A scoping review on 'Maharishi Amrit Kalash', an ayurveda formulation for cancer prevention and management.

BACKGROUND: Cancer is one of the leading causes of morbidity and mortality. Current treatments include chemotherapy, radiotherapy, etc., are known to be associated with several side effects. Hence, complementary and alternative medicine is growing in acceptance around the world, particularly Ayurvedic formulations. MAK is one of the most scientifically acclaimed formulations with potential anti-neoplastic and chemoprotective properties. OBJECTIVE: To study literature available on the anti-neoplastic and chemoprotective effects of MAK. MATERIAL AND METHODS: A systematic literature review was conducted using multiple web-based sources: Google Scholar (185), PubMed (33), DHARA (49), AYUSH research portal (2), EBSCO (66), and CTRI (1) for all studies published before February 2021 using keywords: Maharishi Amrit Kalash, Amrit Kalash, Amrit, MAK-4, MAK-5, MAK-7, and others. A manual search was conducted on the reference list of all included articles to identify additional studies. Studies with cancer and/or chemotoxicity outcomes were selected manually. Evidence from both preclinical and clinical level studies have been included in the current review. RESULTS: Out of total 79 studies on applications of MAK, 13 studies were found to state its anti-neoplastic and chemoprotective effects. The studies showed role of MAK in initiation of neoplastic transformation of cancer cells (1), carcinogenesis inhibition (4), metastases inhibition/reduction (1), cancer growth inhibition (4), induction of morphological and biochemical differentiation of cancer cells (3), and reduction in chemotoxicity (4). In studies with controlled clinical trial design (3), MAK use among patients with cancer showed a significant reduction in anorexia, vomiting, and other side effects associated with chemotherapy. A general improvement in quality-of-life scores (Karnofsky Performance Status) and well-being was also observed among patients using MAK. CONCLUSION: Evidence from pre-clinical studies show promising results for use of MAK as an anti-cancer and a chemoprotective agent. More clinical studies are needed to assess the impact of MAK use for tumour regression among patients with cancer. Current scoping review provides sufficient evidence on MAK to be considered for further exploration for its anti-cancer/chemoprotective effects in bigger randomized clinical trials.

Identification and characterization of a novel decalin derivative with anti-Candida activity from Streptomyces chrestomyceticus strain ADP4.

A novel decalin derivative, trans-1-oxo-2,4-diacetylaminodecalin (1) with anti-Candida activity, had been isolated from Streptomyces chrestomyceticus strain ADP4. The structure of the compound was determined from the analysis of spectral data (LCMS/MS, UV, FTIR, 1D- and 2D-NMR). The anti-Candida activity of 1 was specific to Candida albicans and Candida auris. Further, it displayed inhibition of the early-stage biofilm of C. albicans. In-silico analysis of the compound revealed its drug likeness properties without any violations and PAINS alert when investigated for ADME properties. Along with the overall bioavailability, compound 1 did not show any predicted bioaccumulation and mutagenicity in the analysis by TEST software. Non-cytotoxic property was further confirmed by in-vitro assay on the HepG2 cell line.

Potentiation of Adipogenesis by Reactive Oxygen Species Is a Unifying Mechanism in the Proadipogenic Properties of Bisphenol A and Its New Structural Analogues.

Aims: Structural analogues of bisphenol A (BPA), including bisphenol S (BPS) and bisphenol F (BPF), are emerging environmental toxicants as their presence in the environment is rising since new regulatory restrictions were placed on BPA-containing infant products. The adipogenesis-enhancing effect of bisphenols may explain the link between human exposure and metabolic disease; however, underlying molecular pathways remain unresolved. Results: Exposure to BPS, BPF, BPA, or reactive oxygen species (ROS) generators enhanced lipid droplet formation and expression of adipogenic markers after induction of differentiation in adipose-derived progenitors isolated from mice. RNAseq analysis in BPS-exposed progenitors revealed modulation in pathways regulating adipogenesis and responses to oxidative stress. ROS were higher in bisphenol-exposed cells, while cotreatment with antioxidants attenuated adipogenesis and abolished the effect of BPS. There was a loss of mitochondrial membrane potential in BPS-exposed cells and mitochondria-derived ROS contributed to the potentiation of adipogenesis by BPS and its analogues. Male mice exposed to BPS during gestation had higher whole-body adiposity, as measured by time domain nuclear magnetic resonance, while postnatal exposure had no impact on adiposity in either sex. Innovation: These findings support existing evidence showing a role for ROS in regulating adipocyte differentiation and are the first to highlight ROS as a unifying mechanism that explains the proadipogenic properties of BPA and its structural analogues. Conclusion: ROS act as signaling molecules in the regulation of adipocyte differentiation and mediate bisphenol-induced potentiation of adipogenesis. Antioxid. Redox Signal. 40, 1-15.

Empty stomach together with menstrual bleeding as predictors of committed suicides among women of reproductive age: What a primary physician must know.

Background: Women of reproductive age group (WoRAG) are among the most vulnerable groups to suicide in India. The present study intended to develop a mathematical model to differentiate suicides from homicides among WoRAG. Methods: It was a cross-sectional study based on a record review of autopsy at Patna, India, from 2016 to 2021. The cause of deaths was ascertained by autopsies and other records independently by two investigators to reduce the interobserver bias. Independent variables were tested with confirmed suicides to calculate statistically significant association. These variables were further used for developing prediction models for the suicides by multivariate logistic regression analysis. Results: Out of total of 520 autopsies of WoRAG performed by investigators, the cause of death has been confirmed for 62. Of them, 30 were confirmed as suicides. In univariate analysis, suicides were associated with the menstrual bleed (OR 35 CI 6.9,179), gastric emptying (OR 3.9 CI 1.2,12.8), hanging, poisoning, and drowning as mode of death (OR 435 CI 37.4,5061.9). By logistic regression, three prediction models were built to predict suicide; Model I: gastric emptying, Model II: menstrual bleed, and Model III: including both. The area under the curve (AUC) for Models I, II, and III was 0.67 (95%CI 0.34,0.99), 0.92 (95%CI 0.75,1.00), and 0.94 (95%CI 0.82,1.00), respectively. The AUC of Model III differs significantly from that of Model I (P value 0.03) but not with Model II (P value 0.11). Conclusion: Menstrual bleed, gastric emptying, and mode of death may be used as a supplement tool in ascertaining the cause of death among WoRAG in medical and legal proceedings.

Phenyl Pentyl Ketone and m-isobutyl Methoxy Benzoate Produced by Streptomyces Chrestomyceticus ADP4 are Potent Antimicrobial Agents Displaying Broad Spectrum Activities.

Isolation and identification of two antimicrobial compounds, a phenyl pentyl ketone (CP1) and m-isobutyl methoxy benzoate (CP2), from Streptomyces chrestomyceticus ADP4 have been reported. Structure of the compounds were elucidated from analyses of spectral data that included LCMS/MS, NMR, FTIR and UV spectroscopies. Both the compounds displayed significant inhibition of albicans and non-albicans species of Candida (NAC) pathogens including C. auris, which is currently a pathogen of global concern. Also, the compounds showed potent antagonistic activity against Staphylococcus aureus, another significant human pathogen. No in-vitro cytotoxicity against HePG2 cells was observed with either of the compounds. Both displayed favourable drug likeness properties as determined by in-silico ADME and toxicological studies. Also, this is the first report on production of these anti-microbial compounds by an actinobacterium. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01068-7.

Anti-Candida attributes and in-silico drug-likeness properties of phenyl 2'ß, 6'ß-trimethyl cyclohexyl ketone and phenyl nonanyl ether produced by Streptomyces chrestomyceticus ADP4.

AIM: To isolate and characterize anti-Candida compounds from soil actinobacterium Streptomyces chrestomyceticus ADP4 and to assess their drug likeness. METHODS AND RESULTS: Two anti-Candida compounds, Phenyl 2'α, 2'ß, 6'ß-trimethyl cyclohexyl ketone (1PB1) and Phenyl nonanyl ether (1PB2), were isolated from the metabolites produced by Streptomyces chrestomyceticus ADP4. Their structures were deduced by extensive analyses of spectral data obtained from liquid chromatography with tandem mass spectrometry (LCMS/MS), nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FTIR) and ultraviolet (UV) spectroscopies. While both the compounds inhibited growth of the Candida spp., 1PB2 was effective in inhibiting biofilm formed by Candida albicans ATCC 10231. The compounds did not show any cytotoxicity against HepG2 cells and were found to be safe when predicted theoretically on rat model, bioaccumulation and mutagenicity by using the software: toxicity estimation software tool (TEST). The compounds displayed drug-like properties when analyzed by using SwissADME software. CONCLUSIONS: 1PB1 and 1PB2 are being reported for the first time from any natural source along with their anti-Candida properties. In-silico studies revealed their druggability and suitability to take up further work on the compounds for their possible application in treating Candida-associated infections. SIGNIFICANCE AND IMPACT OF THE STUDY: The increasing prevalence of Candidiasis associated with drug-resistant strains of Candida spp. highlighted the urgent need for discovery of new compounds with anti-Candida properties that could hold promise as potential drug candidate.

Exploring oxidative stress and endothelial dysfunction as a mechanism linking bisphenol S exposure to vascular disease in human umbilical vein endothelial cells and a mouse model of postnatal exposure.

BACKGROUND: Structural analogues used to replace bisphenol A (BPA) since the introduction of new regulatory restrictions are considered emerging environmental toxicants and remain understudied with respect to their biological actions and health effects. Studies reveal a link between BPA exposure and vascular disease in human populations, whereas the vascular effects of BPA substitutes remain largely unknown. OBJECTIVES: To determine the effect of BPS, a commonly used BPA substitute, on redox balance, nitric oxide (NO) availability and microvascular NO-dependent dilation. METHODS: In human umbilical vein endothelial cells (HUVEC), production of reactive oxygen species (ROS) and NO after exposure to BPS was measured using fluorescent probes for DCFDA and DAF-FM diacetate, respectively. The contribution of endothelial NO synthase (eNOS) uncoupling to ROS generation was determined by measuring ROS in the presence or absence of an eNOS inhibitor (L-NAME) or eNOS co-factor, BH4, while the contribution of mitochondria-derived ROS was determined by treating cells with mitochondria-specific antioxidants prior to BPS exposure. Bioenergetic profiles were assessed using Seahorse extracellular flux analysis and mitochondria membrane polarization was measured with TMRE and JC-1 assays. In a mouse model of low dose BPS exposure, NO-mediated endothelial function was assessed in pressurized microvessels by inducing endothelium-dependent dilation in the presence or absence of L-NAME. RESULTS: BPS exposure (≥25 nM) reduced NO and increased ROS production in HUVEC, the latter corrected by treating cells with L-NAME or BH4. BPS exposure led to a loss of mitochondria membrane potential but had no impact on bioenergetic parameters except for a decrease in the spare respiratory capacity. Treatment of HUVEC with mitochondria-specific antioxidants abolished the effect of BPS on NO and ROS. NO-mediated vasodilation was impaired in male mice exposed to BPS. DISCUSSION: Exposure to BPS may promote cardiovascular disease by perturbing NO-mediated vascular homeostasis through the induction of oxidative stress.

Prenatal exposure to a low dose of BPS causes sex-dependent alterations to vascular endothelial function in adult offspring.

Background: Bisphenol S (BPS) is among the most commonly used substitutes for Bisphenol A (BPA), an endocrine disrupting chemical used as a plasticizer in the manufacture of polycarbonate plastics and epoxy resins. Bisphenols interfere with estrogen receptor (ER) signaling, which modulates vascular function through stimulation of nitric oxide (NO) production via endothelial nitric oxide synthase (eNOS). BPS can cross into the placenta and accumulates in the fetal compartment to a greater extent than BPA, potentially interfering with key developmental events. Little is known regarding the developmental impact of exposure to BPA substitutes, particularly with respect to the vasculature. Objective: To determine if prenatal BPS exposure influences vascular health in adulthood. Methods: At the time of mating, female C57BL/6 dams were administered BPS (250 nM) or vehicle control in the drinking water, and exposure continued during lactation. At 12-week of age, mesenteric arteries were excised from male and female offspring and assessed for responses to an endothelium-dependent (acetylcholine, ACh) and endothelium-independent (sodium nitroprusside, SNP) vasodilator. Endothelium-dependent dilation was measured in the presence or absence of L-NAME, an eNOS inhibitor. To further explore the role of NO and ER signaling, wire myography was used to assess ACh responses in aortic rings after acute exposure to BPS in the presence or absence of L-NAME or an ER antagonist. Results: Increased ACh dilation and increased sensitivity to Phe were observed in microvessels from BPS-exposed females, while no changes were observed in male offspring. Differences in ACh-induced dilation between control or BPS-exposed females were eliminated with L-NAME. Increased dilatory responses to ACh after acute BPS exposure were observed in aortic rings from female mice only, and differences were eliminated with inhibition of eNOS or inhibition of ER. Conclusion: Prenatal BPS exposure leads to persistent changes in endothelium-dependent vascular function in a sex-specific manner that appears to be modulated by interaction of BPS with ER signaling.

Gestational exposure to silver nanoparticles enhances immune adaptation and protection against streptozotocin-induced diabetic nephropathy in mice offspring.

Silver nanoparticles (AgNPs) possess unique antimicrobial properties. As a result, they are being increasingly used in a wide range of applications. Several studies have shown detrimental effects of AgNPs exposure, including inflammation, accumulation, and cellular damage to different organs. However, the effect of AgNPs exposure during gestation, a critical and susceptible period of human development, on pregnant females and its long-term effects on offspring's health has not been studied. Therefore, we conducted a long-term study where we assessed the effect of gestational AgNPs exposure on pregnant mice and followed their offspring until the age of 12 months. Gestational exposure to AgNPs induced systemic inflammation in the pregnant mice at gestational day (GD) 18. Interestingly, developing fetuses exposed to AgNPs, showed anti-inflammatory conditions as indicated by reduced expression of inflammatory genes in fetal organs at GD 18 and reduced serum levels of TNF-α, IFN-γ, IL-17A, IL-6, and MCP-1 in AgNPs exposed pups at postnatal day (PD) 2. Surprisingly, post-weaning, AgNPs exposed offspring showed a heightened immune activation as shown by upregulation of inflammatory cytokines at PD 28, which persisted till late in life. Moreover, we observed metabolic alterations which persisted until adulthood in mice. To understand the impact of long-term immunometabolic changes on the progression of diabetes and kidney diseases under stressed conditions, we exposed offspring to streptozotocin which revealed a protective role of low-dose gestational AgNPs exposure against streptozotocin-induced diabetes and associated nephropathy.

Prenatal exposure to environmental pro-oxidants induces mitochondria-mediated epigenetic changes: a cross-sectional pilot study.

Mitochondria play a central role in maintaining cellular and metabolic homeostasis during vital development cycles of foetal growth. Optimal mitochondrial functions are important not only to sustain adequate energy production but also for regulated epigenetic programming. However, these organelles are subtle targets of environmental exposures, and any perturbance in the defined mitochondrial machinery during the developmental stage can lead to the re-programming of the foetal epigenetic landscape. As these modifications can be transferred to subsequent generations, we herein performed a cross-sectional study to have an in-depth understanding of this intricate phenomenon. The study was conducted with two arms: whereas the first group consisted of in utero pro-oxidant exposed individuals and the second group included controls. Our results showed higher levels of oxidative mtDNA damage and associated integrated stress response among the exposed individuals. These disturbances were found to be closely related to the observed discrepancies in mitochondrial biogenesis. The exposed group showed mtDNA hypermethylation and changes in allied mitochondrial functioning. Altered expression of mitomiRs and their respective target genes in the exposed group indicated the possibilities of a disturbed mitochondrial-nuclear cross talk. This was further confirmed by the modified activity of the mitochondrial stress regulators and pro-inflammatory mediators among the exposed group. Importantly, the disturbed DNMT functioning, hypermethylation of nuclear DNA, and higher degree of post-translational histone modifications established the existence of aberrant epigenetic modifications in the exposed individuals. Overall, our results demonstrate the first molecular insights of in utero pro-oxidant exposure associated changes in the mitochondrial-epigenetic axis. Although, our study might not cement an exposure-response relationship for any particular environmental pro-oxidant, but suffice to establish a dogma of mito-epigenetic reprogramming at intrauterine milieu with chronic illness, a hitherto unreported interaction.

Prenatal exposure to arsenic promotes sterile inflammation through the Polycomb repressive element EZH2 and accelerates skin tumorigenesis in mouse.

Prenatal and postnatal life stress could be a potent programmer of phenotype or disease state of an individual in the later life. Prenatal arsenic exposure has been shown to promote developmental defects, low birth weight, immunotoxicity and is associated with various cancers including skin cancer in adulthood. To investigate the association between prenatal arsenic exposure and adult life skin carcinogenesis, we used a two-stage cutaneous carcinogenesis model in which BALB/c mice were prenatally exposed to 0.04 mg/kg and 0.4 mg/kg arsenic (As). Exposure to arsenic was sufficient to shorten the tumor latency period and promote epidermal hyperplasia in the offspring upon challenge with dimethylbenz[a]/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA). The levels of inflammatory and tissue microenvironment remodeling factors such as IL-1α and TNF-α were persistently elevated in the skin, and their inhibition through diacerein led to a significant decrease in the tumor response, suggesting their role in tumorigenesis. While there was overexpression of multiple epigenetic regulators at tissue level, we found decreased enrichment of Polycomb repressive complex 2 (PRC2) member EZH2 and H3K27me3 mark at the upstream of the affected inflammatory genes. The higher expression of the inflammatory genes suggests the gene specific selective nature of EZH2 repression which was also associated with increased binding of the activator KDM6a (demethylase). Further, arsenic conditioned basal keratinocytes cells (BKCs) showed increased migration and proliferation along with higher expression of tumor associated cytokines. Inhibition of EZH2 in the BKCs lead to their further upregulation suggesting that BKCs might be the potential cell type for the interaction of EZH2 and inflammatory cytokines. The present study provides new evidence for the role of PRC2 group regulators in inflammatory conditioning and development of skin cancer in offspring prenatally exposed to arsenic.

Prenatal arsenic exposure induces immunometabolic alteration and renal injury in rats.

Arsenic (As) exposure is progressively associated with chronic kidney disease (CKD), a leading public health concern present worldwide. The adverse effect of As exposure on the kidneys of people living in As endemic areas have not been extensively studied. Furthermore, the impact of only prenatal exposure to As on the progression of CKD also has not been fully characterized. In the present study, we examined the effect of prenatal exposure to low doses of As 0.04 and 0.4 mg/kg body weight (0.04 and 0.4 ppm, respectively) on the progression of CKD in male offspring using a Wistar rat model. Interestingly, only prenatal As exposure was sufficient to elevate the expression of profibrotic (TGF-ß1) and proinflammatory (IL-1α, MIP-2α, RANTES, and TNF-α) cytokines at 2-day, 12- and 38-week time points in the exposed progeny. Further, alteration in adipogenic factors (ghrelin, leptin, and glucagon) was also observed in 12- and 38-week old male offspring prenatally exposed to As. An altered level of these factors coincides with impaired glucose metabolism and homeostasis accompanied by progressive kidney damage. We observed a significant increase in the deposition of extracellular matrix components and glomerular and tubular damage in the kidneys of 38-week-old male offspring prenatally exposed to As. Furthermore, the overexpression of TGF-ß1 in kidneys corresponds with hypermethylation of the TGF-ß1 gene-body, indicating a possible involvement of prenatal As exposure-driven epigenetic modulations of TGF-ß1 expression. Our study provides evidence that prenatal As exposure to males can adversely affect the immunometabolism of offspring which can promote kidney damage later in life.

Accelerated developmental adipogenesis programs adipose tissue dysfunction and cardiometabolic risk in offspring born to dams with metabolic dysfunction.

This study determined if a perturbation in in utero adipogenesis leading to later life adipose tissue (AT) dysfunction underlies programming of cardiometabolic risk in offspring born to dams with metabolic dysfunction. Female mice heterozygous for the leptin receptor deficiency (Hetdb) had 2.4-fold higher prepregnancy fat mass and in late gestation had higher plasma insulin and triglycerides compared with wild-type (Wt) females (P < 0.05). To isolate the role of the intrauterine milieu, wild-type (Wt) offspring from each pregnancy were studied. Differentiation potential in isolated progenitors and cell size distribution analysis revealed accelerated adipogenesis in Wt pups born to Hetdb dams, accompanied by a higher accumulation of neonatal fat mass. In adulthood, whole body fat mass by NMR was higher in male (69%) and female (20%) Wt offspring born to Hetdb versus Wt pregnancies, along with adipocyte hypertrophy and hyperlipidemia (all P < 0.05). Lipidomic analyses by gas chromatography revealed an increased lipogenic index (16:0/18:2n6) after high-fat/fructose diet (HFFD). Postprandial insulin, ADIPO-IR, and ex vivo AT lipolytic responses to isoproterenol were all higher in Wt offspring born to Hetdb dams (P < 0.05). Intrauterine metabolic stimuli may direct a greater proportion of progenitors toward terminal differentiation, thereby predisposing to hypertrophy-induced adipocyte dysfunction.NEW & NOTEWORTHY This study reveals that accelerated adipogenesis during the perinatal window of adipose tissue development predisposes to later life hypertrophic adipocyte dysfunction, thereby compromising the buffering function of the subcutaneous depot.

Gold based nano-photonic approach for point-of-care detection of circulating long non-coding RNAs.

Development of a rapid, sensitive and easy to use point of care assay for detection of circulating long non-coding RNAs (lncRNAs) is of great importance. These biomolecules possess the ability to regulate vital cellular processes and act as biomarkers for various human non-communicable diseases. The present work aimed to develop a simplified and reliable cytometric fluorescence-based approach for precise recognition of circulating lncRNAs in a given sample using biotinylated uracil-modified oligonucleotide tethered AlexaFluor488-labeled streptavidin gold colloidal (BiO-StrAG) nano-conjugates. The fluorophores in close proximity to the gold nanoparticles result in quenching of fluorescence; however, specific recognition of target lncRNAs increases this distance which causes plasmonic enhancement of fluorescence. As per the flow cytometry and fluorometry investigations, the developed methodology provides a precise and sensitive approach for detection of the target lncRNAs (up to 5 nM in any given sample). With advantages of high selectivity and feasibility, our strategy offers great potential of being developed as a promising tool for interrogating aberrant regulation of lncRNAs functions, especially indicated in various diseased states.

Perinatal exposure to silver nanoparticles reprograms immunometabolism and promotes pancreatic beta-cell death and kidney damage in mice.

Silver nanoparticles (AgNPs) are extensively utilized in food, cosmetics, and healthcare products. Though the effects of AgNPs exposure on adults are well documented, the long-term effects of gestational/perinatal exposure upon the health of offspring have not been addressed. Herein, we show that only perinatal exposure to AgNPs through the mother could lead to chronic inflammation in offspring which persists till adulthood. Further, AgNPs exposure altered offspring's immune responses against environmental stresses. AgNPs exposed offspring showed an altered response in splenocyte proliferation assay when challenged to lipopolysaccharide, concanavalin-A, AgNPs, or silver ions. Perinatal AgNPs exposure affected metabolic parameters (resistin, glucagon-like peptide-1, leptin, insulin) and upregulated JNK/P38/ERK signaling in the pancreas. We observed pancreatic damage, reduced insulin level, and increased blood glucose levels. Further, we observed renal damage, particularly to tubular and glomerular regions as indicated by histopathology and electron microscopy. Our study thus shows that only perinatal exposure to AgNPs could induce persistent inflammation, alter immune responses against foreign antigens and metabolism which may contribute to pancreatic and renal damage later in life.

Developmental Exposure to Endocrine Disrupting Chemicals and Its Impact on Cardio-Metabolic-Renal Health.

Developmental origin of health and disease postulates that the footprints of early life exposure are followed as an endowment of risk for adult diseases. Epidemiological and experimental evidence suggest that an adverse fetal environment can affect the health of offspring throughout their lifetime. Exposure to endocrine disrupting chemicals (EDCs) during fetal development can affect the hormone system homeostasis, resulting in a broad spectrum of adverse health outcomes. In the present review, we have described the effect of prenatal EDCs exposure on cardio-metabolic-renal health, using the available epidemiological and experimental evidence. We also discuss the potential mechanisms of their action, which include epigenetic changes, hormonal imprinting, loss of energy homeostasis, and metabolic perturbations. The effect of prenatal EDCs exposure on cardio-metabolic-renal health, which is a complex condition of an altered biological landscape, can be further examined in the case of other environmental stressors with a similar mode of action.

Isolation and Characterization of a New Endophytic Actinobacterium Streptomyces californicus Strain ADR1 as a Promising Source of Anti-Bacterial, Anti-Biofilm and Antioxidant Metabolites.

In view of the fast depleting armamentarium of drugs against significant pathogens, like methicillin-resistant Staphylococcus aureus (MRSA) and others due to rapidly emerging drug-resistance, the discovery and development of new drugs need urgent action. In this endeavor, a new strain of endophytic actinobacterium was isolated from the plant Datura metesl, which produced secondary metabolites with potent anti-infective activities. The isolate was identified as Streptomyces californicus strain ADR1 based on 16S rRNA gene sequence analysis. Metabolites produced by the isolate had been investigated for their antibacterial attributes against important pathogens: S. aureus, MRSA, S. epidermis, Enterococcus faecium and E. faecalis. Minimum inhibitory concentration (MIC90) values against these pathogens varied from 0.23 ± 0.01 to 5.68 ± 0.20 µg/mL. The metabolites inhibited biofilm formation by the strains of S. aureus and MRSA (Biofilm inhibitory concentration [BIC90] values: 0.74 ± 0.08-4.92 ± 0.49 µg/mL). The BIC90 values increased in the case of pre-formed biofilms. Additionally, the metabolites possessed good antioxidant properties, with an inhibitory concentration (IC90) value of 217.24 ± 6.77 µg/mL for 1, 1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging. An insight into different classes of compounds produced by the strain ADR1 was obtained by chemical profiling and GC-MS analysis, wherein several therapeutic classes, for example, alkaloids, phenolics, terpenes, terpenoids and glycosides, were discovered.

Plasticizers and Cardiovascular Health: Role of Adipose Tissue Dysfunction.

Since the 1950s, the production of plastics has increased 200-fold, reaching 360 million tonnes in 2019. Plasticizers, additives that modify the flexibility and rigidity of the product, are ingested as they migrate into food and beverages. Human exposure is continuous and widespread; between 75 and 97% of urine samples contain detectable levels of bisphenols and phthalates, the most common plasticizers. Concern over the toxicity of plasticizers arose in the late 1990s, largely focused around adverse developmental and reproductive effects. More recently, many studies have demonstrated that exposure to plasticizers increases the risk for obesity, type 2 diabetes, and cardiovascular disease (CVD). In the 2000s, many governments including Canada, the United States and European countries restricted the use of certain plasticizers in products targeted towards infants and children. Resultant consumer pressure motivated manufacturers to substitute plasticizers with analogues, which have been marketed as safe. However, data on the effects of these new substitutes are limited and data available to-date suggest that many exhibit similar properties to the chemicals they replaced. The adverse effects of plasticizers have largely been attributed to their endocrine disrupting properties, which modulate hormone signaling. Adipose tissue has been well-documented to be a target of the disrupting effects of both bisphenols and phthalates. Since adipose tissue function is a key determinant of cardiovascular health, adverse effects of plasticizers on adipocyte signaling and function may underlie their link to cardiovascular disease. Herein, we discuss the current evidence linking bisphenols and phthalates to obesity and CVD and consider how documented impacts of these plasticizers on adipocyte function may contribute to the development of CVD.

Quantum Dot Based Nano-Biosensors for Detection of Circulating Cell Free miRNAs in Lung Carcinogenesis: From Biology to Clinical Translation.

Lung cancer is the most frequently occurring malignancy and the leading cause of cancer-related death for men in our country. The only recommended screening method is clinic based low-dose computed tomography (also called a low-dose CT scan, or LDCT). However, the effect of LDCT on overall mortality observed in lung cancer patients is not statistically significant. Over-diagnosis, excessive cost, risks associated with radiation exposure, false positive results and delay in the commencement of the treatment procedure questions the use of LDCT as a reliable technique for population-based screening. Therefore, identification of minimal-invasive biomarkers able to detect malignancies at an early stage might be useful to reduce the disease burden. Circulating nucleic acids are emerging as important source of information for several chronic pathologies including lung cancer. Of these, circulating cell free miRNAs are reported to be closely associated with the clinical outcome of lung cancer patients. Smaller size, sequence homology between species, low concentration and stability are some of the major challenges involved in characterization and specific detection of miRNAs. To circumvent these problems, synthesis of a quantum dot based nano-biosensor might assist in sensitive, specific and cost-effective detection of differentially regulated miRNAs. The wide excitation and narrow emission spectra of these nanoparticles result in excellent fluorescent quantum yields with a broader color spectrum which make them ideal bio-entities for fluorescence resonance energy transfer (FRET) based detection for sequential or simultaneous study of multiple targets. In addition, photo-resistance and higher stability of these nanoparticles allows extensive exposure and offer state-of-the art sensitivity for miRNA targeting. A major obstacle for integrating QDs into clinical application is the QD-associated toxicity. However, the use of non-toxic shells along with surface modification not only overcomes the toxicity issues, but also increases the ability of QDs to quickly detect circulating cell free miRNAs in a non-invasive mode. The present review illustrates the importance of circulating miRNAs in lung cancer diagnosis and highlights the translational prospects of developing QD-based nano-biosensor for rapid early disease detection.

Programming of Vascular Dysfunction in the Intrauterine Milieu of Diabetic Pregnancies.

With the rising global tide of obesity, gestational diabetes mellitus (GDM) burgeoned into one of the most common antenatal disorders worldwide. Macrosomic babies born to diabetic mothers are more likely to develop risk factors for cardiovascular disease (CVD) before they reach adulthood. Rodent studies in offspring born to hyperglycemic pregnancies show vascular dysfunction characterized by impaired nitric oxide (NO)-mediated vasodilation and increased production of contractile prostanoids by cyclooxygenase 2 (COX-2). Vascular dysfunction is a key pathogenic event in the progression of diabetes-related vascular disease, primarily attributable to glucotoxicity. Therefore, glucose-induced vascular injury may stem directly from the hyperglycemic intrauterine environment of GDM pregnancy, as evinced by studies showing endothelial activation and inflammation at birth or in childhood in offspring born to GDM mothers. This review discusses potential mechanisms by which intrauterine hyperglycemia programs dysfunction in the developing vasculature.