Multiple Azoarenes Based Systems - Photoswitching, Supramolecular Chemistry and Application Prospects.

In the recent decades, the investigations on photoresponsive molecular systems with multiple azoarenes are quite popular in diverse perspectives ranging from fundamental understanding of multiple photoswitches, supramolecular chemistry, and various application prospects. In fact, several insightful and conceptual designs of such systems were investigated with architectural distinctions. In particular, the demonstration of applications such as data storage with the help of multistate or orthogonal photoswitches, light modulation of catalysis via cooperative switching, sensors using supramolecular host-guest interactions, and materials such as liquid crystals, grating, actuators, etc. are some of the milestones in this area. Herein, we cover the recent advancements in the research areas of multiazoarenes containing systems that have been classified into Type-1 {linear, non-linear, and core-based (A)}, Type-2 {tripodal C3 -symmetric (C3)} and Type-3 {macrocyclic (M)} structural motifs.

Light-controlled shape-changing azomacrocycles exhibiting reversible modulation of pyrene fluorescence emission.

We report the design, synthesis, and study of light-induced shape-changing azomacrocycles. These systems have been incorporated with azobenzene photoswitches using alkoxy tethers and triazole units to afford flexibility and binding. We envision that such azomacrocycles are capable of reversibly binding with the guest molecule. Remarkably, we have demonstrated fully light-controlled fluorescence quenching and enhancement in the monomeric emission of pyrene (guest). Such modulations have been achieved by the photoisomerization of the azomacrocycle and, in turn, host-guest interactions. Also, the azomacrocycles tend to aggregate and can also be controlled by light or heat. We uncovered such phenomena using spectroscopic, microscopic, and isothermal titration calorimetry (ITC) studies and computations.

Direct detection of resistance to fluoroquinolones/SLIDs in sputum specimen by GenoType MTBDRsl v.2.0 assay A study from Eastern Uttar Pradesh, India.

BACKGROUND: According to World Health Organization (WHO), drug-resistant tuberculosis (DR-TB) is a major contributor to antimicrobial resistance globally and continues to be a public health threat. Annually, about half a million people fall ill with DR-TB globally. The gradual increase in resistance to fluoroquinolones (FQs) and second-line injectable drugs (SLIDs), poses a serious threat to effective TB control and adequate patient management. Therefore, WHO suggests the use of GenoType MTBDRsl v.2.0 assay for detection of multiple mutations associated with FQs and SLIDs. Hence, the study was conducted to determine the prevalence of resistance to FQs and SLIDs by comparing direct GenoType MTBDRsl v.2.0 assay with phenotypic drug susceptibility testing (DST). METHODS: The study was conducted on 1320 smear positive sputum samples from a total of 2536 RR-TB, confirmed by GeneXpert MTB/RIF. The smear positive specimens were decontaminated, and DNA extraction was performed. Furthermore, the extracted DNA was used for GenoType MTBDRsl v.2.0 assay. While 20% of the decontaminated specimens were inoculated in Mycobacterium growth indicator tube (MGIT) for drug susceptibility testing (DST). RESULTS: Out of 1320 smear positive sputum samples, 1178 were identified as Mycobacterium tuberculosis complex (MTBC) and remaining were negative by GenoType MTBDRsl v.2.0 assay. Of the 1178 MTBC positive, 26.6% were sensitive to both FQs and SLIDs, whereas 57.3% were only FQs resistant and 15.9% were resistant to both FQs and SLIDs. Further DST of 225 isolates by liquid culture showed that 17% were sensitive to both FQs and SLIDs, 61.3% were only FQs resistant and 21.3% were resistant to both. The specificity for FQs and SLIDs was 92.31% and 100% whereas sensitivity was 100% respectively by GenoType MTBDRsl v.2.0 assay in direct sputum samples. CONCLUSIONS: Our study clearly suggests that GenoType MTBDRsl v.2.0 assay is a reliable test for the rapid detection of resistance to second-line drugs after confirmation by GeneXpert MTB/RIF assay for RR-TB. Though, high rate FQ (ofloxacin) resistance was seen in our setting, moxifloxacin could be used as treatment option owing to very low resistance.

Arylazo-3,5-dimethylisoxazoles: Azoheteroarene Photoswitches Exhibiting High Z-Isomer Stability, Solid-State Photochromism, and Reversible Light-Induced Phase Transition.

Reversibly photoswitchable phenylazo-3,5-dimethylisoxazole and 37 aryl-substituted derivatives were synthesized. Excellent photoswitching ability of these compounds in solution and the solid state was demonstrated. Through kinetics studies by means of NMR spectroscopy, high Z-isomer stability was demonstrated. Interestingly, the majority of the derivatives showed light-induced contrasting color changes in solution and the solid state. Besides, many of the derivatives exhibit partial phase transition upon UV irradiation. The highlight of this class of photoswitches is the reversible light-induced phase transition between solid and liquid phases in the parent compound, which can be used in patterned crystallization. These results show that this new class of azoheteroarene based photoswitches has opportunities to be useful in various domains.

Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors.

BACKGROUND: Based on pre-clinical and clinical activity in adult refractory tumors, and absence of significant neuro-, nephro-, or oto-toxicity, we conducted a pediatric phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of satraplatin, an oral platinum analogue, in children and young adults with refractory solid tumors. PROCEDURE: Satraplatin was administered orally once daily on days 1-5 of a 28-day cycle at dose level (DL) 1 (60 mg/m(2) /dose), and DL2 (80 mg/m(2) /dose). Toxicities, responses, satraplatin pharmacokinetics, and pharmacogenomic expression of specific DNA repair genes were evaluated. RESULTS: Nine patients received 1-15 cycles (median = 2). The MTD was exceeded at DL2 with delayed prolonged myelosuppression as dose-limiting toxicity (DLT) in 2/4 patients. At DL1, 0/5 patients had DLTs. Common non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No significant neuro-, nephro-, or oto-toxicity was observed. No objective responses were observed but 2 patients experienced prolonged disease stabilization (---6-15 cycles). Satraplatin exposure (day 1 plasma ultrafiltrate area under the curve) was similar at DL1 and DL2. A strong correlation between estimated creatinine clearance and satraplatin pharmacokinetic parameters (clearance, area under the curve, and peak concentration) was observed. CONCLUSIONS: The MTD of oral satraplatin in children with solid tumors was 60 mg/m(2) /dose daily ×5 days every 28 days, which is lower than the adult recommended dose of 80-120 mg/m(2) /dose. The toxicity profile was similar to adults and delayed myelosuppression was the DLT. No significant neuro-, nephro- or oto-toxicities were observed.

Effects of unregulated anthropogenic activities on mixing ratios of volatile organic air pollutants--A case study.

UNLABELLED: During the months of October to November, many important festivals are celebrated in India. Celebration of these festivals are marked by extensive use of fireworks or pyrotechnics, bonfire, incense burning, open air community cooking, and temporary eateries using crude fuel such as coal, wood, kerosene, cow dung, burning of raw/semiwood, and coconut shells. The present study deals with the influence of these unregulated anthropogenic activities on ambient mixing level of volatile organic compounds (VOCs), especially some carbonyl compounds. The study was undertaken in the metropolitan city of Kolkata, India, with very high population density, which is even higher during festival period. The average total carbonyl level at different sites in Kolkata varied from 134.8 to 516.5 µg m(-3) in pre-festival season, whereas in post-festival season the same varied from 252.2 to 589.3 µg m(-3). Formaldehyde to acetaldehyde ratio altered from 0.62 in pre-festival season to 1.78 in post-festival season. Diurnal variation also altered, indicating variation in source composition of carbonyls. The total ozone forming potential calculated for all 14 carbonyls in pre-festival season increased by 35% in post-festival season. The effect of anthropogenic activities typical to the event of Diwali night characterized by intense execution of pyrotechnics resulted in significantly high level of carbonyl VOCs. Principal component analysis study for the event of Diwali shows clear contribution of the event on certain carbonyl VOCs. The results indicate elevated primary emissions of these pollutants and also their effect on formation of secondary pollutants. The study emphasizes the need of generating awareness among the communities in society as well as need for regulations to minimize the emissions and related hazards to the extent possible. IMPLICATIONS: Altered anthropogenic activities typical of festival season including extensive use of pyrotechnics affect ambient level of volatile organic compounds, especially some carbonyls. Such activities have considerable effect on interspecies ratio and diurnal variation. They also affect formation of secondary pollutants such as tropospheric ozone. Principal component analysis (PCA) study shows clear contribution of the pyrotechnics execution on certain carbonyl VOCs. The findings emphasize the need of generating awareness in society and need for regulations to minimize the emissions.

Emission, speciation, and evaluation of impacts of non-methane volatile organic compounds from open dump site.

Surface emission from Dhapa, the only garbage disposal ground in Kolkata, is a matter of concern to the local environment and also fuels the issues of occupational and environmental health. Surface emission of the Dhapa landfill site was studied using a flux chamber measurement for nonmethane volatile organic compounds (NMVOCs). Eighteen noncarbonyl volatile organic compounds (VOCs) and 14 carbonyl VOCs, including suspected and known carcinogens, were found in appreciable concentrations. The concentrations of the target species in the flux chamber were found to be significantly higher for most of the species in summer than winter. Surface emission rate of landfill gas was estimated by using two different approaches to assess the applicability for an open landfill site. It was found that the emissions predicted using the model Land GEM version 3.02 is one to two orders less than the emission rate calculated from flux chamber measurement for the target species. Tropospheric ozone formation has a serious impact for NMVOC emission. The total ozone-forming potential (OFP) of the Dhapa dumping ground considering all target NMVOCs was estimated to be 4.9E+04 and 1.2E+05 g/day in winter and summer, respectively. Also, it was found that carbonyl VOCs play a more important role than noncarbonyl VOCs for tropospheric ozone formation. Cumulative cancer risk estimated for all the carcinogenic species was found to be 2792 for 1 million population, while the total noncancer hazard index (HI) was estimated to be 246 for the occupational exposure to different compounds from surface emission to the dump-site workers at Dhapa. Implications: This paper describes the real-time surface emission of NMVOCs from an open municipal solid waste (MSW) dump site studied using a flux chamber. Our study findings indicate that while planning for new landfill site in tropical meteorology, real-time emission data must be considered, rather than relying on modeled data. The formation of tropospheric ozone from emitted NMVOC has also been studied. Our result shows how an open landfill site acts as a source and adds to the tropospheric ozone for the airshed of a metropolitan city.

Structure-property relationship in functionalized azobenzene photoswitches and their supramolecular behavior.

Herein, we report the design, synthesis, and supramolecular behavior of 30 structurally diverse photoresponsive azobenzene molecular systems. To establish structure-property relationships, azobenzenes appended with N-picolinyl and/or N-benzyl groups tethered directly through carboxamides or via triazolylmethyl carboxamide linkages were explored. We have evaluated the photoswitching characteristics and thermal stability of the Z isomers through systematic studies. All the targets were also screened for their aggregation behavior and supramolecular aspects. Among all the derivatives, a few carboxamide-based systems formed microcrystals upon aggregation, showing light responsiveness. In contrast, the derivatives tethered via triazolylmethyl carboxamide linkage exhibited hydrogel formation with excellent water-absorbing capacity. All supramolecular aspects of the morphology of the microcrystal and hydrogel states and their stimuli-responsiveness have been studied using spectroscopy and various microscopic techniques.

Mitochondrial dysfunction and oxidative stress: Role in chronic kidney disease.

Chronic kidney disease (CKD) is associated with a variety of distinct disease processes that permanently change the function and structure of the kidney across months or years. CKD is characterized as a glomerular filtration defect or proteinuria that lasts longer than three months. In most instances, CKD leads to end-stage kidney disease (ESKD), necessitating kidney transplantation. Mitochondrial dysfunction is a typical response to damage in CKD patients. Despite the abundance of mitochondria in the kidneys, variations in mitochondrial morphological and functional characteristics have been associated with kidney inflammatory responses and injury during CKD. Despite these variations, CKD is frequently used to define some classic signs of mitochondrial dysfunction, including altered mitochondrial shape and remodeling, increased mitochondrial oxidative stress, and a marked decline in mitochondrial biogenesis and ATP generation. With a focus on the most significant developments and novel understandings of the involvement of mitochondrial remodeling in the course of CKD, this article offers a summary of the most recent advances in the sources of procured mitochondrial dysfunction in the advancement of CKD. Understanding mitochondrial biology and function is crucial for developing viable treatment options for CKD.

Volatile organic compound emissions from municipal solid waste disposal sites: a case study of Mumbai, India.

Improper solid waste management leads to aesthetic and environmental problems. Emission ofvolatile organic compounds (VOCs) is one of the problems from uncontrolled dumpsite. VOCs are well known to be hazardous to human health and many of them are known or potential carcinogens. They also contribute to ozone formation at ground level and climate change as well. The qualitative and quantitative analysis of VOCs emitting from two municipal waste (MSW) disposal sites in Mumbai, India, namely Deonar and Malad, are presented in this paper. Air at dumpsites was sampled and analyzed on gas chromatography-mass spectrometry (GC-MS) in accordance with U.S. Environmental Protection Agency (EPA) TO-17 compendium method for analysis of toxic compounds. As many as 64 VOCs were qualitatively identified, among which 13 are listed under hazardous air pollutants (HAPs). Study of environmental distribution of a few major VOCs indicates that although air is the principal compartment of residence, they also get considerably partitioned in soil and vegetation. The CO2 equivalent of target VOCs from the landfills in Malad and Deonar shows that the total yearly emissions are 7.89E+03 and 8.08E+02 kg, respectively. The total per hour ozone production from major VOCs was found to be 5.34E-01 ppb in Deonar and 9.55E-02 ppb in Malad. The total carcinogenic risk for the workers in the dumpsite considering all target HAPs are calculated to be 275 persons in 1 million in Deonar and 139 persons in 1 million in Malad.

Involvement of Inflammasome Components in Kidney Disease.

Inflammasomes are multiprotein complexes with an important role in the innate immune response. Canonical activation of inflammasomes results in caspase-1 activation and maturation of cytokines interleukin-1ß and -18. These cytokines can elicit their effects through receptor activation, both locally within a certain tissue and systemically. Animal models of kidney diseases have shown inflammasome involvement in inflammation, pyroptosis and fibrosis. In particular, the inflammasome component nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) and related canonical mechanisms have been investigated. However, it has become increasingly clear that other inflammasome components are also of importance in kidney disease. Moreover, it is becoming obvious that the range of molecular interaction partners of inflammasome components in kidney diseases is wide. This review provides insights into these current areas of research, with special emphasis on the interaction of inflammasome components and redox signalling, endoplasmic reticulum stress, and mitochondrial function. We present our findings separately for acute kidney injury and chronic kidney disease. As we strictly divided the results into preclinical and clinical data, this review enables comparison of results from those complementary research specialities. However, it also reveals that knowledge gaps exist, especially in clinical acute kidney injury inflammasome research. Furthermore, patient comorbidities and treatments seem important drivers of inflammasome component alterations in human kidney disease.

RIPK3-MLKL signaling activates mitochondrial CaMKII and drives intrarenal extracellular matrix production during CKD.

Intrarenal extracellular matrix production or kidney fibrosis is a prevalent feature of all forms of chronic kidney disease (CKD). The transforming growth factor-beta (TGFß) is believed to be a major driver of extracellular matrix production. Nevertheless, anti-TGFß therapies have consistently failed to reduce extracellular matrix production in CKD patients indicating the need for novel therapeutic strategies. We have previously shown that necroinflammation contributes to acute kidney injury. Here, we show that chronic/persistent necroinflammation drives intrarenal extracellular matrix production during CKD. We found that renal expression of receptor-interacting protein kinase-1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) increases with the production of intrarenal extracellular matrix and declined kidney function in both humans and mice. Furthermore, we found that TGFß exposure induces the translocation of RIPK3 and MLKL to mitochondria resulting in mitochondrial dysfunction and ROS production. Mitochondrial ROS activates the serine-threonine kinase calcium/calmodulin-dependent protein kinases-II (CaMKII) that increases phosphorylation of Smad2/3 and subsequent production of alpha-smooth muscle actin (αSMA), collagen (Col) 1α1, etc. in response to TGFß during the intrarenal extracellular matrix production. Consistent with this, deficiency or knockdown of RIPK3 or MLKL as well as pharmacological inhibition of RIPK1, RIPK3, and CaMKII prevents the intrarenal extracellular matrix production in oxalate-induced CKD and unilateral ureteral obstruction (UUO). Together, RIPK1, RIPK3, MLKL, CaMKII, and Smad2/3 are molecular targets to inhibit intrarenal extracellular matrix production and preserve kidney function during CKD.

Advanced non-invasive diagnostic techniques for visualization and estimation of kidney fibrosis.

Kidney fibrosis is marked by excessive extracellular matrix deposition during disease progression. Unfortunately, existing kidney function parameters do not predict the extent of kidney fibrosis. Moreover, the traditional histology methods for the assessment of kidney fibrosis require liquid and imaging biomarkers as well as needle-based biopsies, which are invasive and often associated with kidney injury. The repetitive analyses required to monitor the disease progression are therefore difficult. Hence, there is an unmet medical need for non-invasive and informative diagnostic approaches to monitor kidney fibrosis during the progression of chronic kidney disease. Here, we summarize the modern advances in diagnostic imaging techniques that have shown promise for non-invasive estimation of kidney fibrosis in pre-clinical and clinical studies.

6,7-Dihydroxycoumarin ameliorates crystal-induced necroptosis during crystal nephropathies by inhibiting MLKL phosphorylation.

AIMS: Mineralization of crystalline particles and the formation of renal calculi contribute to the pathogenesis of crystal nephropathies. Several recent studies on the biology of crystal handling implicated intrarenal crystal deposition-induced necroinflammation in their pathogenesis. We hypothesized that 6,7-dihydroxycoumarin (DHC) inhibit intrarenal crystal cytotoxicity and necroinflammation, and ameliorate crystal-induced chronic kidney disease (CKD). MAIN METHODS: An unbiased high content screening coupled with fluorescence microscopy was used to identify compounds that inhibit CaOx crystal cytotoxicity. The ligand-protein interactions were identified using computational models e.g. molecular docking and molecular dynamics simulations. Furthermore, mice and rat models of oxalate-induced CKD were used for in-vivo studies. Renal injury, crystal deposition, and fibrosis were assessed by histology analysis. Western blots were used to quantify the protein expression. Data were expressed as boxplots and analyzed using one way ANOVA. KEY FINDINGS: An unbiased high-content screening in-vitro identified 6,7-DHC as a promising candidate. Further, 6,7-DHC protected human and mouse cells from calcium oxalate (CaOx) crystal-induced necroptosis in-vitro as well as mice and rats from oxalate-induced CKD in either preventive or therapeutic manner. Computational modeling demonstrated that 6,7-DHC interact with MLKL, the key protein in the necroptosis machinery, and inhibit its phosphorylation by ATP, which was evident in both in-vitro and in-vivo analyses. SIGNIFICANCE: Together, our results indicate that 6,7-DHC possesses a novel pharmacological property as a MLKL inhibitor and could serve as a lead molecule for further development of coumarin-based novel MLKL inhibitors. Furthermore, our data identify 6,7-DHC as a novel therapeutic strategy to combat crystal nephropathies.

Insights from a Pan India Sero-Epidemiological survey (Phenome-India Cohort) for SARS-CoV2.

To understand the spread of SARS-CoV2, in August and September 2020, the Council of Scientific and Industrial Research (India) conducted a serosurvey across its constituent laboratories and centers across India. Of 10,427 volunteers, 1058 (10.14%) tested positive for SARS-CoV2 anti-nucleocapsid (anti-NC) antibodies, 95% of which had surrogate neutralization activity. Three-fourth of these recalled no symptoms. Repeat serology tests at 3 (n = 607) and 6 (n = 175) months showed stable anti-NC antibodies but declining neutralization activity. Local seropositivity was higher in densely populated cities and was inversely correlated with a 30-day change in regional test positivity rates (TPRs). Regional seropositivity above 10% was associated with declining TPR. Personal factors associated with higher odds of seropositivity were high-exposure work (odds ratio, 95% confidence interval, p value: 2.23, 1.92-2.59, <0.0001), use of public transport (1.79, 1.43-2.24, <0.0001), not smoking (1.52, 1.16-1.99, 0.0257), non-vegetarian diet (1.67, 1.41-1.99, <0.0001), and B blood group (1.36, 1.15-1.61, 0.001).

Indifference curves as a tool for environment impact assessment.

Use of indifference curves, defined as functionality between development index and pollution load to evaluate environmental impact, is proposed. Existing Battelle environmental evaluation methodology is subjective in its approach. The use of indifference curves lends a more objective approach to environment assessment methodology. The extent of environmental damage we are prepared to accept, for a development, can be explained by Willingness to Pay and Willingness to Accept approach. The application of proposed approach has been demonstrated taking an example of Power plant set up in forest area. The curves clearly show that cost of EMP considering mitigation of ecological damage is higher than the EMP mitigating impacts of air and water pollution only. The example stresses the need for willingness to accept along with willingness to pay.

Emission inventory of evaporative emissions of VOCs in four metro cities in India.

High concentrations of volatile organic compounds (VOCs) in ambient air of urban areas stress the need for the control of VOC emissions due to the toxic and carcinogenic nature of many VOCs commonly encountered in urban air. Emission inventories are an essential tool in the management of local air quality, which provide a listing of sources of air pollutant emissions within a specific area over a specified period of time. This study intended to provide a level IV emission inventory as par the United States Environmental Protection Agency (USEPA) definition for evaporative VOC emissions in the metro cities of India namely Delhi, Mumbai, Chennai, and Kolkata. The vehicular evaporative emissions are found to be the largest contributor to the total evaporative emissions of hydrocarbons followed by evaporative losses related to petrol loading and unloading activities. Besides vehicle-related activities, other major sources contributing to evaporative emissions of hydrocarbons are surface coating, dry cleaning, graphical art applications, printing (newspaper and computer), and the use of consumer products. Various specific preventive measures are also recommended for reducing the emissions.

'PARP'ing fibrosis: repurposing poly (ADP ribose) polymerase (PARP) inhibitors.

Fibrosis is a wound-healing process that results in tissue scarring and organ dysfunction. Several novel mechanisms of fibrogenesis have been discovered recently. In this review, we focus on the role of poly-ADP ribose polymerase (PARP) in major organ fibrosis, such as lungs, heart, liver, and kidneys. PARP is a dynamic enzyme that modulates different cellular proteins by the addition of PAR groups and mediates an array of cellular events in both normal physiological and pathophysiological states. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) recently approved several PARP inhibitors, such as olaparib, niraparib, talazoparib, and rucaparib, for the treatment of ovarian and germline BRCA-mutant breast cancers. Consequently, repurposing these drugs could provide an opportunity to counter organ fibrosis.

Coarse particle (PM10-2.5) source profiles for emissions from domestic cooking and industrial process in Central India.

To develop coarse particle (PM10-2.5, 2.5 to 10µm) chemical source profiles, real-world source sampling from four domestic cooking and seven industrial processing facilities were carried out in "Raipur-Bhilai" of Central India. Collected samples were analysed for 32 chemical species including 21 elements (Al, As, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Mo, Na, Ni, Pb, S, Sb, Se, V, and Zn) by atomic absorption spectrophotometry (AAS), 8 water-soluble ions (Na+, K+, Mg2+, Ca2+, Cl-, F-, NO3-, and SO42-) by ion chromatography, ammonium (NH4+) by spectrophotometry, and carbonaceous fractions (OC and EC) by thermal/optical transmittance. The carbonaceous fractions were most abundant fraction in household fuel and municipal solid waste combustion emissions while elemental species were more abundant in industrial emissions. Most of the elemental species were enriched in PM2.5 (<2.5µm) size fraction as compared to the PM10-2.5 fraction. Abundant Ca (13-28%) was found in steel-rolling mill (SRM) and cement production industry (CPI) emissions, with abundant Fe (14-32%) in ferro-manganese (FEMNI), steel production industry (SPI), and electric-arc welding emissions. High coefficients of divergence (COD) values (0.46 to 0.88) among the profiles indicate their differences. These region-specific source profiles are more relevant to source apportionment studies in India than profiles measured elsewhere.