Anti-inflammatory and healing effect of the polysaccharidic extract of Opuntia ficus-indica cladodes in cutaneous excisional wounds in rats.

This study aimed to investigate the anti-inflammatory and wound healing effects of the polysaccharide extract from Opuntia ficus-indica cladodes (TPL-Ofi) using a rat cutaneous wound model. After anaesthesia, four 7-mm-diameter dorsal wounds per animal (n = 6/group for each experimental day of evaluation) were created in female Wistar rats using a surgical punch. The animals were treated topically twice daily with TPL-Ofi (0.01-1%; treated group) or sterile saline (control group) for a period of 21 days. Ulcerated tissue was collected for analysis of histological parameters (inflammation score, number of polymorphonuclear, mononuclear, fibroblast/myofibroblasts and blood vessels), immunohistochemical (fibroblast growth factor 2 [FGF-2]) and oxidative stress markers (myeloperoxidase [MPO] and glutathione [GSH]). After 21 days of treatment, body weight, net organ weight and plasma biochemical levels were measured. TPL-Ofi, containing a total carbohydrate content of 65.5% and uronic acid at 2.8%, reduced oedema on the second day and increased the nociceptive threshold on the second and third days. TPL-Ofi reduced mononuclear infiltrate on the second and MPO activity on the fifth day. TPL-Ofi increased GSH levels on the second day, as well as fibroblast/myofibroblasts counts, neoangiogenesis and FGF-2 levels on the fifth and seventh days. No changes were observed in body weight, net organ weight or toxicology assessment. Topical application of TPL-Ofi exhibited anti-inflammatory and antinociceptive effects, ultimately improving wound healing in cutaneous wounds.

STING recognition of viral dsDNA by nociceptors mediates pain in mice.

Pain is often one of the initial indicators of a viral infection, yet our understanding of how viruses induce pain is limited. Immune cells typically recognize viral nucleic acids, which activate viral receptors and signaling, leading to immunity. Interestingly, these viral receptors and signals are also present in nociceptors and are associated with pain. Here, we investigate the response of nociceptors to nucleic acids during viral infections, specifically focusing on the role of the viral signal, Stimulator of Interferon Genes (STING). Our research shows that cytosolic double-stranded DNA (dsDNA) from viruses, like herpes simplex virus 1 (HSV-1), triggers pain responses through STING expression in nociceptors. In addition, STING agonists alone can elicit pain responses. Notably, these responses involve the direct activation of STING in nociceptors through TRPV1. We also provided a proof-of-concept showing that STING and TRPV1 significantly contribute to the mechanical hypersensitivity induced by HSV-1 infection. These findings suggest that STING could be a potential therapeutic target for relieving pain during viral infections.

Galactomannan of Delonix regia seeds modulates cytokine expression and oxidative stress eliciting anti-inflammatory and healing effects in mice cutaneous wound.

The galactomannans property of forming viscous solutions, along with the traditional use of Delonix regia as anti-inflammatory, antinociceptive and wound healing, justify the investigation of the healing mechanism of Delonix regia galactomannan (GM-DR) in a model of excisional cutaneous wound. GM-DR (% 0.01-1) was topically applied to the wounds of female Swiss mice during 14 days. The wound healing effect of GM-DR was evaluated by the following parameters: wound closure and clinical signs (hyperemia, edema and exudate by macroscopy, nociception by analgesimetry), oxidative stress markers (malondialdehyde - MDA, reduced glutathione - GSH) by ELISA, histopathological (HE and Picrosirius red), and histomorphometric (collagenesis, blood vessels, polymorphonuclear, mononuclear, fusiform cells) and immunohistochemistry (inflammatory and growth factor mediators) by tissue microarrayer. GM-DR reduced wound area (7-14th day) and hypernociception (6 h - 5th day), leukocyte infiltration (2 -7th days), expression and levels of IL-1ß (2th day), IL-6 (2th day), MDA (44% - 2th day), and increased fusiform cells, granulation tissue, collagen deposition, GSH (25 - 50%, 2-5th day), expression of the transforming growth factor beta (TGF-ß) (7-10th day) and smooth muscle alpha actin (α-SMA) (7-14th day). In conclusion, GM-DR accelerates the mice healing process acting both in the inflammatory and proliferative phases.

PD-1/PD-L1 Inhibition Enhances Chemotherapy-Induced Neuropathic Pain by Suppressing Neuroimmune Antinociceptive Signaling.

Cytotoxic agents synergize with immune checkpoint inhibitors and improve outcomes for patients with several cancer types. Nonetheless, a parallel increase in the incidence of dose-limiting side effects, such as peripheral neuropathy, is often observed. Here, we investigated the role of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis in the modulation of paclitaxel-induced neuropathic pain. We found that human and mouse neural tissues, including the dorsal root ganglion (DRG), expressed basal levels of PD-1 and PD-L1. During the development of paclitaxel-induced neuropathy, an increase in PD-L1 expression was observed in macrophages from the DRG. This effect depended on Toll-like receptor 4 activation by paclitaxel. Furthermore, PD-L1 inhibited pain behavior triggered by paclitaxel or formalin in mice, suggesting that PD-1/PD-L1 signaling attenuates peripheral neuropathy development. Consistent with this, we observed that the combined use of anti-PD-L1 plus paclitaxel increased mechanical allodynia and chronic neuropathy development induced by single agents. This effect was associated with higher expression of inflammatory markers (Tnf, Il6, and Cx3cr1) in peripheral nervous tissue. Together, these results suggest that PD-1/PD-L1 inhibitors enhance paclitaxel-induced neuropathic pain by suppressing PD-1/PD-L1 antinociceptive signaling.

Pharmacological effects of the isomeric mixture of alpha and beta amyrin from Protium heptaphyllum: a literature review.

Protium heptaphyllum Aubl. belongs to the Burseraceae family. It is commonly called 'almecegueira' and is known to produce an amorphous resin which has constituents such as α- and ß-amyrin, taraxastan-3-oxo-20-ol and sitostenonein. The α- and ß-amyrin from P. heptaphyllum have pharmacological activities in several systems, such as central and peripheral nervous system, gastrointestinal tract and immunological system. In this study, our objective was to review pharmacological activities and to gather more information on the mixture of α- and ß-amyrin obtained from P. heptaphyllum to guide future preclinical and clinical studies using this compound. This review consisted of searches performed using scientific databases such as PubMed, SciELO, LILACS, SciFinder and Science Direct. Some uses of α- and ß-amyrin have been partially confirmed by previous studies demonstrating analgesic, anti-inflammatory, anticonvulsant, antidepressive, gastroprotective, hepatoprotective, antipancreatitic, anticholytic, antihyperglycemic and hypolipidemic effects. It is noteworthy that there are no α- and ß-amirin toxicity tests described in the literature as recommended in the international guidelines, and such tests are one of the research stages to proceed in clinical and preclinical trials if this compound was to be used.

Venom of the giant ant Dinoponera quadriceps attenuates inflammatory pain in mouse cutaneous wound healing model

Arthropod venoms are potential sources of bioactive substances, providing tools for the validation of popular use and new drugs design. Ants belonging to the genus Dinoponera are used in the folk medicine to treat inflammatory conditions. It was previously demonstrated that the venom of the giant ant Dinoponera quadriceps (DqV), containing a mixture of polypeptides, elicit antinociceptive effect in mice models of chemical, mechanical and thermal nociception. The aim of this study was to evaluate DqV antiinflammatory and antihypernociceptive effects in a mice model of traumatic cutaneous wound. Colonies of D. quadriceps were collected in the ‘‘Serra de Maranguape’’ (State of Ceará, northeastern Brazil), a small mountain range located on the coastal zone, and the venom secreted by the ant glands was extracted with capillary tubes, further lyophilized and maintained at -20 ± 1ºC until use. Wounds were performed in the dorsum of Swiss mice. Animals received intravenous (i.v.) injection of DqV (50 µg -1kg day-1) during 3 days for evaluation of inflammatory parameters present in the wounds: hypernociception, leukocyte infiltrate, myeloperoxidase activity, nitrite nitrate-1 content. Data was tested by two-way ANOVA and Bonferroni’s post-hoc test. DqV reduced (2.7 folds) hypernociception at 48 hours, leukocyte infiltration by 65% at 6 hours and myeloperoxidase activity by 60% at 0.5 hour after wound induction. In conclusion, the venom extracted from D. quadriceps glands attenuates inflammation and hypernociception in mice cutaneous wounds.