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Tuberculosis is a disease caused by a single pathogen that leads to a death toll estimated to be more than a million per year. Mycobacterium tuberculosis (Mtb), which affects mainly the lungs, spreads by airborne transmission when infectious respiratory particles from an infected human enter the respiratory tract of another person. Despite diagnosis and treatment being well established, the rise of cases of patients infected with Mtb strains with multidrug resistance to the antibiotics used in the regimen against the disease is alarming. Indole used as a core molecule has been described as a promising structure to treat several diseases. 5-Fluoroindole (5-FI) compound, evaluated in the free base and in the hydrochloride (5-FI.HCl) forms, inhibited the growth of pan-sensitive Mtb H37Rv strain in the same range (4.7-29.1 μM) of clinical isolates that have resistance to at least two first-line drugs. Although 5-FI showed no cytotoxicity in Vero and HepG2 cells, high permeability (2.4.10 -6 cm/s) in the PAMPA assay, and high metabolic stability (Cl int 9.0 mL/min/kg) in rat liver microsomes, limited solubility at plasmatic and intestinal pH values prompted formation and employment of its salt form (5-FI.HCl). Although the 5-FI.HCl compound showed increased solubility at pH values of 7.4 and 9.1 and increased stability in aqueous solutions, data for intrinsic clearance (Cl int = 48 mL/min/kg) and a half-life ( t 1/2 = 12 min) showed decreased metabolic stability. As 5-FI.HCl showed both good absorption and ability to reach the systemic circulation of animals without the need to use vehicles containing cosolvents or surfactants, it was chosen to evaluate its effectiveness in the model of tuberculosis in mice. The in vivo results showed the concentration of the compound in plasma increasing within 30 min in the systemic circulation and the capacity of reducing the Mtb burden in the lungs at the concentration of 200 μmol/kg after 21 days of infection, with no toxicity in mice., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Migraine is a highly disabling disease, for which current therapies are limited to symptom alleviation. There is compelling evidence linking migraine with metabolic disorders, but the causal relationship is not clear. Omega-3 (n-3) fatty acids have anti-inflammatory properties, with clear benefits in metabolic disorders, but its effects on migraine remains to be tested. We hypothesized that fructose-induced metabolic syndrome could aggravate migraine by increasing neuroinflammation and that n-3 treatment could mitigate it., Methods: Male Wistar rats were used. Animals that received 10% high fructose diet (HFD) or tap water were subdivided into two additional groups: with or without n-3 supplementation. Fifteen days before euthanasia, each group was subdivided into two additional groups: with or without nitroglycerin (NTG)-induced migraine., Results: HFD lessened the migraine-like painful symptoms, as indicated by decreased grimace scores, which paralleled with reduced CGRP and leptin serum levels, increased hypothalamic CGRP, and decreased hypothalamic adiponectin and IL-6. There was a recovery of body and adipose tissue weight, besides a reduction of crown-like structures (CLS) in the inguinal adipose tissue. N-3 supplementation had no effect on NTG-related pain, but it decreased body and adipose tissue weight of HFD and tap water NTG-injected rats. N-3 improved NTG-related affective behavior and inflammatory parameters in tap water NTG-injected rats, with decreased hypothalamic TNF, serum CGRP and inguinal adipose-tissue CLS., Conclusions: HFD relieved NTG-induced pain, possibly due to decreased energy expenditure, minimizing migraine energy needs. N-3 exhibited favorable effects regarding affective behavior and central and peripheral inflammation, irrespective of HFD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-21-5699/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Human thymidine phosphorylase (hTP) is overexpressed in several solid tumors and is commonly associated with aggressiveness and unfavorable prognosis. 6-(((1,3-Dihydroxypropan-2-yl)amino)methyl)-5-iodopyrimidine-2,4(1H,3H)-dione (CPBMF-223) is a noncompetitive hTP inhibitor, which has been described as a tumor angiogenesis inhibitor. The present study investigated the effects of CPBMF-223 in a xenograft tumor induced by human colorectal carcinoma cells (HCT-116). Additionally, CPBMF-223 capacity to reduce cell migration, its toxicological profile, and pharmacokinetic characteristics, were also evaluated. The intraperitoneal treatment with CPBMF-223 markedly prevented the relative tumor growth with an efficacy similar to that observed for 5-fluorouracil. Interestingly, number of vessels were significantly decreased in the treated groups. Moreover, CPBMF-223 significantly reduced the migration of cell line HCT-116. In the Ames assay and in an acute oral toxicity test, the molecule did not alter any evaluated parameter. Using the zebrafish toxicity model, cardiac and locomotor parameters were slightly changed. Regarding the pharmacokinetics profile, CPBMF-223 showed clearance of 9.42 L/h/kg after intravenous administration, oral bioavailability of 13.5%, and a half-life of 0.75 h. Our findings shed new light on the role of hTP in colorectal cancer induced by HCT-116 cell in mice, pointing out CPBMF-223 as, hopefully, a promising drug candidate., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Dry extracts from the Eurasian plants, Ajuga turkestanica , Eurycoma longifolia , and Urtica dioica have been used as anabolic supplements, despite the limited scientific data on these effects. To assess their actions on early sarcopenia signs, male and female castrated mice were supplemented with lyophilized extracts of the three plants, isolated or in association (named TLU), and submitted to resistance exercise. Ovariectomy (OVX) led to body weight increase and non-high-density cholesterol (HDL) cholesterol elevation, which had been restored by exercise plus U. dioica extract, or by exercise and TLU, respectively. Orchiectomy (ORX) caused skeletal muscle weight loss, accompanied by increased adiposity, being the latter parameter reduced by exercise plus E. longifolia or U. dioica extracts. General physical activity was improved by exercise plus herbal extracts in either OVX or ORX animals. Exercise combined with TLU improved resistance to fatigue in OVX animals, though A. turkestanica enhanced the grip strength in ORX mice. E. longifolia or TLU also reduced the ladder climbing time in ORX mice. Resistance exercise plus herbal extracts partly altered gastrocnemius fiber size frequencies in OVX or ORX mice. We provide novel data that tested ergogenic extracts, when combined with resistance exercise, improved early sarcopenia alterations in castrated male and female mice.

Kinins and their receptors have been implicated in a series of pathological alterations, representing attractive pharmacological targets for several diseases. The present review article aims to discuss the role of the kinin system in infectious diseases. Literature data provides compelling evidence about the participation of kinins in infections caused by diverse agents, including viral, bacterial, fungal, protozoan, and helminth-related ills. It is tempting to propose that modulation of kinin actions and production might be an adjuvant strategy for management of infection-related complications.

Immune-mediated inflammatory diseases of the central nervous system (CNS) are a group of neurological disorders in which inflammation and/or demyelination are induced by cellular and humoral immune responses specific to CNS antigens. They include diseases such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), acute disseminated encephalomyelitis (ADEM) and anti-NMDA receptor encephalitis (NMDAR encephalitis). Over the years, many in vivo and in vitro models were used to study clinical, pathological, physiological and immunological features of these neuroimmunological disorders. Nevertheless, there are important aspects of human diseases that are not fully reproduced in the experimental models due to their technical limitations. In this review, we describe the preclinical models of neuroimmune disorders, and how they contributed to the understanding of these disorders and explore potential treatments. We also describe the purpose and limitation of each one, as well as the recent advances in this field., (Copyright © 2020 da Silva, Silva, Goi, Molina, Machado and Sato.)

This study has characterized a rat model with temporomandibular osteoarthritis (TMJ-OA) following a surgical anterior displacement of their articular disc (ADD). The well-established model of OA, induced by an intra-articular injection of complete Freund's adjuvant (CFA) into the TMJ, was used for comparison purposes. Male Wistar rats were assigned into two surgical groups, namely, ADD (anterior disc displacement) and sham-operated (surgical access, without ADD). Additional groups received an intra-articular infiltration of CFA (50 μl/site; 1:1 oil/saline emulsion), or the vehicle (0.9% NaCl). The separate experimental subgroups were euthanized at 15, 30 or 60 days and their left TMJs were collected for histological, immunohistochemistry and micro-CT analyses. The serum levels of IL-1β, IL-6 and TNF were analyzed. The fibrocartilage thicknesses were increased in the ADD groups at all of the analyzed time-points. In the CFA group, fibrocartilage thickenings were seen only in the posterior thirds at 15 days. The ADD group displayed an increase of the proteoglycan contents and ADAMTS5 immunopositivity in the fibrocartilage at 30 and 60 days, without any variations of the collagen contents or the osteoclast activation. Upon the micro-CT evaluation, the ADD group presented increments of their trabecular separations and bone surfaces, with reduced trabecular thicknesses and bone volumes, plus osteophyte formations and condyle flattenings, from 30 to 60 days. The IL-1β, TNF or IL-6 serum levels were undetectable. The surgical ADD in the rats led to long-term OA-like alterations, with typical structural and morphological derangements of the TMJ, representing a reliable experimental model to investigate the TMJ-OA-related mechanisms., Competing Interests: None.