The increasingly dominant role of climate change on length of day variations.

The melting of ice sheets and global glaciers results in sea-level rise, a pole-to-equator mass transport increasing Earth's oblateness and resulting in an increase in the length of day (LOD). Here, we use observations and reconstructions of mass variations at the Earth's surface since 1900 to show that the climate-induced LOD trend hovered between 0.3 and 1.0 ms/cy in the 20th century, but has accelerated to 1.33 [Formula: see text] 0.03 ms/cy since 2000. We further show that surface mass transport fully explains the accelerating trend in the Earth oblateness observed in the past three decades. We derive an independent measure of the decreasing LOD trend induced by Glacial Isostatic Adjustment (GIA) of [Formula: see text]0.80 [Formula: see text] 0.10 ms/cy, which provides a constraint for the mantle viscosity. The sum of this GIA rate and lunar tidal friction fully explains the secular LOD trend that is inferred from the eclipse record in the past three millennia prior to the onset of contemporary climate change. Projections of future climate warming under high emission scenarios suggest that the climate-induced LOD rate may reach 2.62 [Formula: see text] 0.79 ms/cy by 2100, overtaking lunar tidal friction as the single most important contributor to the long-term LOD variations.

Targeting prolyl-tRNA synthetase via a series of ATP-mimetics to accelerate drug discovery against toxoplasmosis.

The prolyl-tRNA synthetase (PRS) is a validated drug target for febrifugine and its synthetic analog halofuginone (HFG) against multiple apicomplexan parasites including Plasmodium falciparum and Toxoplasma gondii. Here, a novel ATP-mimetic centered on 1-(pyridin-4-yl) pyrrolidin-2-one (PPL) scaffold has been validated to bind to Toxoplasma gondii PRS and kill toxoplasma parasites. PPL series exhibited potent inhibition at the cellular (T. gondii parasites) and enzymatic (TgPRS) levels compared to the human counterparts. Cell-based chemical mutagenesis was employed to determine the mechanism of action via a forward genetic screen. Tg-resistant parasites were analyzed with wild-type strain by RNA-seq to identify mutations in the coding sequence conferring drug resistance by computational analysis of variants. DNA sequencing established two mutations, T477A and T592S, proximal to terminals of the PPL scaffold and not directly in the ATP, tRNA, or L-pro sites, as supported by the structural data from high-resolution crystal structures of drug-bound enzyme complexes. These data provide an avenue for structure-based activity enhancement of this chemical series as anti-infectives.

Double drugging of prolyl-tRNA synthetase provides a new paradigm for anti-infective drug development.

Toxoplasmosis is caused by Toxoplasma gondii and in immunocompromised patients it may lead to seizures, encephalitis or death. The conserved enzyme prolyl-tRNA synthetase (PRS) is a validated druggable target in Toxoplasma gondii but the traditional 'single target-single drug' approach has its caveats. Here, we describe two potent inhibitors namely halofuginone (HFG) and a novel ATP mimetic (L95) that bind to Toxoplasma gondii PRS simultaneously at different neighbouring sites to cover all three of the enzyme substrate subsites. HFG and L95 act as one triple-site inhibitor in tandem and form an unusual ternary complex wherein HFG occupies the 3'-end of tRNA and the L-proline (L-pro) binding sites while L95 occupies the ATP pocket. These inhibitors exhibit nanomolar IC50 and EC50 values independently, and when given together reveal an additive mode of action in parasite inhibition assays. This work validates a novel approach and lays a structural framework for further drug development based on simultaneous targeting of multiple pockets to inhibit druggable proteins.

Naringenin mitigates aluminum toxicity-induced learning memory impairments and neurodegeneration through amelioration of oxidative stress.

Aluminum chloride (AlCl3) is a potent neurotoxic substance known to cause memory impairment and oxidative stress-dependent neurodegeneration. Naringenin (NAR) is a dietary flavonoid with potent antioxidant and anti-inflammatory properties which was implemented against AlCl3-induced neurotoxicity to ascertain its neuroprotective efficacy. Experimental neurotoxicity in mice was induced by exposure of AlCl3 (10 mg/kg, p.o.) followed by treatment with NAR (10 mg/kg, p.o.) for a total of 63 days. Assessed the morphometric, learning memory dysfunction (novel object recognition, T- and Y-maze tests), neuronal oxidative stress, and histopathological alteration in different regions of the brain, mainly cortex, hippocampus, thalamus, and cerebellum. AlCl3 significantly suppressed the spatial learning and memory power which were notably improved by administration of NAR. The levels of oxidative stress parameters nitric oxide, advanced oxidation of protein products, protein carbonylation, lipid peroxidation, superoxide dismutase, catalase, glutathione reductase, reduced glutathione, and the activity of acetylcholine esterase were altered 1.5-3 folds by AlCl3 significantly. Treatment of NAR remarkably restored the level of oxidative stress parameters and maintained the antioxidant defense system. AlCl3 suppressed the expression of neuronal proliferation marker NeuN that was restored by NAR treatment which may be a plausible mechanism. NAR showed therapeutic efficacy as a natural supplement against aluminum-intoxicated memory impairments and histopathological alteration through a mechanism involving an antioxidant defense system and neuronal proliferation.

Beta-caryophyllene attenuates experimental hepatocellular carcinoma through downregulation of oxidative stress and inflammation.

Hepatocellular carcinoma (HCC) is caused by various factors including toxic substances and xenobiotics. Numerous treatment strategies are used to address toxicity to the liver and HCC, yet their adverse effects are drawbacks. This study aimed to assess the effect of DEN/CCl4 on morphological changes in the liver, body weight, tumor incidence, and hematological tumor incidence, hematological parameters, hepatic markers, and histopathological analysis in mice following a preventive measure by using ß-caryophyllene (BCP). Adult Balb/c mice were administered a single dose of DEN 1-mg/kg body weight and 0.2-mL CCl4/kg body weight intraperitoneal twice a week (i.p.) for 22 weeks. BCP was treated in one group of mice at 30-mg/kg body weight, intraperitoneal, for 7 weeks. BCP alone was treated in one group of mice at 300-mg/kg body weight intraperitoneal for 22 weeks. DEN/CCl4 caused a reduction in mice's body weight, which was significantly attenuated by BCP administration. BCP supplementation attenuated the tumor incidence DEN/CCl4 (100%) to about 25%. DEN/CCl4 caused alterations in the hematological parameters, serum total protein albumin globulin, A/G ratio, liver function markers (AST, ALT, ALP, GGT, ACP, and bilirubin), and lipid profile markers that were significantly reinstated by BCP administration. Oxidative stress markers (MDA, SOD, CAT, NO, LDH, and GST) were reduced by DEN/CCl4, which were significantly increased in BCP-treated groups. The liver histopathology alterations caused by DEN/CCl4 were amended considerably by BCP treatment. Immunohistochemical studies suggest that AFP, caspase-3, and COX-2 were chronically overexpressed in DEN/CCl4-exposed mice, notably attenuated by BCP administration. BCP suppressed tumor incidence by downregulating inflammation and inducing caspase-3-mediated apoptosis. Conclusively, BCP appears to be a potent natural supplement capable of repressing liver inflammation and carcinoma through the mitigation of oxidative stress and inflammation pathways.

Capsicum annuum L. and its bioactive constituents: A critical review of a traditional culinary spice in terms of its modern pharmacological potentials with toxicological issues.

Capsicum annuum L., commonly known as chili pepper, is used as an important spice globally and as a crude drug in many traditional medicine systems. The fruits of C. annuum have been used as a tonic, antiseptic, and stimulating agent, to treat dyspepsia, appetites, and flatulence, and to improve digestion and circulation. The article aims to critically review the phytochemical and pharmacological properties of C. annuum and its major compounds. Capsaicin, dihydrocapsaicin, and some carotenoids are reported as the major active compounds with several pharmacological potentials especially as anticancer and cardioprotectant. The anticancer effect of capsaicinoids is mainly mediated through mechanisms involving the interaction of Ca2+ -dependent activation of the MAPK pathway, suppression of NOX-dependent reactive oxygen species generation, and p53-mediated activation of mitochondrial apoptosis in cancer cells. Similarly, the cardioprotective effects of capsaicinoids are mediated through their interaction with cellular transient receptor potential vanilloid 1 channel, and restoration of calcitonin gene-related peptide via Ca2+ -dependent release of neuropeptides and suppression of bradykinin. In conclusion, this comprehensive review presents detailed information about the traditional uses, phytochemistry, and pharmacology of major bioactive principles of C. annuum with special emphasis on anticancer, cardioprotective effects, and plausible toxic adversities along with food safety.

Targeting cancer cells with nanotherapeutics and nanodiagnostics: Current status and future perspectives.

Nanotechnology is reshaping health care strategies and is expected to exert a tremendous impact in the coming years offering better healthcare facilities. It has led to not only therapeutic drug delivery feasibility but also to diagnostics. Materials in the size of nano range (1-100 nm) used in the design, fabrication, regulation, and application of therapeutic drugs or devices are classified as medical nanotechnology and nanopharmacology. Delivery of more complex molecules to the specific site of action as well as gene therapy has pushed forward the nanoparticle-based drug delivery to its maximum. Areas that benefit from nano-based drug delivery systems are cancer, diabetes, infectious diseases, neurodegenerative diseases, blood disorders and orthopedic-related ailments. Moreover, development of nanotherapeutics with multi-functionalities has a considerable potential to fill the gaps that exist in the present therapeutic domain. In cancer treatment, nanomedicines have superiority over current therapeutic practices as they can effectively deliver the drug to the affected tissues, thus reducing drug toxicities. Along this line, polymeric conjugates of asparaginase and polymeric micelles of paclitaxel have recently been recommended for the treatment of various types of cancers. Nanotechnology-based therapeutics and diagnostics provide greater effectiveness with less or no toxicity concerns. Similarly, diagnostic imaging holds promising future applications with newer nano-level imaging elements. Advancements in nanotechnology have emerged to a newer direction which use nanorobotics for various applications in healthcare. Accordingly, this review comprehensively highlights the potentialities of various nanocarriers and nanomedicines for multifaceted applications in diagnostics and drug delivery, especially the potentialities of polymeric nanoparticle, nanoemulsion, solid-lipid nanoparticle, nanostructured lipid carrier, self-micellizing anticancer lipids, dendrimer, nanocapsule and nanosponge-based therapeutic approaches in the field of cancer. Furthermore, this article summarizes the most recent literature pertaining to the use of nano-technology in the field of medicine, particularly in treating cancer patients.

Inhibition of Plasmodium falciparum Lysyl-tRNA Synthetase via a Piperidine-Ring Scaffold Inspired Cladosporin Analogues.

Plasmodium falciparum lysyl-tRNA synthetase (PfKRS) represents a promising therapeutic anti-malarial target. Cladosporin was identified as a selective and potent PfKRS inhibitor but lacks metabolic stability. Here, we report chemical synthesis, biological evaluation and structural characterization of analogues where the tetrahydropyran (THP) frame of cladosporin is replaced with the piperidine ring bearing functional group variations. Thermal binding, enzymatic, kinetic and parasitic assays complemented with X-ray crystallography reveal compounds that are moderate in potency. Co-crystals of Cla-B and Cla-C with PfKRS reveal key atomic configurations that allow drug binding to and inhibition of the enzyme. Collectively these piperidine ring scaffold inhibitors lay a framework for further structural editing and functional modifications of the cladosporin scaffold to obtain a potent lead.

Andrographolide Induces Apoptosis in Gastric Cancer Cells through Reactivation of p53 and Inhibition of Mdm-2.

Andrographolide is a labdane diterpenoid isolated from Andrographis paniculata. The plant extract and andrographolide has long been used in traditional medicine practices mainly for gastrointestinal diseases and improving liver function. Andrographolide has shown various pharmacological properties including anti-inflammatory, antioxidant and anticancer activity. This study evaluated the effect of andrographolide on proliferation of human gastric carcinoma cells in relevance to p53 and Mdm-2 pathways. Andrographolide inhibited the proliferation of SGC7901 and AGS cells in a dose-dependent manner with estimated IC50 values 38 and 44 µM respectively. Effect of andrographolide on p53 activity was ascertained by using a p53 activator (RITA) which showed synergistic inhibition of cell proliferation. While andrographolide when used in combination with a p53 inhibitor (pifithrin-α) showed potent restriction over its response. Andrographolide caused decrease in mitochondrial membrane potential as an indicator of apoptotic activity. Andrographolide activated the expression of p53 protein and gene and downregulated the levels of Mdm-2 (negative regulator of p53). Andrographolide inhibited the colony formation abilities in SGC7901 in a p53-dependent manner followed by induction of mitochondrial intrinsic apoptosis through activation of caspases-9 and -3, cleavage of PARP, and inhibition of pro-apoptotic Bcl-2. Andrographolide induced p53 mediated apoptosis in gastric carcinoma cells which adds to a novel approach in anticancer therapies.

Goldenseal (Hydrastis canadensis L.) and its active constituents: A critical review of their efficacy and toxicological issues.

Goldenseal (Hydrastis canadensis L.) is a medicinal plant widely used in various traditional systems of medicine and as a food supplement. It has been traditionally used by Native Americans as a coloring agent and as medicinal remedy for common diseases and conditions like wounds, digestive disorders, ulcers, skin and eye ailments, and cancer. Over the years, goldenseal has become a popular food supplement in the USA and other regions. The rhizome of this plant has been used for the treatment of a variety of diseases including, gastrointestinal disorders, ulcers, muscular debility, nervous prostration, constipation, skin and eye infections, cancer, among others. Berberine is one of the most bioactive alkaloid that has been identified in different parts of goldenseal. The goldenseal extract containing berberine showed numerous therapeutic effects such as antimicrobial, anti-inflammatory, hypolipidemic, hypoglycemic, antioxidant, neuroprotective (anti-Alzheimer's disease), cardioprotective, and gastrointestinal protective. Various research finding suggest the health promoting effects of goldenseal components and their extracts. However, few studies have also suggested the possible neurotoxic, hepatotoxic and phototoxic activities of goldenseal extract and its alkaloids. Thus, large randomized, double-blind clinical studies need to be conducted on goldenseal supplements and their main alkaloids to provide more evidence on the mechanisms responsible for the pharmaceutical activity, clinical efficacy and safety of these products. Thus, it is very important to review the scientific information about goldenseal to understand about the current scenario.

Assessment of chemotherapy on various biochemical markers in breast cancer patients.

Chemotherapy is a standard treatment method for the patients with locally advanced breast cancer. Lately, cyclophosphamide (CYP) and doxorubicin (DOX) are used as the major chemotherapeutic agents especially for the treatment of breast cancer. Till date, no serum biomarker has been able to provide an early diagnosis of breast cancer. This study aimed to assess inflammatory, cardiac, renal and hematological markers in 56 breast cancer patients (BCP) before, during and after termination of chemotherapy with CYP and DOX. Blood samples were collected from the patients at the each treatment stages mentioned above. These samples were assessed for interleukin 6 (IL-6), interleukin 10 (IL-10), lactate dehydrogenase (LDH), creatine kinase (CK), creatinine, hemoglobin (Hb), leukocyte, platelet and Na+ /K+ -ATPase levels either by ELISA or colorimetric methods. The results suggest a significant increase in IL-6 level at all the stages in BCP as compared to control group. On the other hand, IL-10, CK and Na+ /K+ -ATPase levels were found to be significantly declined during all the stages. Moreover, the majority of hematological parameters remained unchanged throughout the treatment period with the exception of creatinine and Hb which showed slight modulation in their level at different stages. Based on the results, we conclude that breast cancer and co-treatment with CYP and DOX, interfere arious biological markers, thereby, showing the physiological imbalance.

Mycotoxin-assisted mitochondrial dysfunction and cytotoxicity: Unexploited tools against proliferative disorders.

Mitochondria are the powerhouse of cells, which upon dysfunctions may lead to several diseases. Mycotoxins are the toxic secondary metabolites from fungi which are capable of causing diseases and death in humans and animals. They have a versatile mechanism of action in biological systems and can be used as lead compounds to treat some diseases including cancer. The present work encompasses analysis on the effects of mycotoxins on mitochondrial dysfunction. Electronic databases such as PubMed, ScienceDirect, Scopus, Web of Science, and Google Scholar were thoroughly searched for up-to-date published information associated with those mycotoxins and their effect on mitochondrial dysfunction. Findings suggest that mycotoxins such as citrinin, aflatoxin, and T-2 toxin exert multi-edged sword-like effects in test systems causing mitochondrial dysfunction. Mycotoxins can induce oxidative stress even at low concentration/dose that may be one of the major causes of mitochondrial dysfunction. On the other hand, activation of apoptotic caspases and other proteins by mycotoxins may lead to apoptotic cell death. Thus, mycotoxins-mediated mitochondrial dysfunction may be related to several chronic diseases which also makes these mycotoxins considerable as lead compounds for inducing toxic effects in cells. Their cytotoxic effects on cancer cells suggest their possible application as chemotherapeutic tools. © 2018 IUBMB Life, 70(11):1084-1092, 2018.

A systematic review on the neuroprotective perspectives of beta-caryophyllene.

Beta (ß)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect. This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords "beta (ß)-caryophyllene" and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action. A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer's disease. Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.

Protective and therapeutic potential of ginger (Zingiber officinale) extract and [6]-gingerol in cancer: A comprehensive review.

Natural dietary agents have attracted considerable attention due to their role in promoting health and reducing the risk of diseases including cancer. Ginger, one of the most ancient known spices, contains bioactive compounds with several health benefits. [6]-Gingerol constitutes the most pharmacologically active among such compounds. The aim of the present work was to review the literature pertaining to the use of ginger extract and [6]-gingerol against tumorigenic and oxidative and inflammatory processes associated with cancer, along with the underlying mechanisms of action involved in signaling pathways. This will shed some light on the protective or therapeutic role of ginger derivatives in oxidative and inflammatory regulations during metabolic disturbance and on the antiproliferative and anticancer properties. Data collected from experimental (in vitro or in vivo) and clinical studies discussed in this review indicate that ginger extract and [6]-gingerol exert their action through important mediators and pathways of cell signaling, including Bax/Bcl2, p38/MAPK, Nrf2, p65/NF-κB, TNF-α, ERK1/2, SAPK/JNK, ROS/NF-κB/COX-2, caspases-3, -9, and p53. This suggests that ginger derivatives, in the form of an extract or isolated compounds, exhibit relevant antiproliferative, antitumor, invasive, and anti-inflammatory activities.

Scaling morphogen gradients during tissue growth by a cell division rule.

Morphogen gradients guide the patterning of tissues and organs during the development of multicellular organisms. In many cases, morphogen signaling is also required for tissue growth. The consequences of this interplay between growth and patterning are not well understood. In the Drosophila wing imaginal disc, the morphogen Dpp guides patterning and is also required for tissue growth. In particular, it was recently reported that cell division in the disc correlates with the temporal increase in Dpp signaling. Here we mathematically model morphogen gradient formation in a growing tissue, accounting also for morphogen advection and dilution. Our analysis defines a new scaling mechanism, which we term the morphogen-dependent division rule (MDDR): when cell division depends on the temporal increase in morphogen signaling, the morphogen gradient scales with the growing tissue size, tissue growth becomes spatially uniform and the tissue naturally attains a finite size. This model is consistent with many properties of the wing disc. However, we find that the MDDR is not consistent with the phenotype of scaling-defective mutants, supporting the view that temporal increase in Dpp signaling is not the driver of cell division during late phases of disc development. More generally, our results show that local coupling of cell division with morphogen signaling can lead to gradient scaling and uniform growth even in the absence of global feedbacks. The MDDR scaling mechanism might be particularly beneficial during rapid proliferation, when global feedbacks are hard to implement.

Tunneling Time and Weak Measurement in Strong Field Ionization.

Tunneling delays represent a hotly debated topic, with many conflicting definitions and little consensus on when and if such definitions accurately describe the physical observables. Here, we relate these different definitions to distinct experimental observables in strong field ionization, finding that two definitions, Larmor time and Bohmian time, are compatible with the attoclock observable and the resonance lifetime of a bound state, respectively. Both of these definitions are closely connected to the theory of weak measurement, with Larmor time being the weak measurement value of tunneling time and Bohmian trajectory corresponding to the average particle trajectory, which has been recently reconstructed using weak measurement in a two-slit experiment [S. Kocsis, B. Braverman, S. Ravets, M. J. Stevens, R. P. Mirin, L. K. Shalm, and A. M. Steinberg, Science 332, 1170 (2011)]. We demonstrate a big discrepancy in strong field ionization between the Bohmian and weak measurement values of tunneling time, and we suggest this arises because the tunneling time is calculated for a small probability postselected ensemble of electrons. Our results have important implications for the interpretation of experiments in attosecond science, suggesting that tunneling is unlikely to be an instantaneous process.

Seroprevalence of TORCH infections in antenatal and HIV positive patient populations.

BACKGROUND: The TORCH (Toxoplasma gondii, Rubella, Cytomegalovirus (CMV) and the Herpes Simplex Virus) cause range of diseases in pregnant women and HIV patients and lead to adverse fetal outcomes when not treated on time, in HIV positive can cause life threating infections. There is inadequate data available of these infections in India. METHODS: A retrospective study was undertaken to determine the seroprevalence of the TORCH infections in antenatal and HIV/AIDS patients at a tertiary care centre. The laboratory data pertaining to the period Jan 2012-May 2014 was analyzed. The study population involved 162 antenatal cases and 729 HIV/AIDS patients under review at an ART centre. Laboratory testing was done for the presence of IgM and IgG antibodies against the TORCH infections by ELISA method. RESULTS: Among the antenatal cases, 30 (18.52%) samples were found to be seropositive for Toxoplasma IgM, CMV IgM antibodies were found in 47 (29.01%) samples, HSV IgM antibodies were found in 12 (7.40%) samples, Rubella IgM antibodies were found in 13 (8.02%) samples, indicating recent infection. Among the HIV/AIDS cases, indicative of recent or current infection, 160 (21.94%) samples were positive for Toxoplasma IgM, CMV IgM was found in 99 (13.58%), HSV IgM antibodies were found in 98 (13.44%) and Rubella IgM in 47 (6.44%). CONCLUSIONS: The study showed a high seroprevalence of the infections caused by the TORCH complex amongst pregnant women and HIV/AIDS patients despite improved hygiene conditions and health awareness. Maximum seroprevalence for CMV was observed followed by Rubella and HSV infection.

Naringenin suppresses aluminum-induced experimental hepato-nephrotoxicity in mice through modulation of oxidative stress and inflammation.

Aluminum is a widely used metal substance in daily life activities that has been shown to cause severe hepato-nephrotoxicity with long-term exposure. Natural dietary flavonoids are being utilized as a newer pharmaceutical approach against various acute and chronic diseases. Naringenin (NAR) has shown efficient therapeutic properties, including effects against metal toxicities. However, the protective efficacy of NAR on aluminum chloride (AlCl3)-induced hepato-renal toxicity needs investigation as aluminum has shown serious environmental toxicity and bioaccumulation behavior. In this study, mice were treated with AlCl3 (10 mg/kg b.w./day) to assess toxicities, and a group of mice were co-treated with NAR (10 mg/kg b.w./day) to assess the protective effects of NAR against hepato-nephrotoxicity. The levels of blood serum enzymes, oxidative stress biomarkers, inflammatory cytokines, and the apoptosis marker caspase-3 were measured using histological examinations. NAR treatment in AlCl3-treated mice resulted in maintained levels of liver and kidney function enzymes and lipid profiles. NAR treatment attenuated oxidative stress by regulating the levels of nitric oxide, advance oxidation of protein products, protein carbonylation, and lipid peroxidation. NAR also replenished reduced antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and reduced the levels of glutathione and oxidized glutathione. NAR regulated the levels of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and elevated the levels of anti-inflammatory cytokines (IL-4, IL-10, and IFN-γ). The histological study further confirmed the protective effects of NAR against AlCl3-induced hepato-renal alterations. NAR decreased the expression of caspase-3 as a mechanism of protective effects against apoptotic damage in the liver and kidney of AlCl3-treated mice. In summary, this study demonstrated the antioxidant and anti-inflammatory properties of NAR, leading to the suppression of AlCl3-triggered hepato-renal apoptosis and histological alterations. The results suggest that aluminum toxicity needs to be monitored in daily life usage, and supplementation of the natural dietary flavonoid naringenin may help maintain liver and kidney health.

ATP mimetics targeting prolyl-tRNA synthetases as a new avenue for antimalarial drug development.

The prolyl-tRNA synthetase (PRS) is an essential enzyme for protein translation and a validated target against malaria parasite. We describe five ATP mimetics (L95, L96, L97, L35, and L36) against PRS, exhibiting enhanced thermal stabilities in co-operativity with L-proline. L35 displays the highest thermal stability akin to halofuginone, an established inhibitor of Plasmodium falciparum PRS. Four compounds exhibit nanomolar inhibitory potency against PRS. L35 exhibits the highest potency of ∼1.6 nM against asexual-blood-stage (ABS) and ∼100-fold (effective concentration [EC50]) selectivity for the parasite. The macromolecular structures of PfPRS with L95 and L97 in complex with L-pro reveal their binding modes and catalytic site malleability. Arg401 of PfPRS oscillates between two rotameric configurations when in complex with L95, whereas it is locked in one of the configurations due to the larger size of L97. Harnessing such specific and selective chemical features holds significant promise for designing potential inhibitors and expediting drug development efforts.