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The interaction between gut microbes and gastrointestinal (GI) tract carcinogenesis has always attracted researchers' attention to identify therapeutic targets or potential prognostic biomarkers. Various studies have suggested that the microbiota do show inflammation and immune dysregulation, which led to carcinogenesis in GI tract. In this review, we have focused on the role of microbes present in the gut, intestine, or faeces in GI tract cancers, including esophageal cancer, gastric cancer, and colorectal cancer. Herein, we have discussed the importance of the microbes and their metabolites, which could serve as diagnostic biomarkers for cancer detection, especially in the early stage, and prognostic markers. To maximize the effect of the treatment strategies, an accurate evaluation of the prognosis is imperative for clinicians. There is a vast difference in the microbiota profiles within a population and across the populations depending upon age, diet, lifestyle, genetic makeup, use of antibiotics, and environmental factors. Therefore, the diagnostic efficiency of the microbial markers needs to be further validated. A deeper understanding of the GI cancer and the host microbiota is needed to acquire pivotal information about disease status.

Transcriptomic analysis in metabolically active tissues allows a systems genetics approach to identify causal genes and networks involved in metabolic disease. Outbred heterogeneous stock (HS) rats are used for genetic mapping of complex traits, but to-date, a systems genetics analysis of metabolic tissues has not been done. We investigated whether adiposity-associated genes and gene co-expression networks in outbred heterogeneous stock (HS) rats overlap those found in humans. We analyzed RNAseq data from adipose tissue of 415 male HS rats, correlated these transcripts with body weight (BW) and compared transcriptome signatures to two human cohorts: the African American Genetics of Metabolism and Expression and Metabolic Syndrome in Men. We used weighted gene co-expression network analysis to identify adiposity-associated gene networks and mediation analysis to identify genes under genetic control whose expression drives adiposity. We identified 554 orthologous “consensus genes” whose expression correlates with BW in the rat and with body mass index (BMI) in both human cohorts. Consensus genes fell within eight co-expressed networks and were enriched for genes involved in immune system function, cell growth, extracellular matrix organization and lipid metabolic processes. We identified 19 consensus genes for which genetic variation may influence BW via their expression, including those involved in lipolysis (e.g., Hcar1), inflammation (e.g., Rgs1), adipogenesis (e.g., Tmem120b) or no previously known role in obesity (e.g., St14, Msa4a6). Strong concordance between HS rat and human BW/BMI associated transcripts demonstrates translational utility of the rat model, while identification of novel genes expands our knowledge of the genetics underlying obesity.

Development of ocular drug delivery system is one of the most technically challenging tasks, when compared with other routes of drug delivery. Eye (an intricate organ) is highly sophisticated and sensitive organ due to presence of various structurally differed anatomical layers, which many times limits the drug delivery approaches. Despite several limitations, many advancements have been made as evidence from various recent studies involving improvement of both residence time and permeation of the drug at the ocular region. In the last few decades, albumin(s) based ophthalmic products have been gained most attention to solve the major challenges associated with conventional ocular drug delivery systems. Interestingly, an albumin-based micro, nano, conjugates, and genetically fused target specific to ligand(s) formulation being exploited through many studies for successful ocular delivery of bioactives (mostly repurposed drugs). Past and current studies suggested that albumin(s) based ocular drug delivery system is multifunctional in nature and capable of extending both drug residence time and sustaining the release of drugs to deliver desired pharmacological outcomes. Despite wide applications, still complete progress made in albumin based ocular drug delivery is limited in literature and missing in market. So, herein we presented an overview to explore the key concepts of albumin-based nanocarrier(s) including strategies involved in the treatment of ocular disease, that have yet to be explored.

The microbiota—the diverse set of commensal microbes that normally colonize humans—represents the first line of defense against infectious diseases. In this review, we summarize the direct and indirect mechanisms by which the microbiota modulates susceptibility to, and severity of, infections, with a focus on immunological mechanisms. Moreover, we highlight some of the ways that modern-world lifestyles have influenced the structure-function relationship between the microbiota and infectious diseases. Ultimately, understanding how the microbiota influences infectious risks will facilitate development of microbiota-derived therapeutics that bolster host defenses.

Background: Diabetic nephropathy (DN) is an important and catastrophic complication of diabetes mellitus (DM). Kidney disease has heterogeneity in histology in diabetes patients and includes both diabetic kidney disease (DKD) (albuminuric or nonalbuminuric) and nondiabetic kidney disease (NDKD) either in isolation or in coexistence with DN. Diabetic nephropathy is hard to overturn. While NDKD is treatable and reversible. Materials and methods: We enrolled a total of 50 type 2 diabetes mellitus (T2DM) patients with clinical kidney disease, of both genders and age >18 years, who underwent kidney biopsy from October 2016 to October 2018. Patients with proteinuria

Human microbiome studies have shown diversity to exist among different ethnic populations. However, studies pertaining to the microbial composition of CRC among the Indian population have not been well explored. We aimed to decipher the microbial signature in tumor tissues from North Indian CRC patients. Next-generation sequencing of tumor and adjacent tissue derived bacterial 16s rRNA V3-V4 hypevariable regions was performed to investigate the abundance of specific microbes. The expression profile analysis deciphered a decreased diversity among the tumor-associated microbial communities, and at the phyla level, Proteobacteria was differentially expressed in CRC tissues than adjacent normal. Further, DESeq2 normalization identified 4 out of 79 distinct species (pBacteroides massiliensis, Alistipes onderdonkii, Bifidobacterium pseudocatenulatum, and Corynebacterium appendicis. Thus, our findings suggest the use of these microbial signatures as putative biomarkers that can distinguish CRC tissues from their adjacent normal, which may shed light on the pathogenesis of CRC.

Activation of invariant natural killer T (iNKT) cells by α-galactosylceramides (α-GalCers) stimulates strong immune responses and potent anti-tumor immunity. Numerous modifications of the glycolipid structure have been assessed to derive activating ligands for these T cells with altered and potentially advantageous properties in the induction of immune responses. Here, we synthesized variants of the prototypical α-GalCer, KRN7000, with amide-linked phenyl alkane substitutions on the C4″-position of the galactose ring. We show that these variants have weak iNKT cell stimulating activity in mouse models but substantially greater activity for human iNKT cells. The most active of the C4″-amides in our study showed strong anti-tumor effects in a partially humanized mouse model for iNKT cell responses. In silico analysis suggested that the tether length and degree of flexibility of the amide substituent affected the recognition by iNKT cell antigen receptors of the C4″-amide substituted glycolipids in complex with their antigen presenting molecule CD1d. Our findings establish the use of stable C4″-amide linked additions to the sugar moiety for further exploration of the immunological effects of structural modifications of iNKT cell activating glycolipids and highlight the critical need for more accurate animal models to assess these compounds for immunotherapeutic potential in humans.

Significance Although the overwhelming majority of COVID-19-related deaths are due to respiratory failure, little is known about the host response to SARS-CoV-2 in lung parenchyma. By profiling the lung and colon transcriptome and lung proteome of nine patients who died of COVID-19 during the first wave of the pandemic in Wuhan, China, we obtained molecular insights into the host response to severe SARS-CoV-2 infection. Interestingly, all samples had a low viral burden, a finding that suggests the patients’ deaths may be due to uncontrolled host inflammatory processes rather than an active viral infection. Taken together, our findings shed light on COVID-19 pathophysiology and offer potential therapeutic targets for severe COVID-19 disease., Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection. Here we show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated our transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19.

Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in type 2 diabetes. We hypothesize that differential DNA methylation (DNAm) controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating AT DNAm profiles with transcript profile data measured in a cohort of 230 African Americans (AAs) from the African American Genetics of Metabolism and Expression cohort, we performed cis-expression quantitative trait methylation (cis-eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait–associated transcripts. We identified significantly associated cytosine-guanine dinucleotide regions for 82 transcripts (false discovery rate [FDR]-P < 0.05). The strongest eQTM locus was observed for the proopiomelanocortin (POMC; ρ = −0.632, P = 4.70 × 10−27) gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and 168 cytosine-guanine dinucleotide regions associated (FDR-P < 0.05) with the Matsuda index, SI, and BMI, respectively. Intersection of EWAS, transcript level to trait association, and eQTM results, followed by causal inference test identified significant eQTM loci for 23 genes that were also associated with Matsuda index, SI, and/or BMI in EWAS. These associated genes include FERMT3, ITGAM, ITGAX, and POMC. In summary, applying an integrative multiomics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity.

Idiopathic hypoparathyroidism leads to hypocalcemia and hyperphosphatasemia and usually has a genetic aetiology. The variable but often subtle signs and symptoms usually lead to a misdiagnosis of hypoparathyroidism. Case records of 32 patients of idiopathic hypoparathyroidism admitted over a period of five years were analysed. There was a lag period of 5.94 years from the onset of symptoms to the diagnosis. Carpopedal spasm was the most common indication for admission to the hospital. Trivial symptoms such as fatigue (84%) and paresthesia (62.5%) were the most common reported symptoms. A sum of 46.5% of the patients were on antiepileptic drugs before the correct diagnosis of hypoparathyroidism was made. This observation emphasized that Calcium profile should be obtained in patients with history of paresthesia and seizure to avoid the long delay in diagnosis of hypoparathyroidism.

Mycobacterium tuberculosis, responsible for Tuberculosis (TB), remains the leading cause of mortality among infectious diseases worldwide from a single infectious agent, with an estimated 1.7 million deaths in 2016. Biotin is an essential cofactor in M. tuberculosis that is required for lipid biosynthesis and gluconeogenesis. M. tuberculosis relies on de novo biotin biosynthesis to obtain this vital cofactor since it cannot scavenge sufficient biotin from a mammalian host. The biotin biosynthetic pathway in M. tuberculosis has been well studied and rigorously genetically validated providing a solid foundation for medicinal chemistry efforts. This review examines the mechanism and structure of the enzymes involved in biotin biosynthesis and ligation, summarizes the reported genetic validation studies of the pathway, and then analyzes the most promising inhibitors and natural products obtained from structure-based drug design and phenotypic screening.

Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β-lactamases that destroy the electrophilic β-lactam warhead. We have developed novel β-lactam conjugates, which exploit this inherent β-lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first-line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA "warhead" as well as the β-lactam "promoiety" contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy.

Lead (Pb) is a ubiquitous toxic heavy metal that is known to induce damage to major macromolecules (lipids, proteins, and nucleic acids) by enhancing the level of reactive oxygen species (ROS). Naringenin, a predominant flavonoid primarily found in citrus fruits has attained increasing attention due to its various pharmacological properties. Thus, the present investigation aimed to explore the ameliorative role of naringenin against Pb-induced toxicity in human peripheral blood lymphocytes (PBLs) under in vitro conditions. For this purpose, PBLs were exposed to Pb (350 µg/ml) alone as well in combination with naringenin (10 and 30 µg/ml). Sister chromatid exchange (SCE) and alkaline comet assay were used as genotoxic indices to evaluate the genotoxic and antigenotoxic activity of Pb and naringenin, respectively. Lipid peroxidation (LPO), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH) assays were used as oxidative damage markers. The results revealed that Pb induced a significant (p 0.05) increase in genetic and oxidative damage as compared with the untreated sample whereas the treatment of cells along with naringenin (10 and 30 µg/ml) and Pb (350 µg/ml) caused a significant reduction in genetic damage and elevation in SOD, GPx, and CAT activities and GSH level, accompanied by a significant reduction in LPO level as compared with Pb alone treated sample. So, the present investigation revealed that naringenin might be used as a protective agent against Pb-induced toxicity due to its antigenotoxic and antioxidative properties.

Aging is accompanied by major changes in body composition that can negatively affect functional status in older adults, including a progressive decrease in muscle mass, strength, and quality. The prevalence of sarcopenia has varied considerably, depending on the definition used and the population surveyed-a 2014 meta-analysis across several countries found estimates ranging from 1% to 29% for people aged 60 years or older, who live independently. The potentially relevant studies were retrieved from the ScienceDirect/Medline/PubMed/Public library of science/Mendeley/Springer link and Google Scholar. Multiple keywords were used for the literature search both alone and in combination. Some of the important keywords used for literature search were as follows: "Epidemiology of muscle weakness/muscle disorders," "Pathogenesis of RAAS in muscle weakness," "Role of Angiotensin 1-7/ACE-2/Mas R axis in muscle weakness," and "Correction pathophysiology of muscle weakness via ACE2." The renin-angiotensin system (RAAS), a major blood pressure regulatory system, is a candidate mediator that may promote aging-associated muscle weakness. Previously, studies explored the proof concept for RAAS inhibition as a therapeutic target. Furthermore, in RAAS, angiotensin II, and angiotensin-converting enzyme 2 (ACE2) have been reported to induce endoplasmic reticulum (ER) stress via glucose-regulated protein 78/eukaryotic translation initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4)/CHOP axis in the liver. In addition, other mitochondria and ER physical interactions contribute to skeletal muscle dysfunction. However, very few studies have investigated the relationship between RAAS and ER stress-associated pathophysiological events and ACE2-mediated biological consequences in muscle weakness. Thus, the study has been designed to investigate the RAAS-independent beneficial role of ACE2 in muscle weakness.

In this multicohort retrospective analysis, the genotype clustering frequency ranked method was used for molecular clustering of tumor genomic data from 776 patients withGenotype clustering identified eight molecular subgroups and the CBM characterized their shared cancer pathway characteristics:CBM identified distinct PD-(L)1 immunotherapy sensitivity among molecular subgroups of

Radial neuron migration in the developing cerebral cortex is a complex journey, starting in the germinal zones and ending in the cortical plate. In mice, migratory distances can reach several hundreds of microns, or millimeters in humans. Along the migratory path, radially migrating neurons slither through cellularly dense and complex territories before they reach their final destination in the cortical plate. This task is facilitated by radial glia, the neural stem cells of the developing cortex. Indeed, radial glia have a unique bipolar morphology, enabling them to serve as guides for neuronal migration. The key guiding structure of radial glia is the basal process, which traverses the entire thickness of the developing cortex. Neurons recognize the basal process as their guide and maintain physical interactions with this structure until the end of migration. Thus, the radial glia basal process plays a key role during radial migration. In this review, we highlight the pathways enabling neuron-basal process interactions during migration, as well as the known mechanisms regulating the morphology of the radial glia basal process. Throughout, we describe how dysregulation of these interactions and of basal process morphology can have profound effects on cortical development, and therefore lead to neurodevelopmental diseases.

Plastic pollution has become a serious transboundary challenge to nature and human health, with estimation of reports published - predicting a twofold increase in plastic waste by 2030. However, due to the COVID-19 pandemic, the excessive use of single-use plastics (including face masks, gloves and personal protective equipment) would possibly exacerbate such forecasts. The transition towards eco-friendly alternatives like bio-based plastics and new emerging sustainable technologies would be vital to deal with future pandemics, even though the use or consumption of plastics has greatly enhanced our quality of life; it is however critical to move towards bioplastics. We cannot deny the fact that bioplastics have some challenges and shortcomings, but still, it is an ideal option for opt. The circular economy is the need of the hour for waste management. Along with all these practices, individual accountability, corporate intervention and government policy are also needed to prevent us from moving from one crisis to the next. Only through cumulative efforts, we will be able to cope up with this problem. This article collected scattered information and data about accumulation of plastic during COVID-19 worldwide. Additionally, this paper illustrates the substitution of petroleum-based plastics with bio-based plastics. Different aspects are discussed, ranging from advantages to challenges in the way of bioplastics.

PURPOSE: The Consumer Assessment of Healthcare Providers and Systems (CAHPS) Cancer Care Survey is a systematic assessment of health care experiences of patients with cancer. It supports comparisons among all cancer treatment settings and modalities. METHODS: Formative research included 16 focus groups with patients receiving treatment and family members; advice from a panel of oncology and quality improvement experts; and interviews with stakeholders representing oncology associations, accredited cancer centers, and community oncology practices. We conducted cognitive tests of the instrument and field tests at six cancer centers and four community oncology practices, after which the survey was finalized and obtained the CAHPS trademark. RESULTS: The survey includes 56 questions that form six core composite measures (Getting Timely Care; Supporting Patient Self-Management; Available to Provide Care and Information; Provider Communication; Care Coordination; and Courteous Office Staff); two single-item measures of family participation in care and interpreter services; and two global ratings of cancer care and the treatment team. Sixteen additional items form three supplemental composite measures: Shared Decision-Making, Keeping Patients Informed, and Access to Care. CONCLUSION: Mail-only, mail-telephone mixed-mode, and Web-mail mixed-mode data collection methods are recommended. The questionnaires and instructions for use are free and available in English and Spanish on the CAHPS Website ( www.ahrq.gov/cahps ).

Gastrointestinal (GI) syndrome is a serious side effect and dose-limiting toxicity observed in patients undergoing lower-abdominal radiotherapy. Previous mouse studies show that p53 gene dosage determines susceptibility to GI syndrome development. However, the translational relevance of p53 activity has not been addressed. Here, we used a knock-in mouse in which the p53–Mdm2 negative feedback loop is genetically disrupted. These mice retain biallelic p53 and thus, normal basal p53 levels and activity. However, due to the lack of p53-mediated Mdm2 transcription, irradiated Mdm2(P2/P2) mice exhibit enhanced acute p53 activity, which protects them from GI failure. Intestinal crypt cells residing in the +4 and higher positions exhibit decreased apoptosis, increased p21 expression, and hyperproliferation to reinstate intestinal integrity. Correspondingly, pharmacological augmentation of p53 activity in wild-type mice with an Mdm2 inhibitor protects against GI toxicity without affecting therapeutic outcome. Our results suggest that transient disruption of the p53–Mdm2 interaction to enhance p53 activity could be a viable prophylactic strategy for alleviating GI syndrome in patients undergoing radiotherapy.

BACKGROUND Major lumbar spine surgery causes severe postoperative pain. The primary objective of this randomized controlled study was to compare the effect of ultrasound (US)-guided erector spinae plane (ESP) block on 24-hour postoperative cumulative opioid requirements with standard (opioid-based) analgesia. Postoperative pain control and patient satisfaction were also assessed. MATERIALS AND METHODS Adults scheduled for elective lumbar spine surgery under general anesthesia were randomly assigned to the following (and they are): Control group-no preoperative ESP block, or ESP block group-preoperative bilateral US-guided ESP block. Both groups received standard general anesthesia during surgery. Postoperative pain score, number of patients requiring rescue analgesia, and total morphine consumption during the first 24 postoperative hours were recorded. Patient satisfaction was assessed 24 hours after surgery. RESULTS Postoperative morphine consumption was significantly lower in patients in the ESP group compared with those in the control group (1.4±1.5 vs. 7.2±2.0 mg, respectively; P

Compelling evidence suggest that germs cells are predominantly sensitive to DNA damaging agents in comparison to other cells. High fidelity DNA repair in testicular cells thus becomes indispensable to preserve the genomic integrity for passing on to the progeny. Compromised DNA repair machinery in the testicular cells may result in impaired spermatogenesis and infertility. It remains unclear if the alterations in the expression of DNA repair genes correlate with azoospermia and male infertility. In the present study, 54 non-obstructive azoospermic infertile patients with hypospermatogenesis (HS, n = 26), maturation arrest (MA, n = 15), Sertoli cell only syndrome (SCOS, n = 13) and 14 controls with obstructive azoospermia, but normal spermatogenesis were recruited. Expression profiling of 84 DNA repair genes in testicular biopsy samples was performed using PCR array. Out of 84 genes, 27, 64 and 28 genes showed >5 fold down-regulation in the HS, MA and SCOS groups, respectively. On the basis of differential expression and their functional significance in spermatogenesis, ten genes (MSH2, BRIP1, CCNH, LIG4, MGMT, NTHL1, PMS1, DMC1, POLB and XPA) were selected for validation of transcript levels in a higher number of cases using RT-PCR, which corroborated the findings of array. Four genes (MSH2, LIG4, PMS1 and DMC1) were analyzed for protein levels using immunohistochemistry, which further validated the loss of DNA repair gene expression. Caspase-3 immunostaining showed that the loss of DNA repair correlated with increased testicular apoptosis in patients. Maturation arrest showed the highest apoptotic index with maximum number of downregulated genes. We conclude that the loss of DNA repair genes expression in testis correlates with increased apoptosis, azoospermia and infertility.

The synthesis, absolute stereochemical configuration, complete biological characterization, mechanism of action and resistance, and pharmacokinetic properties of (S)-(−)-acidomycin are described. Acidomycin possesses promising antitubercular activity against a series of contemporary drug susceptible and drug-resistant M. tuberculosis strains (MICs = 0.096–6.2 μM), but is inactive against non-tuberculosis mycobacteria, gram-positive and gram-negative pathogens (MICs > 1000 μM). Complementation studies with biotin biosynthetic pathway intermediates and subsequent biochemical studies confirmed acidomycin inhibits biotin synthesis with a K(i) of approximately 1 μM through the competitive inhibition of biotin synthase (BioB) and also stimulates unproductive cleavage of S-adenosylmethionine (SAM) to generate the toxic metabolite 5′-deoxyadenosine. Cell studies demonstrate acidomycin selectively accumulates in M. tuberculosis providing a mechanistic basis for the observed antibacterial activity. The development of spontaneous resistance by M. tuberculosis to acidomycin was difficult and only low-level resistance to acidomycin was observed by overexpression of BioB. Collectively, the results provide a foundation to advance acidomycin and highlight BioB as a promising target.

Background: Use of sunscreens on the face is becoming popular, and patients with melasma are prescribed sunscreen for use on the face. Results of a few Western studies on the effect of sunscreen use on serum vitamin D concentration are not applicable to Indian conditions. Aims: To examine the effect of use of a high sun protection factor (SPF 50+, PA++++) sunscreen on face in patients with melasma on serum concentration of 25-hydroxyvitamin D. Methods: Forty-five Indian patients (Fitzpatrick skin types III and IV) with melasma were advised to use a sunscreen with SPF 50 + for 3 months, 43 (33 female, 10 male; age 32.9 ± 8 years) completed the study. Patients staying outdoor for 4 hours reapplied sunscreen 4 hours after first application. Patients were provided a container to measure the amount of sunscreen for use, which was approximately equal to recommended thickness. Compliance was tested by weighing the used tubes and tubes in use during monthly visits. Serum concentration of 25-hydroxyvitamin D was tested before and after the study period. Results: Amount of sunscreen advised (100.5 ± 29.2 ml) and the actual amount used (96.6 ± 27.9 ml) were similar (P = 0.53, t-test). The difference between serum concentrations of 25-hydroxyvitamin D at the baseline (19.20 ± 9.06 ng/ml) and at 3 months (18.91 ± 8.39 ng/ml) was not significant (P = 0.87, paired t-test, 95% confidence interval of difference −3.33 to 3.92). No correlation was found between the amount of sunscreen used and the percentage change in serum 25-hydroxyvitamin D concentration at 3 months (rho = 0.099, P = 0.528, Spearman's rank correlation). Limitations: Longer duration of application and a larger sample size may detect minor differences in vitamin D concentration. Conclusion: Using a high SPF sunscreen on the face, along with physical photoprotection advice, in patients with melasma for 3 months does not influence serum 25-hydroxyvitamin D concentration in Indian conditions.

Subcutaneous insulin therapy is associated with important injection site complications, which can influence insulin pharmacokinetics resulting in glycemic fluctuations above and below target levels for blood glucose.Our objective was to assess the prevalence and risk factors of cutaneous complications including insulin derived amyloidosis in insulin-injecting diabetes patients and to study the role of ultrasonography (in comparison to gel-assisted palpation) in early diagnosis of lipohypertrophy (LH).This was a cross-sectional study conducted at a tertiary care center in India, wherein 500 patients injecting insulin for ≥2 years were randomly enrolled and evaluated for the presence of cutaneous complications of insulin therapy through clinical examination, ultrasonography and punch biopsy of skin.Clinical examination detected LH in 44.6% of patients. Ultrasonography diagnosed additional 13.4% of patients with LH which were missed on clinical examination. Incorrect rotation of sites (P0.001) and insulin syringe reusage for more than five times (P0.001) significantly increased the risk of LH. Skin biopsy was performed in 100 cases, out of which two patients showed apple green birefringence and its association with insulin was confirmed by positive staining with anti insulin antibody in these two patients.Improper rotation of sites and reuse of needles were the leading causes of LH in Indian diabetic patients. Ultrasonography is more objective and reliable method of detecting LH. Insulin-derived amyloidosis may be a more common complication of insulin therapy than previously thought.

Rhamnolipids (RLs) are surface-active compounds and belong to the class of glycolipid biosurfactants, mainly produced from Pseudomonas aeruginosa. Due to their non-toxicity, high biodegradability, low surface tension and minimum inhibitory concentration values, they have gained attention in various sectors like food, healthcare, pharmaceutical and petrochemicals. The ecofriendly biological properties of rhamnolipids make them potent materials to be used in therapeutic applications. RLs are also known to induce apoptosis and thus, able to inhibit proliferation of cancer cells. RLs can also act as immunomodulators to regulate the humoral and cellular immune systems. Regarding their antimicrobial property, they lower the surface hydrophobicity, destruct the cytoplasmic membrane and lower the critical micelle concentration to kill the bacterial cells either alone or in combination with nisin possibly due to their role in modulating outer membrane protein. RLs are also involved in the synthesis of nanoparticles for in vivo drug delivery. In relation to economic benefits, the post-harvest decay of food can be decreased by RLs because they prevent the mycelium growth, spore germination of fungi and inhibit the emergence of biofilm formation on food. The present review focuses on the potential uses of RLs in cosmetic, pharmaceutical, food and health-care industries as the potent therapeutic agents.

Peroxiredoxins (Prxs) are antioxidant proteins that are involved in cellular defence against reactive oxygen species and reactive nitrogen species. Humans have six peroxiredoxins, hPrxI-VI, out of which hPrxI and hPrxII belongs to the typical 2-Cys class sharing 90% conservation in their amino acid sequence including catalytic residues required to carry out their peroxidase and chaperone activities. Despite the high conservation between hPrxI and hPrxII, hPrxI behaves differently from hPrxII in its peroxidase and chaperone activity. We recently showed in yeast that in the absence of Tsa1 and Tsa2 (orthologs of hPrx) hPrxI protects the cells against different stressors whereas hPrxII does not. To understand this difference, we expressed catalytic mutants of hPrxI in yeast cells lacking the orthologs of hPrxI/II. We found that the catalytic mutants lacking peroxidase function including hPrxIC52S, hPrxIC173S, hPrxIT49A, hPrxIP45A and hPrxIR128A were not able to grow on media with nitrosative stressor (sodium nitroprusside) and unable to withstand heat stress, but surprisingly they were able to grow on an oxidative stressor (H2O2). Interestingly, we found that hPrxI increases the expression of antioxidant genes, GPX1 and SOD1, and this is also seen in the case of a catalytic mutant, indicating hPrxI can indirectly reduce oxidative stress independently of its own peroxidase function and thus suggesting a novel role of hPrxI in altering the expression of other antioxidant genes. Furthermore, hPrxIC83T was resistant to hyperoxidation and formation of stable high molecular weight oligomers, which is suggestive of impaired chaperone activity. Our results suggest that the catalytic residues of hPrxI are essential to counter the nitrosative stress whereas Cys83 in hPrxI plays a critical role in hyperoxidation of hPrxI., Graphical abstract Image 1

The present study was designed to develop pH-sensitive lipid polymer hybrid nanoparticles (pHS-LPHNPs) for specific cytosolic-delivery of docetaxel (DTX). The pHS-LPHNPs-DTX formulation was prepared by self-assembled nano-precipitation technique and characterized for zeta potential, particle size, entrapment efficiency, polydispersity index (PDI), and in vitro drug release. In vitro cytotoxicity of pHS-LPHNPs-DTX was assessed on breast cancer cells (MDA-MB-231 and MCF-7) and compared with DTX-loaded conventional LPHNPs and bare DTX. In vitro cellular uptake in MDA-MB-231 cell lines showed better uptake of pHS-LPHNPs. Further, a significant reduction in the IC50 of pHS-LPHNPs-DTX against both breast cancer cells was observed. Flow cytometry results showed greater apoptosis in case of pHS-LPHNPs-DTX treated MDA-MB-231 cells. Breast cancer was experimentally induced in BALB/c female mice, and the in vivo efficacy of the developed pHS-LPHNPs formulation was assessed with respect to the pharmacokinetics, biodistribution in the vital organs (liver, kidney, heart, lungs, and spleen), percentage tumor burden, and survival of breast cancer-bearing animals. In vivo studies showed improved pharmacokinetic and target-specificity with minimum DTX circulation in the deep-seated organs in the case of pHS-LPHNPs-DTX compared to the LPHNPs-DTX and free DTX. Mice treated with pHS-LPHNPs-DTX exhibited a significantly lesser tumor burden than other treatment groups. Also, reduced distribution of DTX in the serum was evident for pHS-LPHNPs-DTX treated mice compared to the LPHNPs-DTX and free DTX. In essence, pHS-LPHNPs mediated delivery of DTX presents a viable platform for developing therapeutic-interventions against breast-cancer.

Dyslipidaemia has a prominent role in the onset of notorious atherosclerosis, a disease of medium to large arteries. Atherosclerosis is the prime root of cardiovascular events contributing to the most considerable number of morbidity and mortality worldwide. Factors like cellular senescence, genetics, clonal haematopoiesis, sedentary lifestyle-induced obesity, or diabetes mellitus upsurge the tendency of atherosclerosis and are foremost pioneers to definitive transience. Accumulation of oxidized low-density lipoproteins (Ox-LDLs) in the tunica intima triggers the onset of this disease. In the later period of progression, the build-up plaques rupture ensuing thrombosis (completely blocking the blood flow), causing myocardial infarction, stroke, and heart attack, all of which are common atherosclerotic cardiovascular events today. The underlying mechanism is very well elucidated in literature but the therapeutic measures remains to be unleashed. Researchers tussle to demonstrate a clear understanding of treating mechanisms. A century of research suggests that lowering LDL, statin-mediated treatment, HDL, and lipid-profile management should be of prime interest to retard atherosclerosis-induced deaths. We shall brief the Ox-LDL-induced atherogenic mechanism and the treating measures in line to impede the development and progression of atherosclerosis.

Agriculture has the most significant contribution in fulfilling the basic human need, sustaining life, and strengthening the economy of any country. To feed the exploding population of the world, there has been a quantum jump in the production of agricultural commodities, which has led to the production of a substantial considerable quantity of agricultural and agro-industrial wastes. The bulks of these wastes are lignocellulosic in nature and consist of three main polymeric constituents, i.e., cellulose, hemicellulose, and lignin, which are recalcitrant. The primary significant portions of these remain unutilized and are burnt in the field, leading to severe environmental aggression and wastage of resource. Farmers across the globe, including India, burn these agricultural wastes in their thousands of acre land, which contribute to spoiling the air quality index (AQI). This is very harmful, especially to children, pregnant women, old adults, and for patients suffering from respiratory diseases. The current manuscript sets up an agro-waste management platform by using paddy straw as a substrate for the production of nutritionally and medically rich oyster mushroom, Pleurotus florida (Pf) and which is further used in the green synthesis of bimetallic (gold-platinum) Au-Pt nanoparticle. Yield performance and biological efficiency of Pf were calculated from the degraded paddy straw. The green synthesized Au-Pt NPs were structurally characterized by ultraviolet-visible (UV-Vis), X-ray diffraction (XRD), transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS), and zeta potential analysis. The prepared NPs showed a face-centered cubic crystal structure, icosahedral shape with a mean particle size of 16 nm. Furthermore, we examined the cytotoxic activity of Au-Pt NPs using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, intracellular reactive oxygen species (ROS) generation, and apoptosis by propidium iodide assay. We found that Au-Pt NPs exerted apoptotic activity on the human colon cancer cell line (HCT 116) in a dose-dependent manner from 12.5 to 200 μg/mL. Overall, our findings create a prototype and open a new door to synthesizing functional nanoparticle by using oyster mushroom as the substrate for paddy straw agro-waste management and the applicability of Pf in the synthesis of eco-friendly Au-Pt NPs. This is the first kind of approach that kills two birds with one stone.

Objective Little is known about factors affecting medical care experiences of cancer survivors. This study examined experience of care among cancer survivors and assessed associations of survivors' characteristics with their experience. Materials and Methods We used a newly-developed, unique data resource, SEER-CAHPS (NCI's Surveillance Epidemiology and End Results [SEER] data linked to Medicare Consumer Assessment of Healthcare Providers and Systems [CAHPS] survey responses), to examine experiences of care among breast, colorectal, lung, and prostate cancer survivors age > 66 years who completed CAHPS > 1 year after cancer diagnosis and survived ≥ 1 year after survey completion. Experience of care was assessed by survivor-provided scores for overall care, health plan, physicians, customer service, doctor communication, and aspects of care. Multivariable logistic regression models assessed associations of survivors' sociodemographic and clinical characteristics with care experience. Results Among 19,455 cancer survivors with SEER-CAHPS data, higher self-reported general-health status was significantly associated with better care experiences for breast, colorectal, and prostate cancer survivors. In contrast, better mental-health status was associated with better care experience for lung cancer survivors. College-educated and Asian survivors were less likely to indicate high scores for care experiences. Few differences in survivors' experiences were observed by sex or years since diagnosis. Conclusions The SEER-CAHPS data resources allows assessment of factors influencing experience of cancer among U.S. cancer survivors. Higher self-reported health status was associated with better experiences of care; other survivors' characteristics also predicted care experience. Interventions to improve cancer survivors' health status, such as increased access to supportive care services, may improve experience of care.

ADIPOQ/adiponectin, an adipocytokine secreted by adipocytes in the breast tumor microenvironment, negatively regulates cancer cell growth hence increased levels of ADIPOQ/adiponectin are associated with decreased breast cancer growth. However, its mechanisms of action remain largely elusive. We report that ADIPOQ/adiponectin induces a robust accumulation of autophagosomes, increases MAP1LC3B-II/LC3B-II and decreases SQSTM1/p62 in breast cancer cells. ADIPOQ/adiponectin-treated cells and xenografts exhibit increased expression of autophagy-related proteins. LysoTracker Red-staining and tandem-mCherry-GFP-LC3B assay show that fusion of autophagosomes and lysosomes is augmented upon ADIPOQ/adiponectin treatment. ADIPOQ/adiponectin significantly inhibits breast cancer growth and induces apoptosis both in vitro and in vivo, and these events are preceded by macroautophagy/autophagy, which is integral for ADIPOQ/adiponectin-mediated cell death. Accordingly, blunting autophagosome formation, blocking autophagosome-lysosome fusion or genetic-knockout of BECN1/Beclin1 and ATG7 effectively impedes ADIPOQ/adiponectin induced growth-inhibition and apoptosis-induction. Mechanistic studies show that ADIPOQ/adiponectin reduces intracellular ATP levels and increases PRKAA1 phosphorylation leading to ULK1 activation. AMPK-inhibition abrogates ADIPOQ/adiponectin-induced ULK1-activation, LC3B-turnover and SQSTM1/p62-degradation while AMPK-activation potentiates ADIPOQ/adiponectin's effects. Further, ADIPOQ/adiponectin-mediated AMPK-activation and autophagy-induction are regulated by upstream master-kinase STK11/LKB1, which is a key node in antitumor function of ADIPOQ/adiponectin as STK11/LKB1-knockout abrogates ADIPOQ/adiponectin-mediated inhibition of breast tumorigenesis and molecular analyses of tumors corroborate in vitro mechanistic findings. ADIPOQ/adiponectin increases the efficacy of chemotherapeutic agents. Notably, high expression of ADIPOQ receptor ADIPOR2, ADIPOQ/adiponectin and BECN1 significantly correlates with increased overall survival in chemotherapy-treated breast cancer patients. Collectively, these data uncover that ADIPOQ/adiponectin induces autophagic cell death in breast cancer and provide in vitro and in vivo evidence for the integral role of STK11/LKB1-AMPK-ULK1 axis in ADIPOQ/adiponectin-mediated cytotoxic autophagy.

Tumor suppressor and upstream master kinase Liver kinase B1 (LKB1) plays a significant role in suppressing cancer growth and metastatic progression. We show that low-LKB1 expression significantly correlates with poor survival outcome in breast cancer. In line with this observation, loss-of-LKB1 rendered breast cancer cells highly migratory and invasive, attaining cancer stem cell-like phenotype. Accordingly, LKB1-null breast cancer cells exhibited an increased ability to form mammospheres and elevated expression of pluripotency-factors (Oct4, Nanog and Sox2), properties also observed in spontaneous tumors in Lkb1−/− mice. Conversely, LKB1-overexpression in LKB1-null cells abrogated invasion, migration and mammosphere-formation. Honokiol (HNK), a bioactive molecule from Magnolia grandiflora increased LKB1 expression, inhibited individual cell-motility and abrogated the stem-like phenotype of breast cancer cells by reducing the formation of mammosphere, expression of pluripotency-factors and aldehyde dehydrogenase activity. LKB1, and its substrate, AMP-dependent protein kinase (AMPK) are important for HNK-mediated inhibition of pluripotency factors since LKB1-silencing and AMPK-inhibition abrogated, while LKB1-overexpression and AMPK-activation potentiated HNK’s effects. Mechanistic studies showed that HNK inhibited Stat3-phosphorylation/activation in an LKB1-dependent manner, preventing its recruitment to canonical binding-sites in the promoters of Nanog, Oct4 and Sox2. Thus, inhibition of the coactivation-function of Stat3 resulted in suppression of expression of pluripotency factors. Further, we showed that HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cancer and effective anticancer modulation of this axis with HNK treatment.

Aim: The aim of present research was to complex aceclofenac with lysine (LYS) and the developed aceclofenac–LYS cocrystal was encapsulated in lipid bilayers of liposomes by employing dual carrier approach for the treatment of pain-related disorders in rheumatoid arthritis (RA). Materials & methods: The developed carriers were characterized for particle size, drug release, ex vivo and in vivo studies, dermatokinetic modeling, complete freund's adjuvant (CFA)-induced RA rat model, radiant heat tail-flick method, formalin-induced paw-licking model, paw edema model and xylene-induced ear edema model in mice. Results: The developed nanoliposomes offered nanometric size, controlled drug release and enhanced drug permeation. Further, hydrogel incorporated nanoproduct was found to be rheologically acceptable and substantially compatible with rodent skin. Conclusion: The studies indicated the superiority of LYS-conjugated liposome-entrapped nanocarriers for improved management of conditions like RA over the marketed product.

M3 muscarinic receptor (M3R) expression is increased in colon cancer; M3R activation stimulates colon cancer cell invasion via cross-talk with epidermal growth factor receptors (EGFR), post-EGFR activation of mitogen-activated protein kinase (MAPK) extracellular signal-related kinase 1/2 (ERK1/2), and induction of matrix metalloproteinase-1 (MMP1) expression. MMP1 expression is strongly associated with tumor metastasis and adverse outcomes. Here, we asked whether other MAPKs regulate M3R agonist-induced MMP1 expression. In addition to activating ERK1/2, we found that treating colon cancer cells with acetylcholine (ACh) stimulated robust time- and dose-dependent phosphorylation of p38 MAPK. Unlike ERK1/2 activation, ACh-induced p38 phosphorylation was EGFR-independent and blocked by inhibiting protein kinase C-α (PKC-α). Inhibiting activation of PKC-α, EGFR, ERK1/2, or p38-α/β alone attenuated, but did not abolish ACh-induced MMP1 expression, a finding that predicted potentiating interactions between these pathways. Indeed, ACh-induced MMP1 expression was abolished by incubating cells with either an EGFR or MEK/ERK1/2 inhibitor combined with a p38-α/β inhibitor. Activating PKC-α and EGFR directly with the combination of phorbol 12-myristate 13-acetate (PMA) and EGF potentiated MMP1 gene and protein expression, and cell invasion. PMA- and ACh-induced MMP1 expression were strongly diminished by inhibiting Src and abolished by concurrently inhibiting both p38-α/β and Src, indicating that Src mediates the cross-talk between PKC-α and EGFR signaling. Using siRNA knockdown, we identified p38-α as the relevant p38 isoform. Collectively, these studies uncover novel functional interactions between post-muscarinic receptor signaling pathways that augment MMP1 expression and drive colon cancer cell invasion; targeting these potentiating interactions has therapeutic potential.