Modulation of the Serotonergic Receptosome in the Treatment of Anxiety and Depression: A Narrative Review of the Experimental Evidence.

Serotonin (5-HT) receptors are found throughout central and peripheral nervous systems, mainly in brain regions involved in the neurobiology of anxiety and depression. 5-HT receptors are currently promising targets for discovering new drugs for treating disorders ranging from migraine to neuropsychiatric upsets, such as anxiety and depression. It is well described in the current literature that the brain expresses seven types of 5-HT receptors comprising eighteen distinct subtypes. In this article, we comprehensively reviewed 5-HT1-7 receptors. Of the eighteen 5-HT receptors known today, thirteen are G protein-coupled receptors (GPCRs) and represent targets for approximately 40% of drugs used in humans. Signaling pathways related to these receptors play a crucial role in neurodevelopment and can be modulated to develop effective therapies to treat anxiety and depression. This review presents the experimental evidence of the modulation of the "serotonergic receptosome" in the treatment of anxiety and depression, as well as demonstrating state-of-the-art research related to phytochemicals and these disorders. In addition, detailed aspects of the pharmacological mechanism of action of all currently known 5-HT receptor families were reviewed. From this review, it will be possible to direct the rational design of drugs towards new therapies that involve signaling via 5-HT receptors.

Anti-inflammatory and Antioxidant Activity of Nanoencapsulated Curcuminoids Extracted from Curcuma longa L. in a Model of Cutaneous Inflammation.

The present study evaluated the anti-inflammatory effect of nanoencapsulated curcuminoid preparations of poly(vinyl pyrrolidone) (Nano-cur) and free curcuminoids (Cur) in an experimental model of croton oil-induced cutaneous inflammation. Male Swiss mice, weighing 25-30 g, received oral treatment by gavage 1 h before CO application or topical treatment immediately after CO application (200 µg diluted in 70% acetone) with a single dose of Cur and Nano-cur. After 6 h, the animals were anesthetized and euthanized. The ears were sectioned into disks (6.0 mm diameter) and used to determine edema, myeloperoxidase (MPO) activity, and oxidative stress. Photoacoustic spectroscopy (PAS) was used to evaluate the percutaneous penetration of Cur and Nano-cur. Topical treatment with both preparations had a similar inhibitory effect on the development of edema, MPO activity, and the oxidative response. The PAS technique showed that the percutaneous permeation of both topically applied preparations was similar. Oral Nano-cur administration exerted a higher anti-inflammatory effect than Cur. Topical Cur and Nano-cur application at the same dose similarly inhibited the inflammatory and oxidative responses. Oral Nano-cur administration inhibited such responses at doses that were eight times lower than Cur, suggesting the better bioavailability of Nano-cur compared with Cur.Graphical abstract.

The New Coronavirus (SARS-CoV-2): A Comprehensive Review on Immunity and the Application of Bioinformatics and Molecular Modeling to the Discovery of Potential Anti-SARS-CoV-2 Agents.

On March 11, 2020, the World Health Organization (WHO) officially declared the outbreak caused by the new coronavirus (SARS-CoV-2) a pandemic. The rapid spread of the disease surprised the scientific and medical community. Based on the latest reports, news, and scientific articles published, there is no doubt that the coronavirus has overloaded health systems globally. Practical actions against the recent emergence and rapid expansion of the SARS-CoV-2 require the development and use of tools for discovering new molecular anti-SARS-CoV-2 targets. Thus, this review presents bioinformatics and molecular modeling strategies that aim to assist in the discovery of potential anti-SARS-CoV-2 agents. Besides, we reviewed the relationship between SARS-CoV-2 and innate immunity, since understanding the structures involved in this infection can contribute to the development of new therapeutic targets. Bioinformatics is a technology that assists researchers in coping with diseases by investigating genetic sequencing and seeking structural models of potential molecular targets present in SARS-CoV2. The details provided in this review provide future points of consideration in the field of virology and medical sciences that will contribute to clarifying potential therapeutic targets for anti-SARS-CoV-2 and for understanding the molecular mechanisms responsible for the pathogenesis and virulence of SARS-CoV-2.

Synthesis and Biological Evaluation of New Tyrosol-Salicylate Derivatives as Potential Anti-Inflammatory Agents.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medications in inflammatory illnesses. However, the gastrointestinal bleeding and toxicity associated with NSAIDs long term use prompted the quest towards investigations for new anti-inflammatory agents. Natural and natural-derived molecules proved its anti-inflammatory efficacy in vitro as well as in vivo. Given this background, the scope of this research involves structural changes of the natural polyphenol (tyrosol) generating two new salicylate derivatives and testing their biological properties, focusing on anti-inflammatory effects assessed in vitro and in vivo assays. The first molecular modification was the introduction of a carboxylic acid group adjacent to the phenol group present in this compound, which creates a new salicylate-like tyrosol. In addition, the acetylation of phenol group in this molecule produced an acetylsalicylate derivative, which may be regarded as aspirin-like natural polyphenol. Interestingly, tyrosol and its novel derivatives attenuated the edema in acute inflammatory response on carrageenan- induced local inflammation in mice. In addition, our results demonstrated that tyrosol and its novel derivatives were able to reduce the chemotaxis of neutrophil assessed in vitro model by chemo attractant (fMLP). Furthermore, only derivative 2 was able to reduce this effect in the acute inflammatory model. In (DPPH)- scavenging activity, tyrosol derivatives demonstrated a minor antioxidant activity, which may suggest that radical scavenging is not a major pathway involved in the anti-inflammatory effects of these derivatives. Salicylate-like tyrosol derivatives are of particular interest for future studies.

Pterodon pubescens oil nanoemulsions: physiochemical and microbiological characterization and in vivo anti-inflammatory efficacy studies

Abstract Pterodon pubescens (Benth.) Benth., Fabaceae, fruits have been investigated for their anti-inflammatory and antinociceptive activities, and have demonstrated effectiveness in inflammatory conditions. A physiochemical and microbiological stability study was conducted to investigate two nanoemulsion-based delivery systems of two different hydrophilic surfactants (polyethylene glycol-40H castor oil or polyethylene glycol-40 castor oil). The nanoemulsions, containing P. pubescens oil, lecithin, hydrophilic surfactant and water, were analyzed for droplet size distribution, polydispersity index, pH, consistency index, stability against centrifugal force, and active content/vouacapan derivatives. The physicochemical characteristics were followed for 365 days. The nanoemulsion system was evaluated for anti-inflammatory activity by using with a peritonitis model, immediately after preparation and after 365 days of storage at 25 °C. The stability study demonstrated that proper storage (25 °C) preserved the characteristics of the nanoemulsion containing 7.5% polyethylene glycol-40H castor oil, 5% lecithin, and 5% P. pubescens oil. Further, it ensured a shelf life of 365 days as a phytotherapeutic formulation. In the peritonitis assay induced by carrageenan, nanoemulsion prepared with polyethylene glycol-40H castor oil (125 mg/kg) reduced leukocyte migration, even after 365 days of storage (25 °C), highlighting its potential for the treatment of inflammatory diseases. However, further studies are needed to confirm its clinical effectiveness.

Evidence of anti-inflammatory effect and percutaneous penetration of a topically applied fish oil preparation: a photoacoustic spectroscopy study.

This paper investigates the topical anti-inflammatory effect of a fish oil preparation (FOP) in a croton oil (CO) model of skin inflammation. The photoacoustic spectroscopy (PAS) was applied to estimate the percutaneous penetration of the FOP and as a model to evaluate the topical inflammatory response. After applying CO, the groups of mice received a topical application of a FOP on the left ear. The right ear received the vehicle that was used to dilute the CO. After 6 h, ear tissue was collected to determine the percent inhibition of edema, myeloperoxidase (MPO) activity, and cytokine levels and to perform PAS measurements. Treatment with FOP reduced edema and MPO activity, which was at least partially attributed to a decrease in the levels of tumor necrosis factor, interleukin- 1 ? , interleukin-6, keratinocyte-derived chemokine, and monocyte chemoattractant protein-1. The topically applied FOP penetrated into the tissue and decreased the area of the bands that characterize inflamed tissue. The present results demonstrated the topical anti-inflammatory effect of the FOP. PAS suggests that FOP anti-inflammatory activity is linked with its ability to penetrate through the skin.

Antidepressant-like Effect of Insulin in Streptozotocin-induced Type 2 Diabetes Mellitus Rats.

This study evaluated the antidepressant-like effect of insulin compared to sertraline and a combination of insulin and sertraline in streptozotocin (STZ)-induced type 2 diabetes mellitus (T2DM) rats submitted to the forced swim test (FST). Male Wistar rats were daily treated for 21 days with insulin (1 or 2 IU/kg, i.p.), with the selective serotonin reuptake inhibitor (SSRI), sertraline (10 mg/kg, i.p.), or with a combination of insulin (1 or 2 IU/kg, i.p.) and sertraline (10 mg/kg, i.p.) and submitted to the FST. We also evaluated the water and food intake, urine volume and weight gain of the rats. Rats treated with STZ showed impaired glucose tolerance. Chronic treatment with sertraline showed an antidepressant-like effect in non-diabetic and diabetic rats. Furthermore, sertraline promoted lower weight gain in diabetic rats. Insulin reduced the immobility behaviour in T2DM rats with impaired glucose tolerance. In conclusion, our results showed that insulin has an antidepressant-like effect comparable to that of sertraline. Sertraline is effective as an antidepressant and reduces weight gain, which reinforces its superiority over other SSRIs in the treatment of major depression disorder in patients with T2DM.

Synergistic effects of anethole and ibuprofen in acute inflammatory response.

This study assessed the effect of the combination of anethole and ibuprofen in comparison with monotherapy by either drug alone, using two in vivo inflammatory models, namely the pleurisy and paw edema in rats. We also measured the levels of the TNF protein in plasma, and the ability of anethole to inhibit, in vitro, the activity of the cyclooxygenase 1 and cyclooxygenase 2 enzymes. The test drugs (anethole; ibuprofen; anethole + ibuprofen), at different doses, were administered once (p.o.) 60 min before the induction of the inflammatory response. The association of anethole + ibuprofen inhibited the development of the inflammatory response in both models used. This effect can be partially explained by the inhibitory action on the production of TNF and of COX isoforms. The isobologram analysis evidenced a synergistic effect between ibuprofen and anethole, because the combination of drugs showed a higher inhibitory potential than either drug alone.

Health conditions of recyclable waste pickers.

The presence of chronic non-communicable diseases (NCDs) among vulnerable populations is a rarely discussed subject. Thus, the present cross-sectional descriptive study aimed to analyse the health conditions and access to public health services of 268 waste pickers in southern Brazil. Regarding NCDs, their prevalence of hypertension was 32.8 %, diabetes 11.4 %, dyslipidemia 16.4 %, overweight 51.1 %, obesity 25.7 % and abdominal obesity 57.8 %. Regarding access to health services, 36.9 % of the sample had not consulted with a doctor in more than 1 year, 15.7 % had no access to a healthcare unit, 7.5 % had never measured their blood pressure, 45.9 % had never had a glucose test, and 61.2 % had never had a triglyceride test. The statistical analysis showed that whereas men had gone longer since their last medical consultation and blood pressure measurement, women had increased frequencies of overweight, abdominal obesity, awareness of their hypertension and use of anti-hypertensive drugs (p < 0.05). Therefore, the health profile of waste pickers is critical, with a high prevalence of NCDs and poor healthcare usage. Strategies to improve monitoring and treatment are recommended.

Antihypernociceptive activity of anethole in experimental inflammatory pain.

Anethole has been reported to have antioxidant, antibacterial, antifungal, antiinflammatory, and anesthetic properties. In the present study, we evaluated the effects of anethole in two pain models of inflammatory origin: acute inflammation induced by carrageenan and persistent inflammation induced by Complete Freund's adjuvant. We evaluated the effects of anethole (125, 250, and 500 mg/kg) on the development of paw oedema and mechanical hypernociception. The liver was collected for histological analysis. Paw skin was collected to determine the levels of the cytokines tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-17 (IL-17), and myeloperoxidase activity. Blood was collected to assess alanine transaminase (ALT) and aspartate transaminase (AST). The chemical composition of star anise oil was determined by gas chromatography/mass spectrometry (GC/MS), showing a presence of anethole of 98.1%. Oral pretreatment with anethole in mice inhibited paw oedema, mechanical pernociception, myelopewroxidase activity, TNF-α, IL-1ß and IL-17 levels in acute and persistent inflammation models. Additionally, anethole treatment did not alter prostaglandin E2-induced mechanical hypernociception. Possible side effects were also examined. Seven-day anethole treatment did not alter plasma AST and ALT levels, and the histological profile of liver tissue was normal. The present study provides evidence of the antiinflammatory and analgesic activities of anethole in acute and persistent inflammation models.

Arthritis induced by adjuvant in spontaneously hypertensive and normotensive rats: endogenous glucocorticoid effects on inflammatory response.

The present study investigated arthritis induced by complete Freund adjuvant (AIA) in spontaneously hypertensive and normotensive rats (respectively, SHR and NTR rats). The inflammatory reaction was studied for 28 days by evaluating paw edema and secondary lesions found 10 days after complete Freund adjuvant (CFA) administration. The body weight of the animals and macroscopic alterations of several organs, including spleen, thymus, adrenal glands, and lymph nodes, were also analyzed. The results showed that the AIA manifestations were decreased in SHRs compared with NTRs. Moreover, this altered inflammatory response was not modified by surgical adrenalectomy.

Antifungal activity of ajoene on experimental murine paracoccidioidomycosis.

The natural compound ajoene (4,5,9- trithiadodeca-1,6,11-triene 9-oxide) is capable of controlling infection by Paracoccidioides brasiliensis in experimental models. Swiss mice were inoculated with 5.0 x 10e6 cells of the fungus Paracoccidioides brasiliensis Pb18 by intraperitoneal route and treated with ajoene. In weeks 2, 6, 10 and 13 of treatment, levels of anti-Pb antibodies were measured by the ELISA test and the animals were put down and their lungs, livers and spleens removed for histopathological analysis and determination of the number of viable fungus. The results show that experimental murine paracoccidioidomycosis was well established and that ajoene was capable of controlling the evolution of the disease, as it significantly reduced the levels of antibodies from the 10th week of treatment.

Antifungal activity of ajoene on experimental murine paracoccidioidomycosis

El producto natural ajoeno (4, 5, 9-trithiadodeca-1,6,11-trieno 9-óxido) fuecapaz de controlar parcialmente la infección por Paracoccidioides brasiliensisen un modelo experimental murino. Fueron inoculados por vía intraperitonealratones Swiss con 5,0 x 106 células de la cepa Pb 18 de Paracoccidioidesbrasiliensis. Los animales fueron divididos en cuatro grupos, uno fue tratadocon ajoeno, otro con itraconazol, un tercero no recibió tratamiento y el cuartogrupo no fue infectado y actuó como control. Se midieron los niveles deanticuerpos anti-Pb por ELISA a las dos, seis, 10 y 13 semanas de evolución.Los animales fueron sacrificados y se estudiaron pulmones, hígados y bazos,mediante exámenes histopatológicos y determinación de unidades formadorasde colonias. Los resultados observados permiten establecer que este modelode paracoccidioidomicosis experimental produjo una infección progresiva yque el ajoeno fue capaz de controlar la evolución de la misma, como lodemuestra la reducción de la carga fúngica en hígados y bazos y ladisminución significativa de los títulos de anticuerpos a la décima semana detratamiento(AU)

The natural compound ajoene (4,5,9- trithiadodeca-1,6,11-triene 9-oxide) iscapable of controlling infection by Paracoccidioides brasiliensis in experimentalmodels. Swiss mice were inoculated with 5.0 x 106 cells of the fungusParacoccidioides brasiliensis Pb18 by intraperitoneal route and treated withajoene. In weeks 2, 6, 10 and 13 of treatment, levels of anti-Pb antibodieswere measured by the ELISA test and the animals were put down and theirlungs, livers and spleens removed for histopathological analysis anddetermination of the number of viable fungus. The results show thatexperimental murine paracoccidioidomycosis was well established and thatajoene was capable of controlling the evolution of the disease, as itsignificantly reduced the levels of antibodies from the 10th week of treatment(AU)

Microscopic analysis of subcutaneous reactions to endodontic sealer implants in rats.

The reaction of subcutaneous tissues to Endofill, Endomethasone, Sealer 26, and AH-Plus was investigated microscopically after implantation of in rats polyethylene cannulae, obturated with gutta-percha cones and sealers, in rats. Empty polyethylene cannulae and cannulae filled with gutta-percha cones alone were used as controls. The inflammatory reactions caused by the sealers were evaluated 7, 14, and 30 days after implantation using a descriptive, histopathological analysis. Inflammatory reactions at each implant site were gauged as either absent, discreet, moderate, or intense, and scores from 0 to 3 were attributed, respectively. Microscopic analysis revealed that Endomethasone showed the best biological behavior for all postimplant periods, followed by Sealer 26 and AH Plus, which produced an irritating effect only during the initial pos-implant period. Endofill caused the severest irritation, producing an inflammatory reaction that ranged from moderate to intense over the entire experimental period. Reactions were more intense near those parts of the cannulae containing more sealer. These results reveal that the root canal sealers tested cause inflammation in rat, subcutaneous conjunctive tissue, the intensity of which may be related to the type and quantity of sealer used, and to postimplant period.

Metformin treatment restores the altered microvascular reactivity in neonatal streptozotocin-induced diabetic rats increasing NOS activity, but not NOS expression.

Abnormalities in vascular function are well recognized in diabetes. Hyperglycemia may be central to the pathogenesis of vascular dysfunction but is not certain whether improvements in glycaemic control will improve vascular function. The effects of metformin, an antidiabetic agent that improves insulin sensitivity and glycaemic control, on the microvascular reactivity have not been reported in neonatal streptozotocin-induced (n-STZ) diabetes. Diabetes was induced by STZ injection (160 mg/kg, ip) in neonates (2-day-old) Wistar rats. n-STZ diabetic rats were treated with metformin (300 mg/kg, 15 d, by gavage). Using intravital microscopy the changes in mesenteric arteriolar and venular diameters were determined in anesthetized control and n-STZ diabetic rats, before and after topical application of endothelium-dependent vasodilator agents, mediators or not of the inflammatory response, and endothelium-independent vasodilator agent. We also determined the total nitric oxide synthase (NOS) activity (conversion of L-arginine to citrulline) and endothelial(e), inducible(i), and neuronal(n) NOS expression (using polymerase chain reaction after reverse transcription of the mRNAs into cDNAs) in the mesentery of metformin-treated n-STZ diabetic and vehicle-treated n-STZ diabetic and control rats. Although metformin treatment did not correct the high glycaemic levels and the impaired glucose tolerance, the reduced vasodilator responses and total NOS activity in n-STZ diabetic rats were corrected by the treatment. Neither diabetes nor metformin treatment altered the expression of the three NOS isoforms. We concluded that metformin restores the reduced response to vasodilator agents, independently of the correction of the metabolic alterations. Improvement of total NOS activity might be in part responsible for the correction.