronic obstructive pulmonary disease (COPD). Oxidative stress induced by cigarette smoke (CS) causes protein degradation, DNA damage, and cell death, thereby resulting in acute lung injury (ALI). In this regard, autophagy plays a critical role in regulating inflammatory responses by maintaining protein and organelle homeostasis and cellular viability. Expression of autophagy-related proteins (ARPs) is regulated by the fork head box class O (FOXO) transcription factors. In the current study, we examined the role of FOXO family proteins-FOXO1 and FOXO3a-in regulating CS extract (CSE)-induced autophagy. Using human lung adenocarcinoma cells with type II alveolar epithelial characteristics (A549), we observed CSE-mediated downregulation of FOXO3a. In contrast, there was a pronounced increase in the expression of FOXO1 at both the transcriptional and translational levels in the CSE-challenged cells compared with controls. Interestingly, knockdown of FOXO3a heightened the CSE-mediated increase in expression of cytokines/chemokines (IL-6, IL-8, and MCP-1), ARPs, and the FOXO1 transcription factor. Moreover, FOXO1 knockdown rescued CSE-mediated upregulation of ARPs in A549 cells. In addition, using the ROS inhibitor N-acetyl-L-cysteine (NAC), we observed abrogated mRNA expression of several ARPs and production of inflammatory cytokines/chemokines (IL-6, IL-8, MCP-1, and CCL-5) in the CSE-challenged cells suggesting an important role of ROS in regulating CSE-induced autophagy. Chromatin immunoprecipitation of FOXO1 and FOXO3a demonstrated increased binding of the former to promoter regions of autophagy genes- BECLIN1, ATG5, ATG12, ATG16, and LC3 in CSE challenged cells. These findings suggest the role of FOXO1 in regulating the expression of these genes during CSE exposure. Overall, our findings provide evidence for FOXO3a-dependent FOXO1-mediated regulation of autophagy in the CSE-challenged cells. Graphical abstract.

Lung cancer identification: a review on detection and classification.

Lung cancer is one of the most common diseases among humans and one of the major causes of growing mortality. Medical experts believe that diagnosing lung cancer in the early phase can reduce death with the illustration of lung nodule through computed tomography (CT) screening. Examining the vast amount of CT images can reduce the risk. However, the CT scan images incorporate a tremendous amount of information about nodules, and with an increasing number of images make their accurate assessment very challenging tasks for radiologists. Recently, various methods are evolved based on handcraft and learned approach to assist radiologists. In this paper, we reviewed different promising approaches developed in the computer-aided diagnosis (CAD) system to detect and classify the nodule through the analysis of CT images to provide radiologists' assistance and present the comprehensive analysis of different methods.

Pharmabiotic beads with improved encapsulation and gut survival for management of colonic inflammation associated gut derangements.

Encapsulation techniques and materials, explored for addressing compromised probiotic gut survival, report significant production losses resulting in <10% entrapment. Presently, we report three-time enhanced entrapment (30 ± 1.2%) of Lactobacillus acidophilus (LAB) in calcium-alginate beads, by modifying process parameters and employing polyethylene glycol (PEG). Water-loving, viscolysing and osmotic-building effects of PEG create numerous, fine voids in the alginate gel allowing efficient diffusion of crosslinking calcium ions, resulting in less leaky beads. Eudragit S100 overcoat improved LAB survival by 690 times in simulated GIT stresses.In DMH-DSS induced colitis and precancerous lesions in rats, while free LAB failed to show any protection, pharmabiotic beads significantly (p < .05) reduced lipid peroxidation, increased antioxidant levels; decreased serum inflammatory burden; downregulated COX-2, iNOS, and c-Myc expression; elevated levels of the selected gut bacteria and SCFAs especially butyrate, all of which add up to antioxidant, anti-inflammatory, balanced gut biota, and ultimately anticancer effects.

Co-supplementation of isomalto-oligosaccharides potentiates metabolic health benefits of polyphenol-rich cranberry extract in high fat diet-fed mice via enhanced gut butyrate production.

PURPOSE: Cranberries are a rich source of polyphenolic antioxidants. Purified sugars or artificial sweeteners are being added to cranberry-based food products to mask tartness. Refined sugar and artificial sweeteners intake modulate gut microbiota and result in metabolic complications. We evaluated effects of isomalto-oligosaccharides (IMOs; sweet tasting non-digestible oligosaccharides) with cranberry extract (CRX) on high fat diet (HFD)-induced metabolic alterations in mice. METHODS: Male Swiss albino mice were fed normal chow or HFD (58% fat kcal), and were administered either CRX (200 mg/kg) alone or in combination with IMOs (1 g/kg). Cecal short-chain fatty acids, abundances of selected (1) butyrate producing, (2) metabolically beneficial, and (3) selective lipopolysaccharides producing gram negative gut bacteria were studied. Further, gut-related histological, biochemical, genomic changes along with circulating pro-/anti-inflammatory markers and systemic obesity-associated metabolic changes were studied. RESULTS: Co-supplementation of CRX and IMOs significantly improved cecal SCFAs, especially butyrate levels, selected butyrate-producing bacteria (clostridial cluster XIVa bacteria) and butyrate kinase expression in HFD-fed mice. The combination also significantly improved gut beneficial bacterial abundance, gut histology and related changes (colon mucin production, gut permeability) as compared to individual agents. It also prevented HFD-induced systemic and tissue inflammation, glucose intolerance and systemic obesity-associated metabolic changes in adipose tissue and liver. The combination of CRX and IMOs appeared more effective in the prevention of HFD-induced gut derangements. CONCLUSION: Combination of CRX and IMOs could be advantageous for normalization of metabolic alterations seen in diet-induced obesity via beneficial modulation of gastrointestinal health.

Managing colonic inflammation associated gut derangements by systematically optimised and targeted ginger extract-Lactobacillus acidophilus loaded pharmacobiotic alginate beads.

Presently, we explore a cobiotic-ginger extract (GE; antioxidant-antiinflammatory) and Lactobacillus acidophilus (LAB, probiotic), for control of oxidative-stress, inflammation and dysbiosis mediated gut ailments. Since orally administered LAB looses viability while GE is a gastric irritant with poor ADME, we encapsulated them into calcium-alginate beads. Water-loving, viscolysing, and osmotic-building effects of polyethylene glycol were used to address poor probiotic encapsulation (≤10%) by effective sealing of numerous fine voids formed in the alginate gel. Beads were systematically optimized for maximum entrapment (92±2.3% for GE, and 30±1.2% for LAB) and sustained release, and were coated with eudragit-S100 for colonic-targetability, as established by in-vitro release. In-vivo evaluation in DMH-DSS induced colitis and precancerous lesions, in rats, indicated attenuation of oxidative stress (catalase, SOD, LPO) and inflammatory burden (IL-6 and TNF-α), and downregulation of COX-2, iNOS, and c-Myc by both GE and LAB; restoration of colonic permeability by GE; and modulation of gut bacteria and SCFAs by LAB as the mechanisms of action. Complementing activities of GE and LAB in cobiotic beads lead to better reversals. Histology (H&E and toluidine blue) confirmed healing of precancerous lesions.

Flavocoxid, dual inhibitor of cyclooxygenase-2 and 5-lipoxygenase, exhibits neuroprotection in rat model of ischaemic stroke.

The efficacy of flavocoxid, a prescription medical food used in osteoarthritis in the USA, containing natural flavonoids, baicalin and catechin in experimentally induced cerebral ischaemia in rats was evaluated. Rationale behind the study was that the transient acute ischaemic attack triggers neuroinflammatory cascade. Global cerebral ischaemia was induced transiently by occluding both common carotid arteries for 15 min followed by restoration of perfusion. Flavocoxid (50, 100, 200mg/kg; p.o.) pre-treatment was instituted 6 days prior to surgery and fluoxetine (10mg/kg, p.o.) and rivastigmine (2mg/kg, p.o.) as a standard treatment for depression and cognition impairment was implied from day 1 after the surgery. Different behavioural, biochemical, neurochemical tests, molecular markers of inflammation e.g. tumour necrosis factor-α, interleukin-1 beta, and nuclear factor-kappa B levels and infarct volume were determined. Flavocoxid's strong antioxidant properties figured out from the decreased level of lipid peroxidation and protection of endogenous antioxidants like reduced glutathione and superoxide dismutase. It also reduced TNF-α, IL-1ß, and NF-κB levels, and infarct volume as well as protected the loss of biogenic amines in brain tissue of ischaemic rats. This dual inhibitor of cyclooxygenase-1 and 2 with additional 5-lipoxygenase inhibition activity might be useful as a potential neuroprotectant medical food in ischaemic stroke prone patient population.

Verapamil augments the neuroprotectant action of berberine in rat model of transient global cerebral ischemia.

Various potential molecules with putative positive role in stroke pathology have failed to confer neuro-protection in animal models due to their insufficient bioavailability in brain. Efflux of these molecules by P-glycoprotein (P-gp), on blood brain barrier (BBB) is one of the reasons of their poor bioavailability. Berberine, have anti-inflammatory, antioxidant, anti-apoptotic properties, but also having low oral bioavailabilty. Verapamil, which increased the central nervous system uptake of few drugs, when concomitantly administered with berberine was evaluated in this animal model. Wistar rats were subjected to bilateral common carotid artery occlusion to induce acute cerebral ischemia for 15 min followed by reperfusion resulting in transient global cerebral ischemia. For 19 days berberine (5, 10, 20mg/kg, p.o.) alone and in similar doses concomitantly with verapamil (2mg/kg, p.o.) was evaluated employing various neuro-behavioral test, biochemical parameters and molecular estimations. The adjunction of berberine with verapamil improved the neurological outcome in a battery of behavioral paradigms, improved spatial memory in Morris water maze task, ameliorated the oxidative-nitrosative stress, increased acetylcholinesterase (AChE) activity, as well as improved mitochondrial complex (I, II, and IV) activity, reducing tumor necrosis factor-alpha, interleukin-1 beta and caspase-3 levels in brain tissues as compared to berberine alone group in ischemic rats. There is a strong possibility of improved brain bioavailabity of berberine when combined with verapamil. The findings suggested that the combination of berberine with verapamil, which could enhance its brain uptake, will surely provide a greater impact in neroprotection drug discovery for search of such combination.

Validated reversed-phase column high-performance liquid chromatographic method for separation and quantification of polyphenolics and furocoumarins in herbal drugs.

A rapid column high-performance liquid chromatographic-photodiode array method has been developed for the separation and identification of secondary metabolites, especially different types of phenols and furocoumarins, in a 35 min chromatographic run. The method has been optimized and validated for selectivity, precision, recovery, and robustness with the aim of application for standardization of selected herbal drugs. Almost all of the tested compounds had linearity of >98%, with relative standard deviation <10% in terms of variation of retention time. Interday and intraday variability was <5%. The developed method has been successfully applied in identification and quantification of phenols and furocoumarins present in different plants, viz., Artemisia pallens (whole plant), Hibiscus rosa-sinensis DC (flower), Heracleum candicans DC (fruit), and Ficus carica Linn (bark). The results indicate that the method is rapid, accurate, and robust for the analysis of different types of phenols and furocoumarins and, hence, can be successfully used in the quality control and standardization of plant extracts and herbal drugs.