Explore the vast range of titles available.

It is known that local tissue injuries incurred by snakebites are quickly instilled causing extensive, irreversible, tissue destruction that may include loss of limb function or even amputation. Such injuries are not completely neutralized by the available antivenins, which in general are focused on halting systemic effects. Therefore it is prudent to investigate the potential antiophidic effects of natural and synthetic compounds, perhaps combining them with serum therapy, to potentially attenuate or eliminate the adverse local and systemic effects of snake venom. This study assessed a group of quinones that are widely distributed in nature and constitute an important class of natural products that exhibit a range of biological activities. Of these quinones, lapachol is one of the most important compounds, having been first isolated in 1882 from the bark of Tabebuia avellanedae. It was investigated the ability of lapachol and some new potential active analogues based on the 2-hydroxi-naphthoquinone scaffold to antagonize important activities of Bothrops venoms (Bothrops atrox and Bothrops jararaca) under different experimental protocols in vitro and in vivo. The bioassays used to test the compounds were: procoagulant, phospholipase A2, collagenase and proteolytic activities in vitro, venom-induced hemorrhage, edematogenic, and myotoxic effects in mice. Proteolytic and collagenase activities of Bothrops atrox venom were shown to be inhibited by lapachol and its analogues 3a, 3b, 3c, 3e. The inhibition of these enzymatic activities might help to explain the effects of the analogue 3a in vivo, which decreased skin hemorrhage induced by Bothrops venom. Lapachol and the synthetic analogues 3a and 3b did not inhibit the myotoxic activity induced by Bothrops atrox venom. The negative protective effect of these compounds against the myotoxicity can be partially explained by their lack of ability to effectively inhibit phospholipase A2 venom activity. Bothrops atrox venom also induced edema, which was significantly reduced by the analogue 3a. This research using a natural quinone and some related synthetic quinone compounds has shown that they exhibit antivenom activity; especially the compound 3a. The data from 3a showed a decrease in inflammatory venom effects, presumably those that are metalloproteinase-derived. Its ability to counteract such snake venom activities contributes to the search for improving the management of venomous snakebites.

Current therapeutic ways adopted for the treatment of leishmaniasis are toxic and expensive including parasite resistance is a growing problem. Given this scenario, it is urgent to explore treatment alternatives for leishmaniasis. The aim of this study was to evaluate the effect of 3-phenyl-lawsone (3-PL) naphthoquinone on Leishmania ( Viannia ) braziliensis infection, both in vitro and in vivo , using two local routes of administration: subcutaneous (higher dose) and tattoo (lower dose). In vitro 3-PL showed low toxicity for macrophages (CC 50 >3200 µM/48h) and activity against intracellular amastigotes (IC 50 = 193 ± 19 µM/48h) and promastigotes (IC 50 = 116 ± 26 µM/72h), in which induced increased ROS generation. Additionally, 3-PL up-regulated the production of cytokines such as tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1), interleukin-6 (IL-6) and IL-10 in infected macrophages. However, the anti-amastigote action was independent of nitric oxide production. Treatment of hamsters infected with L. ( V. ) braziliensis from one week after infection with 3-PL by subcutaneous (25 µg/Kg) or tattooing (2.5 µg/Kg) route, during 3 weeks (3 times/week) or 2 weeks (2 times/week) significantly decreased the parasite load (p<0.001) in the lesion. The reduction of parasite load by 3-PL treatment was comparable to reference drug meglumine antimoniate administered by the same routes (subcutaneous 1mg/Kg and tattoo 0.1mg/Kg). In addition, treatment started from five weeks after infection with 3-PL per tattoo also decreased the parasite load. These results show the anti-leishmanial effect of 3-PL against L. ( V. ) braziliensis and its efficacy by subcutaneous (higher dose) and tattoo (lower dose) routes. In addition, this study shows that drug delivery by tattooing the lesion allows the use of lower doses than the conventional subcutaneous route, which may support the development of a new therapeutic strategy that can be adopted for leishmaniasis.

Leishmaniasis remains a significant public health problem in Brazil, particularly due to Leishmania (Viannia) braziliensis, which is associated with severe dermatological syndromes. The current treatments are limited by toxicity and uncertain efficacy, highlighting the need for new compounds with pharmacological potential. This study investigates chalcones as multitarget binding agents for oligopeptidase B (OPB) and cysteine proteinase B (CPB), which are critical pathogenic determinants of L. (V.) braziliensis. The methodology involved replacing methoxy groups with aryl motifs at various positions within the chalcone structures and introducing specific functional groups at the C-4 position. This was followed by a virtual screening approach using molecular docking to assess interactions with the target proteinases. Several chalcones from the virtual library (n = 178) exhibited high binding affinities for OPB and CPB, outperforming control ligands. A total of 30 chalcones with multitarget potential were identified, with fluorinated compounds C-191 and C-135 emerging as promising inhibitors, distinguished by the best energy rankings for both enzymes. ADMET analyses confirmed the viability of these chalcones as drug candidates, with most adhering to Lipinski’s rules. These data suggest that chalcones may provide new multitarget treatment options for leishmaniasis.

Plant compounds that inhibit snake venom activities are relevant and can provide active molecules to counteract snake venom effects. Numerous studies on snake viperid venoms found that metalloproteinases play a significant role in the pathophysiology of hemorrhage that occurs on envenomation. Preclinical studies using vitro and in vivo protocols investigated natural compounds and viperid snake venoms, evaluating the enzymatic, procoagulant, hemorrhagic, edematogenic, myotoxic, and lethal activities. Many studies focused on Bothrops venoms and ascribed that angiorrhexis and hemorrhage resulted from the metalloproteinase action on collagen in the basal lamina. This effect resulted in a combined action with phospholipase A2 and hyaluronidase, inducing hemorrhage, edema, and necrosis. Due to the lack of efficient antivenoms in remote areas, traditional native plant treatments remain common, especially in the Amazon. Our group studied plant extracts, isolated compounds, and lapachol synthetic derivative analogs with selective inhibition for Bothrops venom proteolytic and hemorrhagic activity and devoid of phospholipase activity. We highlight those new synthetic naphthoquinones which inhibit snake venom metalloproteinases and that are devoid of other venom enzyme inhibition. This review shows the potential use of snake venom effects, mainly Bothrops venom metalloproteinase activity, as a tool to identify and develop new active molecules against hemorrhagic effects.

Endemic and pandemic viruses represent significant public health challenges, leading to substantial morbidity and mortality over time. The COVID-19 pandemic has underscored the urgent need for the development and discovery of new, potent antiviral agents. In this study, we present the synthesis and anti-SARS-CoV-2 activity of a series of benzocarbazoledinones, assessed using cell-based screening assays. Our results indicate that four compounds (4a, 4b, 4d, and 4i) exhibit EC50 values below 4 μM without cytotoxic effects in Calu-3 cells. Mechanistic investigations focused on the inhibition of the SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) have used enzymatic assays. Notably, compounds 4a and 4b showed Mpro inhibition activity with IC50 values of 0.11 ± 0.05 and 0.37 ± 0.05 µM, respectively. Furthermore, in silico molecular docking, physicochemical, and pharmacokinetic studies were conducted to validate the mechanism and assess bioavailability. Compound 4a was selected for preliminary drug-likeness analysis and in vivo pharmacokinetics investigations, which yielded promising results and corroborated the in vitro and in silico findings, reinforcing its potential as an anti-SARS-CoV-2 lead compound.

We study the nonlinear absorptive and dispersive optical properties of molecular systems immersed in a thermal reservoir interacting with a four-wave mixing (FWM) signal. Residual spin-orbit Hamiltonians are considered in order to take into account the internal structure of the molecule. As system parameters in the dissipation processes, transverse and longitudinal relaxation times are considered for stochastic solute–solvent interaction processes. The intramolecular coupling effects on the optical responses are studied using a molecule model consisting of two coupled harmonic curves of electronic energies with displaced minima in nuclear energies and positions. In this study, the complete frequency space is considered through the pump–probe detuning, without restricting the derivations to only maximums of population oscillations. This approach opens the possibility of studying the behavior of optical responses, which is very useful in experimental design. Our results indicate the sensitivity of the optical responses to parameters of the molecular structure as well as to those derived from the photonic process of FWM signal generation.

Background. Protease-resistant prion protein (PrPres) accumulation in lymphoreticular tissues indicates prion infection. To date, tonsillectomy and appendectomy samples have been used in population prevalence surveys to detect clinically silent carriers of variant Creutzfeldt-Jakob disease (vCJD). However, the temporal sequence of prion spread in the human body is still not known. We therefore traced the temporal-spatial pattern of PrPres accumulation in the body of a simian vCJD model. Methods. Cynomolgus monkeys were fed brain of (eleven) cows with bovine spongiform encephalopathy, and some were euthanized before and some after onset of neurological signs. PrPres was detected in tissues by a paraffinembedded tissue blot technique and a semiquantitative Western immunoblot assay. Results. Bovine spongiform encephalopathy (BSE)-associated prions were preferentially transported from the gut to the central nervous system (CNS) along sensory nerve fibers and initially entered the simian CNS at lumbar spinal cord levels. In asymptomatic animals, we found BSE in 50% and 12% of gut-and tonsil-derived samples, respectively. Conclusions. Unlike in rodents and ruminants, foodborne BSE-associated prions entered the simian CNS via afferent neurons. From sites of initial CNS invasion, prions spread centrifugally to tonsils and spleen at an advanced stage of the incubation period, thus explaining why tonsil specimens were not reliable for detection of simian disease carriers before onset of clinical signs.