Effects of Euphorbia characias subsp. characias flower extracts on nociceptive pain and acute inflammatory models in mice.

Pain and inflammation are major health issues worldwide, leading to negative consequences. Despite several drugs being available to manage these conditions, their effectiveness can be limited by cost, adverse reactions, and potential tolerance and dependence with long-term use. Euphorbia characias traditionally used in folk medicine for its diverse biological activities - including antiproliferative, antimicrobial, and anti-inflammatory effects - has not been extensively studied in vivo for its analgesic and anti-inflammatory properties. In this study, the antinociceptive and anti-inflammatory properties of the water and ethanolic extracts of E. characias flowers (ECAEFl and ECEEFl) were evaluated using various models. Both extracts significantly reduced paw licking time in a formalin-induced paw licking model, with ECAEFl specifically targeting and ECEEFl affecting both the neurogenic and inflammatory phases. Additionally, in the carrageenan-induced cell migration model, both extracts showed a significant decrease in leukocyte migration, protein extravasation and nitric oxide levels, further demostrating their anti-inflammatory activity. High-Resolution HPLC-ESI-QTOF-MS-MS and HPLC-PDA analysis characterized the chemical composition of the extracts, identifying a significant presence of phenolic compounds, particularly quercetin and its derivatives, which likely contribute to the observed biological activities. These findings highlight the potential of E. characias extracts as natural sources of compounds with antinociceptive and anti-inflammatory properties. Further investigations are needed to elucidate the underlying mechanisms and explore their therapeutic potential in pain and inflammation-related disorders.

Synthesis of cannabidiol-based compounds as ACE2 inhibitors with potential application in the treatment of COVID-19.

Cannabis is a general name for plants of the genus Cannabis. Used as fiber, medicine, drug, for religious, therapeutic, and hedonistic purposes along the millenia, it is mostly known for its psychoactive properties. One of its major constituents, cannabidiol (CBD), a non-psychoactive substance, among many other biological activities, has shown potential as an anti-SARS-CoV-2 drug. In this work, three derivatives and an analogue of CBD were synthesized, and cell viability and antiviral activities were evaluated. None of the compounds showed cytotoxicity up to a maximum concentration of 100 µM and, in contrast, displayed a significant antiviral activity, superior to remdesivir and nafamostat mesylate, with IC50 values ranging from 9.4 to 1.9 µM. In order to search for a possible molecular target, the inhibitory activity of the compounds against ACE2 was investigated, with expressive results (IC50 ranging from 3.96 µM to 0.01 µM).

Tibouchina granulosa Leaves Present Anti-Inflammatory Effect.

The ethanol extract (EE) prepared from the leaves of Tibouchina granulosa, and its fraction in ethyl acetate (fEA) were evaluated concerning their capacity to reduce inflammation in different experimental models. fEA was also studied concerning its chemical constituents. EE and fEA were assayed for their anti-inflammatory potential, using formalin-induced licking behavior and carrageenan-induced inflammation into the subcutaneous air pouch (SAP) models. Reduction in polymorphonuclear cells (PMN) activation was performed in freshly isolated PMN. Chromatographic analysis of fEA was performed by HPLC-DAD. Hispiduloside was isolated as the main constituent in fEA, and its quantity was estimated to be 39.3% in fEA. EE (30 mg/kg) significantly reduced the second phase of formalin-induced licking. fEA demonstrated a reduction in leukocyte migration into the SAP. EE and fEA drastically reduced cytokines (TNF-α, IL-1ß, and IFN-γ), nitric oxide (NO) production, in vitro PMN migration induced by C5a and IL-8, and TNF-α and IL-1ß gene expression. Taken together, our data indicate that either ethanol extract or its fEA fraction from leaves of T. granulosa present an anti-inflammatory effect, contributing to the pharmacological and chemical knowledge of this species and confirming the rationale behind its traditional use.

Phenylbenzohydrazides Obtained from Isatoic Anhydride Present Anti-Inflammatory Activity In Vivo and In Vitro.

BACKGROUND: Despite the existence of a wide variety of anti-inflammatory drugs, the vast majority are classified as steroidal or non-steroidal. Both classes present a variety of side effects that limit usage. Thus, the search for new molecules with anti-inflammatory potential is still important. METHODS: Five phenylbenzohydrazides were synthetized and evaluated in pre-clinical models of acute inflammation in vivo and in vitro. RESULTS: The new substances (INL-06, -07, -10, and -11), as well as AISCT, significantly reduced cell migration induced by carrageenan. It was also observed that all INLs inhibited protein extravasation as well as cytokines (IL-6, IL-1ß, and TNF-α) and nitric oxide (NO) production. The INL-11 was demonstrated to be the most potent, since the inhibition observed in several parameters was significant even when compared with dexamethasone. In vitro INLs also reduced cytokines and NO production and inducible nitric oxide (iNOS) enzyme activity. The INL-11 was the most effective in reducing cell migration in vitro. CONCLUSIONS: Our data suggest that these substances are suitable for further development into a new series of compounds that could lead to new hits and future drug prototypes for anti-inflammatory conditions.

Copaiba Oil Resin Exerts an Additive Effect to Babassu Oil on Behavioral Changes in Human Endometriotic Cell Cultures.

BACKGROUND: Current drugs for the treatment of endometriosis are not able to completely cure the condition, and significant side effects hinder the continuation of treatment. Therefore, it is necessary to search for new drug candidates. In the present paper, the use of plant extracts is highlighted. Babassu oil and Copaiba oil resin have several therapeutic properties. We investigated the in vitro effects of two nanoemulsions containing oil extracted from Babassu (Orbignya speciosa) nuts (called SNEDDS-18) and/or oil resin extracted from Copaiba trunk (Copaifera langsdorffii) (called SNEDDS-18/COPA) on cultured human eutopic endometrium stromal cells from endometrial biopsies of patients without (CESC) and with (EuESC) endometriosis as well as human stromal cells from biopsies of endometriotic lesions (EctESC). METHODS: CESC, EuESC, and EctESC were taken and treated with SNEDDS-18 and SNEDDS-18/COPA to evaluate their effects on cytotoxicity, cell morphology, proliferation, and signaling pathways. RESULTS: After 48 h of incubation with SNEDDS-18 and SNEDDS-18/COPA, cell viability and proliferation were inhibited, especially in EctESC. The lowest concentration of both nanoemulsions reduced cell viability and proliferation and broke down the cytoskeleton in EctESCs. After 24 h of treatment a decrease in IL-1, TNF-α, and MCP-1 was observed, as well as an increase in IL-10 production. CONCLUSIONS: Both nanoemulsions can affect endometriotic stromal cell behaviors, thus revealing two potential candidates for new phytotherapeutic agents for the management of endometriosis.

Novel Regioisomeric Analogues of Naphthyl-N-Acylhydrazone Derivatives and Their Anti-Inflammatory Effects.

BACKGROUND: When homeostasis is disturbed it can result in a pathological event named inflammation. The main drugs used in the treatment consist of non-steroidal and steroidal anti-inflammatory drugs. However, the side effects remain an obstacle during the treatments. In this study, we aimed to evaluate three new regioisomers analogues of naphthyl-N-acylhydrazone derivatives. METHODS: Acute models of inflammation in vivo (formalin-induced licking and carrageenan-induced inflammation) as well as in vitro were used to evaluate the effects of LASSBio-2039, LASSBio-2040, and LASSBio-2041. RESULTS: All three substances (at 1, 10 or 30 µmol/kg) presented significant effects in the in vivo model reducing leukocyte migration, nitric oxide (NO) and interleukin-1ß production. It was observed that only LASSBio-2039 significantly reduced cell migration in vitro. None of the LASSBios affected inducible nitric oxide synthase activity nor presented nitric oxide (NO) scavenger effect. No toxic effect was observed, either in vivo or in vitro. The new regioisomers analogues of naphthyl-N-acylhydrazone derivatives presented significant anti-inflammatory activity, suggesting LASSBio-2039 has a direct effect in leukocytes migratory capacity. CONCLUSIONS: Taken together, the data indicate that these substances present promising effects for the development of a prototype for new drugs.

Endometriosis: A Disease with Few Direct Treatment Options.

Endometriosis is a gynecological condition characterized by the growth of endometrium-like tissues inside and outside the pelvic cavity. The evolution of the disease can lead to infertility in addition to high treatment costs. Currently, available medications are only effective in treating endometriosis-related pain; however, it is not a targeted treatment. The objective of this work is to review the characteristics of the disease, the diagnostic means and treatments available, as well as to discuss new therapeutic options.

Pharmacognostic Study on Elsholtzia ciliata (Thumb.) Hyl: Anatomy, Phytochemistry and Pharmacological Activities.

Elsholtzia ciliata (Thunb.) Hyl, family Lamiaceae, is an important and popular anti-bacterial and anti-inflammatory Traditional Chinese Medicine (TCM). However, there are limited scientific studies on its anatomy and pharmacological activities. Moreover, the information of chemical constituents in relation to its non-volatile constituents are still missing. The current study aimed to evaluate the anatomic, pharmacological and phytochemical profile of Elsholtzia ciliata, providing means for the quality control of this herbal drug. The methodology designed for this study included the preparation of anatomic sections and their description, extraction, chromatography, structural elucidation of isolated compounds by NMR techniques and their quantification by HPLC using pharmacological assays (Formalin, hot plate, DPPH, antimicrobial-Gram positive, Gram Negative and fungus, and MTT assays) to confirm the activities described for this species. Results of the anatomic study are aligned with the pattern expected for plants belonging to the Lamiaceae family; Ursolic acid and Oroxylin were isolated from this plant species. The findings observed in this study indicate that Elsholtzia ciliata possess anti-inflammatory, antinociceptive, antioxidant, antimicrobial and anticancer activities. The chemical compounds isolated from its leaves and the anatomy profile of its parts provide the basis for further quality control for this plant.

Benzo[f]indole-4,9-dione Derivatives Effectively Inhibit the Growth of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor clinical outcome, and currently no effective targeted therapies are available. Indole compounds have been shown to have potential antitumor activity against various cancer cells. In the present study, we found that new four benzo[f]indole-4,9-dione derivatives reduce TNBC cell viability by reactive oxygen species (ROS) accumulation stress in vitro. Further analyses showed that LACBio1, LACBio2, LACBio3 and LACBio4 exert cytotoxic effects on MDA-MB 231 cancer cell line by inducing the intrinsic apoptosis pathway, activating caspase 9 and Bax/Bcl-2 pathway in vitro. These results provide evidence that these new four benzo[f]indole-4,9-dione derivatives could be potential therapeutic agents against TNBC by promoting ROS stress-mediated apoptosis through intrinsic-pathway caspase activation.

Characterization of ßN-Octadecanoyl-5-hydroxytryptamide Anti-Inflammatory Effect.

BACKGROUND: N-octadecanoyl-5-hydroxytryptamide (C18-5HT) is an amide that can be obtained by the coupling of serotonin and octadecanoic acid. This study aims to characterize the in vivo and in vitro anti-inflammatory activity of C18-5HT. METHODS: A subcutaneous air pouch model (SAP) was used. The exudates were collected from SAP after carrageenan injection to assess cell migration and inflammatory mediators production. RAW 264.7 cells were used for in vitro assays. RESULTS: C18-5HT significantly inhibited leukocyte migration into the SAP as well as nitric oxide (NO) and cytokines production and protein extravasation. We also observed an reduction in some cytokines and an increase in IL-10 production. Assays conducted with RAW 264.7 cells indicated that C18-5HT inhibited NO and cytokine produced. CONCLUSIONS: Taken together, our data suggest that C18-5HT presents a significant effect in different cell types (leukocytes collected from exudate, mainly polumorphonuclear leukocytes and cell culture macrophages) and is a promising compound for further studies for the development of a new anti-inflammatory drug.

Antinociceptive activity of puberulin and choisyine from ethanol extract of Choisya ternata Kunth var. Sundance.

Choisya ternata Kunth variety Sundance (CTS) is a plant used in traditional medicine in North America, especially in Mexico. The present study evaluated the antinociceptive activity of the crude ethanolic extract of CTS leaves and tested its isolated compounds puberulin (Pu) and choisyine (Ch). An antinociceptive effect was observed after treatment with CTS extract and the isolated compounds Pu and Ch. Mice orally pre-treated with CTS extract (10, 30 or 100 mg/kg), Pu or Ch (0.3, 1 or 3 mg/kg) were less sensitive to chemical and thermal algesic agents in different animal models (formalin-, glutamate- and capsaicin-induced licking response tests and hot plate test). In addition, an antagonist of the opioid receptor was able to reverse the antinociceptive effect observed for the CTS extract and the isolated substance Ch, but it did not inhibit the effect of Pu. The cholinergic pathway was found to be involved in this antinociceptive effect for the CTS extract and Ch but has no participation in the Pu antinociceptive activity.

Novel Single Inhibitor of HDAC6/8 and Dual Inhibitor of PI3K/HDAC6 as Potential Alternative Treatments for Prostate Cancer.

BACKGROUND: Prostate cancer is the second most frequently diagnosed malignancy worldwide. Here, the cytotoxic and antimetastatic effects of a new HDAC6/8 inhibitor, LASSBio-1911, and a new dual-PI3K/HDAC6 inhibitor, LASSBio-2208, were evaluated against PC3 prostate cancer cell line. METHODS: A MTT assay was used to assess the cell viability. Annexin V/propidium iodide (PI) was used to detect apoptotic cell death and to analyze the cell cycle distribution. Interleukin 6 (IL-6) levels were measured by ELISA. A cell scratch assay was performed to assess cell migration, and the expression of proteins was estimated by Western blotting. RESULTS: LASSBio-1911 and LASSBio-2208 exert cytotoxic effects against PC3 cells. However, LASSBio-2208 was demonstrated to be more potent than LASSBio-1911. The apoptosis assays showed that both compounds trigger apoptotic processes and cause the arrest of cells in the G2/M phase of the cell cycle. The Western blot analysis revealed that LASSBio-2208 significantly decreased the expression of p-JNK and JAK2. However, both compounds reduced the expression of p-STAT3, IL-6 secretion, and cell migration. CONCLUSIONS: LASSBio-1911 and LASSBio-2208 demonstrated significant activity in reducing cell viability and migration. These compounds can be further used as prototypes for the development of new potential anticancer alternative treatments.

Two New ßN-Alkanoyl-5-Hydroxytryptamides with Relevant Antinociceptive Activity.

In this work, we describe a new route for the synthesis and the antinociceptive effects of two new ßN-alkanoyl-5-hydroxytryptamides (named C20:0-5HT and C22:0-5HT). The antinociceptive activities were evaluated using well-known models of thermal-induced (reaction to a heated plate, the hot plate model) or chemical-induced (licking response to paw injection of formalin, capsaicin, or glutamate) nociception. The mechanism of action for C20:0-5HT and C22:0-5HT was evaluated using naloxone (opioid receptor antagonist, 1 mg/kg), atropine (muscarinic receptor antagonist, 1 mg/kg), AM251 (cannabinoid CB1 receptor antagonist, 1 mg/kg), or ondansetron (5-HT3 serotoninergic receptor antagonist, 0.5 mg/kg) 30 min prior to C20:0-5HT or C22:0-5HT. The substances both presented significant effects by reducing licking behavior induced by formalin, capsaicin, and glutamate and increasing the latency time in the hot plate model. Opioidergic, muscarinic, cannabinoid, and serotoninergic pathways seem to be involved in the antinociceptive activity since their antagonists reversed the observed effect. Opioid receptors are partially involved due to tolerant mice demonstrating less antinociception when treated with both compounds. Our data showed a quicker and simpler route for the synthesis of the new ßN-alkanoyl-5-hydroxytryptamides. Both compounds demonstrated significant antinociceptive effects. These new compounds could be used as a scaffold for the synthesis of analogues with promising antinociceptive effects.

The role of kallikrein-kinin and renin-angiotensin systems in COVID-19 infection.

In November 2019 the first cases of a novel acute respiratory syndrome has been reported in Wuhan province, China. Soon after, in January 2020 the World Health Organization declared a pandemic state due to the dissemination of a virus named SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the cause of coronavirus disease 2019 (COVID-19). Being an unknown disease, it is essential to assess not only its main characteristic features and overall clinical symptomatology but also its patient infection mode and propagation to design appropriate clinical interventions and treatments. In this review the pathophysiology of SARS-CoV-2 infection and how the virus enters the cells and activates the immune system are described. The role of three systems involved in the SARS- CoV-2 infection (renin-angiotensin, kinin and coagulation systems) is discussed with the objectives to identify and try to explain several of the events observed during the evolution of the disease and to suggest possible targets for therapeutic interventions.

Therapeutic Effects of Anti-Inflammatory N-Acylhydrazones in the Resolution of Experimental Colitis.

Inflammatory bowel diseases are caused by inflammation of the gastrointestinal tract, which may or may not have a specific cause or pathogen. They affect millions of people around the world and there are still few effective treatments. The aim of this work is to investigate the anti-inflammatory effect of the IKK-ß inhibitor LASSBio-1524 and its three analogs, LASSBio-1760, LASSBio-1763, and LASSBio-1764, on mediator production and expression of inflammatory enzymes using experimental animal models of intestinal inflammatory diseases. Colitis was performed using two different models, which mimic Crohn disease (induced by dinitrobenzene acid) and ulcerative colitis (induced by sodium dextran sulfate) in mice. In both models, a therapeutic protocol with a daily dose of 1, 3, or 30 µmol/kg was performed. LASSBio-1524 and its three analogs reduced the secretion of tumor necrosis factor-α, IL-1ß, IL-6, IL-12, and IFN-γ and increased secretion of IL-10, protecting gastrointestinal homeostasis. All compounds reduced macro- and microscopic colonic damage caused by experimental colitis and p38 mitogen-activated protein kinase expression in the colon, as well as leukocytosis and anemia resulting from the disease. Our data may suggest LASSBio-1524 and its analogs (LASSBio-1760, LASSBio-1763, and LASSBio-1764) as promising candidates for new prototypes designed to treat inflammatory bowel diseases. SIGNIFICANCE STATEMENT: Three new N-acylhydrazones were synthetized as analogs of LASSBio-1524. All new substances were evaluated in dextran sulfate- and dinitrobenzene acid-induced colitis, with LASSBio-1760, LASSBio-1762, and LASSBio-1763 presenting a significant effect in both models of colitis without toxic effects. The new substances could be considered as a new prototype for the development of new anti-inflammatory treatments of colitis.

Pharmacological Evaluation of Artemisia cina Crude CO2 Subcritical Extract after the Removal of Santonin by Means of High Speed Countercurrent Chromatography.

Artemisia species are highly important due to their economic significance as medicines, fodder and food. Artemisia cina is an endemic species to Kazakhstan. In folk medicine, water extract of A. cina was used in the treatment of bronchial asthma while the alcohol extract has larvicidal and antituberculosis activity. The most common and most extensively studied compound from this species is the terpenoid santonin. The toxicity of this compound occurs at the doses of 60 mg for children and 200 mg for adults causing among other issues xanthopsia, leading to blindness. Having this in mind, the main idea of this work was to remove santonin from the crude extract and to check if the santonin-free extract would still be of any pharmacological importance. A CO2 subcritical extract was chromatographed using high-speed countercurrent chromatography (HSCCC) for the removal of santonin. The santonin-free CO2 subcritical extract (SFCO2E) as well as the isolated compound pectolinarigenin, a flavonoid, were assessed for their pharmacological actions. From the results obtained we can safely suggest that HSCCC is an efficient methodology to completely remove santonin from the CO2 subcritical extract. It was also possible to observe promising antinociceptive and anti-inflammatory activities for both SFCO2E and pectolinarigenin at concentrations that can justify the production of a phytomedicine with this endemic plant from Kazakhstan.

Aristolochia trilobata: Identification of the Anti-Inflammatory and Antinociceptive Effects.

Aristolochia trilobata, popularly known as "mil-homens," is widely used for treatment of stomach aches, colic, asthma, pulmonary diseases, diabetes, and skin affection. We evaluated the antinociceptive and anti-inflammatory activities of the essential oil (EO) and the main constituent, 6-methyl-5-hepten-2-yl acetate (sulcatyl acetate, SA). EO and SA (1, 10, and 100 mg/kg, p.o.) were evaluated using chemical (formalin-induced licking) and thermal (hot-plate) models of nociception or inflammation (carrageenan-induced cell migration into the subcutaneous air pouch, SAP). The mechanism of antinociceptive activity was evaluated using opioid, cholinergic receptor antagonists (naloxone and atropine), or nitric oxide synthase inhibitor (L-NAME). EO and SA presented a central antinociceptive effect (the hot-plate model). In formalin-induced licking response, higher doses of EO and SA also reduced 1st and 2nd phases. None of the antagonists and enzyme inhibitor reversed antinociceptive effects. EO and SA reduced the leukocyte migration into the SAP, and the cytokines tumor necrosis factor and interleukin-1 (TNF-α and IL-1ß, respectively) produced in the exudate. Our results are indicative that EO and SA present peripheral and central antinociceptive and anti-inflammatory effects.

New 2-amino-pyridinyl-N-acylhydrazones: Synthesis and identification of their mechanism of anti-inflammatory action.

AIMS: The main aim of this paper was the synthesis and the evaluation of the anti-inflammatory activity of LASSBio-1828 (an amino-pyridinyl-N-acylhydrazone) and its respective hydrochloride, based on a p38α MAPK inhibitor (LASSBio-1824) previously synthesized by our group. MAIN METHODS: The compounds were tested regarding their cell viability effect and on acute models of inflammation such as formalin-induced licking test, cell migration and inflammatory mediators quantification. KEY FINDINGS: Treatment with the compounds inhibited p38α, reduced inflammatory pain, cell migration and inflammatory mediators that participate on the MAPK pathway such as TNF-α and IL-1ß. SIGNIFICANCE: Taken together, these results suggest that the synthesis of the corresponding hydrochloride of LASSBio-1828 enhanced its potency as a p38 inhibitor, and also that this compound could be considered a good anti-inflammatory drug candidate after further studies.

Study on the Antinociceptive Activity and Mechanism of Action of Isolated Saponins from Siolmatra brasiliensis (Cogn.) Baill.

Infusions of roots of Siolmatra brasiliensis (Cogn.) Baill, ("taiuiá", "cipó-tauá") are used for toothache pain and ulcers. We aimed to study the antinociceptive effects and identify the possible mechanism of action of this plant and its isolated substances (cayaponoside A1, cayaponoside B4, cayaponoside D, and siolmatroside I). Hydroethanol extract (HE), ethyl acetate fraction (EtOAc), and isolated saponins were evaluated in chemical and thermal models of pain in mice. Animals were orally pretreated and evaluated in the capsaicin- or glutamate-induced licking and in the hot plate tests. The antinociceptive mechanism of action was evaluated using the hot plate test with the following pretreatments: Atropine (cholinergic antagonist), naloxone (opioid antagonist), or L-NAME (nitric oxide synthase inhibitor). All extracts and isolated saponins increased the area under the curve in the hot plate test. Tested substances induced a higher effect than the morphine-treated group. Our data suggest that stems of S. brasiliensis and their isolated substances present antinociceptive effects. Cholinergic and opioidergic pathways seem to be involved in their mechanism of action. Taken together our data corroborate the traditional use of the plant and expands the information regarding its use.

Chemical composition and evaluation of antinociceptive activity of the essential oil of Stevia serrata Cav. from Guatemala.

The composition and the antinociceptive activity of the essential oil of Stevia serrata Cav. from a population located in the west highlands of Guatemala were evaluated. A yield of 0.2% (w/w) of essential oil was obtained by hydrodistillation of the dried aerial parts of the plant. The essential oil analysed by GC-FID and GC-MS showed a high content of sesquiterpenoids, with chamazulene (60.1%) as the major component and 91.5% of the essential oil composition was identified. To evaluate antinociceptive activity in mice, the essential oil of S. serrata Cav. was administered as gavage, using three different doses. In the formalin test, the animals were pre-treated with oral doses of the essential oil before the administration of formalin. Oral administration of S. serrata Cav. essential oil produced a marked antinociceptive activity. Therefore, the plant could be domesticated as a source of essential oil rich in chamazulene for developing medicinal products.