Visible-Light-Sensitive Photoliquefiable Arylazoisoxazoles for the Solar Energy Conversion, Storage and Controlled-Release of Heat at Room Temperature or Lower Temperatures.

The photoswitchable MOlecular Solar Thermal (MOST) energy storage systems that are capable of exhibiting high energy storage densities are found to suffer from the poor cyclability, the use of less abundant UV light of the solar spectrum, or reduced charging/discharging rates and poor photoconversions in solid states. Herein, we have designed and readily synthesized a novel set of para-thioalkyl substituted arylazoisoxazoles, that undergo high trans-cis and cis-trans photoconversions under visible light, and show fast charging/discharging and impressive cyclability. Remarkably, the presence of C6-or C10-thioalkyl chainin photochromes permitted reversible solid-liquid phase transition with the formation of cis-enriched charged states by 400 nm light irradiation and trans-enriched discharged states by 530 nm light at various temperatures (10-35 °C). The solid-to-liquid phase transition enabled storage of the latent heat in addition to the isomerization energy, resulting in a high net energy storage density of 189-196 J/g, which are substantially higher than that of many recently reported azobenzene-based MOST compounds (100-161 J/g). Using a high-resolution infrared camera, we further demonstrated that a brief irradiation of green light can be employed to readily release the trapped photon energy as heat. Our results suggest that the arylazoisoxazole with C6-thioalkyl chain at para-position can serve as an effective and eco-friendly photoliquefiable MOST material.

Antioxidant Polymers with Phenolic Pendants for the Mitigation of Cellular Oxidative Stress.

Overproduction of reactive oxygen species (ROS) in cells is a major health concern as it may lead to various diseases through oxidative damage of biomolecules. Commonly used traditional small molecular antioxidants (polyphenols, carotenoids, vitamins, etc.) have inadequate efficacy in lowering excessive levels of ROS due to their poor aqueous solubility and bioavailability. In response to the widespread occurrence of antioxidant polyphenols in various biorenewable resources, we aimed to develop water-soluble antioxidant polymers with side chain phenolic pendants. Four different types of copolymers (P1-P4) containing phenyl rings with different numbers of hydroxy (-OH) substituents (0: phenylalanine, 1: tyrosyl, 2: catechol, or 3: gallol) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization with a desired molar mass (8500-10000 g/mol) and a narrow dispersity (D ≤ 1.3). After successful characterizations of P1-P4, their in vitro antioxidant properties were analyzed by different methods, including 2,2-diphenyl-1-picrylhydrazyl (DPPH•), 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS•+), 4,4'-diamino-3,3',5,5'-tetramethylbiphenyl (TMB), and ß-carotene (ßC) assays. Our results revealed that the gallol pendant polymers can effectively scavenge ROS. Furthermore, electron paramagnetic resonance (EPR) spectroscopy with DPPH• also confirmed the radical quenching ability of the synthesized polymers. The gallol pendant polymers, at a well-tolerated concentration, could effectively penetrate the macrophage cells and restore the H2O2-induced ROS to the basal level. Overall, the present approach demonstrates the efficacy of water-soluble antioxidant polymers with gallol pendants toward the mitigation of cellular oxidative stress.

Reduction in the COVID-19 pneumonia case fatality rate by silver nanoparticles: A randomized case study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has devastated mankind. To date, no approved treatment is available to completely combat this disease. Although many studies reported the potential of silver nanoparticles' (AgNPs) action mechanism and effect against SARS-CoV-2, this is the first clinical trial that aimed to prove this effect. This open-label, randomized, parallel-group, investigator-initiated study (IIS) was conducted in India from 2021 to 2022 and included 40 patients diagnosed with moderately-severe to severe COVID-19 pneumonia. This study proved a significantly higher survival rates (p < 0.05) and significantly lower number of days until supplemental oxygenation was required (p < 0.0001) for patients receiving intravenous AgNPs in form of AgSept® in addition to the standard COVID-19 treatment. This study highlights the importance of intravenous AgNPs administration in the treatment of virus-induced pneumonia.

A RGS7-CaMKII complex drives myocyte-intrinsic and myocyte-extrinsic mechanisms of chemotherapy-induced cardiotoxicity.

Dose-limiting cardiotoxicity remains a major limitation in the clinical use of cancer chemotherapeutics. Here, we describe a role for Regulator of G protein Signaling 7 (RGS7) in chemotherapy-dependent heart damage, the demonstration for a functional role of RGS7 outside of the nervous system and retina. Though expressed at low levels basally, we observed robust up-regulation of RGS7 in the human and murine myocardium following chemotherapy exposure. In ventricular cardiomyocytes (VCM), RGS7 forms a complex with Ca2+/calmodulin-dependent protein kinase (CaMKII) supported by key residues (K412 and P391) in the RGS domain of RGS7. In VCM treated with chemotherapeutic drugs, RGS7 facilitates CaMKII oxidation and phosphorylation and CaMKII-dependent oxidative stress, mitochondrial dysfunction, and apoptosis. Cardiac-specific RGS7 knockdown protected the heart against chemotherapy-dependent oxidative stress, fibrosis, and myocyte loss and improved left ventricular function in mice treated with doxorubicin. Conversely, RGS7 overexpression induced fibrosis, reactive oxygen species generation, and cell death in the murine myocardium that were mitigated following CaMKII inhibition. RGS7 also drives production and release of the cardiokine neuregulin-1, which facilitates paracrine communication between VCM and neighboring vascular endothelial cells (EC), a maladaptive mechanism contributing to VCM dysfunction in the failing heart. Importantly, while RGS7 was both necessary and sufficient to facilitate chemotherapy-dependent cytotoxicity in VCM, RGS7 is dispensable for the cancer-killing actions of these same drugs. These selective myocyte-intrinsic and myocyte-extrinsic actions of RGS7 in heart identify RGS7 as an attractive therapeutic target in the mitigation of chemotherapy-driven cardiotoxicity.

Hepatic Regulator of G Protein Signaling 6 (RGS6) drives non-alcoholic fatty liver disease by promoting oxidative stress and ATM-dependent cell death.

The pathophysiological mechanism(s) driving non-alcoholic fatty liver disease, the most prevalent chronic liver disease globally, have yet to be fully elucidated. Here, we identify regulator of G protein signaling 6 (RGS6), up-regulated in the livers of NAFLD patients, as a critical mediator of hepatic steatosis, fibrosis, inflammation, and cell death. Human patients with high hepatic RGS6 expression exhibited a corresponding high inflammatory burden, pronounced insulin resistance, and poor liver function. In mice, liver-specific RGS6 knockdown largely ameliorated high fat diet (HFD)-driven oxidative stress, fibrotic remodeling, inflammation, lipid deposition and cell death. RGS6 depletion allowed for maintenance of mitochondrial integrity restoring redox balance, improving fatty acid oxidation, and preventing loss of insulin receptor sensitivity in hepatocytes. RGS6 is both induced by ROS and increases ROS generation acting as a key amplification node to exacerbate oxidative stress. In liver, RGS6 forms a direct complex with ATM kinase supported by key aspartate residues in the RGS domain and is both necessary and sufficient to drive hyperlipidemia-dependent ATM phosphorylation. pATM and markers of DNA damage (γH2AX) were also elevated in livers from NAFLD patients particularly in samples with high RGS6 protein content. Unsurprisingly, RGS6 knockdown prevented ATM phosphorylation in livers from HFD-fed mice. Further, RGS6 mutants lacking the capacity for ATM binding fail to facilitate palmitic acid-dependent hepatocyte apoptosis underscoring the importance of the RGS6-ATM complex in hyperlipidemia-dependent cell death. Inhibition of RGS6, then, may provide a viable means to prevent or reverse liver damage by mitigating oxidative liver damage.

G protein ß5-ATM complexes drive acetaminophen-induced hepatotoxicity.

Excessive ingestion of the common analgesic acetaminophen (APAP) leads to severe hepatotoxicity. Here we identify G protein ß5 (Gß5), elevated in livers from APAP overdose patients, as a critical regulator of cell death pathways and autophagic signaling in APAP-exposed liver. Liver-specific knockdown of Gß5 in mice protected the liver from APAP-dependent fibrosis, cell loss, oxidative stress, and inflammation following either acute or chronic APAP administration. Conversely, overexpression of Gß5 in liver was sufficient to drive hepatocyte dysfunction and loss. In hepatocytes, Gß5 depletion ameliorated mitochondrial dysfunction, allowed for maintenance of ATP generation and mitigated APAP-induced cell death. Further, Gß5 knockdown also reversed impacts of APAP on kinase cascades (e.g. ATM/AMPK) signaling to mammalian target of rapamycin (mTOR), a master regulator of autophagy and, as a result, interrupted autophagic flux. Though canonically relegated to nuclear DNA repair pathways, ATM also functions in the cytoplasm to control cell death and autophagy. Indeed, we now show that Gß5 forms a direct, stable complex with the FAT domain of ATM, important for autophosphorylation-dependent kinase activation. These data provide a viable explanation for these novel, G protein-independent actions of Gß5 in liver. Thus, Gß5 sits at a critical nexus in multiple pathological sequelae driving APAP-dependent liver damage.

Biphasic changes in TGF-ß1 signaling drive NSAID-induced multi-organ damage.

The clinical utility of non-steroidal anti-inflammatory drugs (NSAIDs), used extensively worldwide, is limited by adverse cardiac events resulting from chronic drug exposure. Here, we provide evidence identifying transforming growth factor ß (TGF-ß1), released from multiple tissues, as a critical driver of NSAID-induced multi-organ damage. Biphasic changes in TGF-ß1 levels in liver and heart were accompanied by ROS generation, cell death, fibrotic remodeling, compromised cardiac contractility and elevated liver enzymes. Pharmacological inhibition of TGF-ßRI signaling markedly improved heart and liver function and increased overall survival of animals exposed to multiple NSAIDs, effects likely mediated by reductions in NOX-dependent ROS generation. Notably, the beneficial impact of TGF-ßRI blockade was confined to a critical window wherein consecutive, but not concurrent, inhibitor administration improved cardiac and hepatic endpoints. Remarkably, in addition to ameliorating indomethacin-mediated myofilament disruptions, cardiac TGF-ßRI knockdown lead to drastic reductions in TGF-ß1 production accompanied by lessening in intestinal lesioning underscoring the importance of endocrine TGF-ß1 signaling in NSAID-driven tissue injury. Indeed, gastric ulceration was associated with a higher incidence of cardiac complications in a human cohort underscoring the critical importance of circulation-facilitated peripheral organ system interconnectedness in efforts seeking to mitigate the toxic side effects of chronic NSAID use.

Study of hot stress dynamic IR thermography for detecting surface cancerous tissue.

The early diagnosis of cancer at any location of the human body can help in enhancing the survival rate and in reducing the cost of the treatment. Among the several techniques, the conventional infra-red (IR) thermography suffers from several limitations, including higher patient discomfort and longer time for tumour detection based on the temperature difference between tumour and adjacent healthy tissues. Hence, in this work, a novel non-invasive hot stress dynamic IR thermography system is proposed to detect surface tumour without severe discomfort to the patient. The system is designed to detect the surface tumour under 3 min within a temperature range of 42 and 37 °C. A two-dimensional numerical model based on the bio-heat transfer of tissue consists of cancerous and healthy cells is developed and validated to analysis the thermal contrast arises due to the presence of cancerous and healthy cells while cooling naturally. A light source is introduced with appropriate intensity to achieve a suitable temperature contrast. Moreover, the effects of natural convective heat loss from the tissue to the ambient and the scanning speed of IR Thermography on the tissue are investigated. A temperature difference of about 1.5 °C is found after cooling of tissues for 140 s, which can be detected using a thermographic camera. Finally, a sensitivity study is conducted to access the importance of the individual parameter over the final temperature field. The results predict the blood perfusion rate as the most significant parameter that significantly influences the temperature distribution in the considered domain.