Search

TNFalpha plays a pivotal role in rheumatoid arthritis (RA) but little is known of the mechanisms that link the inflammatory and nociceptive effects of TNFalpha. We have established a murine model of TNFalpha-induced TRPV1-dependent bilateral thermal hyperalgesia that then allowed us to identify distinct peripheral mechanisms involved in mediating TNFalpha-induced ipsilateral and contralateral hyperalgesia. Thermal hyperalgesia and inflammation were assessed in both hindpaws following unilateral intraplantar (i.pl.) TNFalpha. The hyperalgesic mechanisms were analysed through pharmacogenetic approaches involving TRPV1(-/-) mice and TRPV1 antagonists. To study the mediators downstream of TNFalpha, cyclooxygenase (COX) and PKC inhibitors were utilised and cytokine and prostaglandin levels assessed. The role of neutrophils was determined through use of the selectin inhibitor, fucoidan. We show that TNFalpha (10pmol) causes thermal hyperalgesia (1-4h) in the ipsilateral inflamed and contralateral uninjured hindpaws, which is TRPV1-dependent. GF109203X, a PKC inhibitor, suppressed the hyperalgesia indicating that PKC is involved in TRPV1 sensitisation. Ipsilateral COX-2-derived prostaglandins were also crucial to the development of the bilateral hyperalgesia. The prevention of neutrophil accumulation with fucoidan attenuated hyperalgesia at 4 but not at 1h, indicating a role in the maintenance but not in the induction of bilateral hyperalgesia. However, TNFalpha-induced IL-1beta generation in both paws and the presence of local IL-1beta in the contralateral paw were essential for the development of bilateral hyperalgesia. These results identify a series of peripheral events through which TNFalpha triggers and maintains bilateral inflammatory pain. This potentially allows a better understanding of mechanisms involved in TNFalpha-dependent pain pathways in symmetrical diseases such as arthritis. [ABSTRACT FROM AUTHOR]

Silybin, a flavonolignan extracted from the seeds of the plant species Silybum marianum (L.) Gaertn., has a variety of pharmacological activities, including antimicrobial activity against several microorganisms of clinical interest. This review analyzes the existing studies on silybin's antimicrobial activity and possible mechanisms of action. Silybin has been shown to inhibit the growth of Gram-positive and Gram-negative bacteria, as well as some fungi, viruses, and protozoa. In general, possible mechanisms of antimicrobial action include the inhibition of efflux pumps, prevention of biofilm formation, reduction of the expression of virulence factors, induction of apoptosis-like effects, and plasma membrane damage, as well as the inhibition of nucleic acid and protein synthesis. Silybin has been shown to have synergistic effects when combined with conventional antibiotics against both drug-sensitive and drug-resistant microorganisms. However, the low bioavailability observed for this flavonolignan has been a challenge to its clinical use. In this context, nanotechnology has been used to increase silybin's bioavailability while enhancing its antimicrobial activity. Furthermore, certain structural modifications have been able to enhance its antimicrobial activity in comparison to that of the natural molecule. Overall, this review provides insights into the scientific understanding of the mechanism of action of silybin and its desired properties for the effective treatment of infections.

The biological activities of plant-derived soluble dietary fibres (SDFs) have been widely investigated. Pectin from yellow passion fruit (YPF-peSDF) peels was suggested as a protective macromolecule in ulcers and colitis due to its antioxidant and anti-inflammatory properties. Sepsis has high mortality and morbidity and is characterised by inflammatory and oxidative stress imbalances. Evidence suggests that pectins may aid sepsis treatment; however, the effects of YPF-peSDF on sepsis remain unclear. Herein, polymicrobial sepsis was induced by cecal-ligation and puncture in mice treated with YPF-peSDF (1 and 10 mg/kg; gavage). YPF-peSDF accelerated mortality, reaching 100% in 24 h. Inflammation was present in the colons and small intestines (SI) of both vehicle- and fibre-treated mice. Although crypt depth and width, and villus height were preserved in the SI of septic mice administered YPF-peSDF, they exhibited exacerbated muscle layer atrophy and mucosa and submucosa hypertrophy, along with shortened enterocytes. Larger crypts and shorter enterocytes were noted in their colons in comparison with vehicle-controls. YPF-peSDF also reduced inflammatory cell numbers and exacerbated IL-6 levels in peritoneal lavage fluid (PELF) samples. YPF-peSDF modulated SI but not colon cytokines. Lipoperoxidation and antioxidant capacity levels were attenuated in PELF samples. Overall, in contrast to previous evidence, YPF-peSDF worsened polymicrobial sepsis outcomes in mice.

Sepsis treatment is a challenging condition due to its complexity, which involves host inflammatory responses to a severe and potentially fatal infection, associated with organ dysfunction. The aim of this study was to analyze the scientific literature on the immunomodulatory effects of glucans in a murine model of systemic infection induced by cecal ligation and puncture. This study comprises an integrative literature review based on systematic steps, with searches carried out in the PubMed, ScienceDirect, Scopus, Web of Science, and Embase databases. In most studies, the main type of glucan investigated was β -glucan, at 50 mg/kg, and a reduction of inflammatory responses was identified, minimizing the occurrence of tissue damage leading to increased animal survival. Based on the data obtained and discussed in this review, glucans represent a promising biotechnological alternative to modulate the immune response and could potentially be used in the clinical management of septic individuals., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Jesse P. M. Viana et al.)

TRPC5 is a non-selective cation channel that is expressed in cardiomyocytes, but there is a lack of knowledge of its (patho)physiological role in vivo. Here, we examine the role of TRPC5 on cardiac function under basal conditions and during cardiac hypertrophy. Cardiovascular parameters were assessed in wild-type (WT) and global TRPC5 knockout (KO) mice. Despite no difference in blood pressure or activity, heart rate was significantly reduced in TRPC5 KO mice. Echocardiography imaging revealed an increase in stroke volume, but cardiac contractility was unaffected. The reduced heart rate persisted in isolated TRPC5 KO hearts, suggesting changes in basal cardiac pacing. Heart rate was further investigated by evaluating the reflex change following drug-induced pressure changes. The reflex bradycardic response following phenylephrine was greater in TRPC5 KO mice but the tachycardic response to SNP was unchanged, indicating an enhancement in the parasympathetic control of the heart rate. Moreover, the reduction in heart rate to carbachol was greater in isolated TRPC5 KO hearts. To evaluate the role of TRPC5 in cardiac pathology, mice were subjected to abdominal aortic banding (AAB). An exaggerated cardiac hypertrophy response to AAB was observed in TRPC5 KO mice, with an increased expression of hypertrophy markers, fibrosis, reactive oxygen species, and angiogenesis. This study provides novel evidence for a direct effect of TRPC5 on cardiac function. We propose that (1) TRPC5 is required for maintaining heart rate by regulating basal cardiac pacing and in response to pressure lowering, and (2) TRPC5 protects against pathological cardiac hypertrophy.

The current study was motivated by an interest in deepening understanding of Brazilian twin research, which is underrepresented internationally, in an effort to rectify this situation. Our aim was threefold: (1) to carry out a comprehensive investigation of Brazilian research on twins according to the area of knowledge; (2) to evaluate the representation of research in the field of psychology in comparison with other areas; (3) to evaluate characteristics of the research that may have contributed to its exclusion from the comprehensive meta-analysis of 50 years of twin research. A scoping review was performed according to PRISMA guidelines. Titles and abstracts were searched up to 2022 in six databases: CAPES, BDLTD, PePSIC, PubMed, Google Scholar, and SciELO, using selected keywords both in Portuguese and in English (e.g., 'twins' and 'Brazil'; 'twinning' and 'Brazil'; 'gemelaridade' [twinning], and 'gêmeos' [twins]). Three hundred and forty publications were included in the review. Approximately half (53.8‰) used the classic twin design to investigate the heritability of several traits, and the other half (46.2%) used other research designs. The scoping review showed that the number of publications doubled approximately every 10 years. Most publications were from the health area, with medicine accounting for approximately half of the studies, followed by psychology, odontology, and biology. We found that the interest in studying twins among Brazilian scientists is increasing over the years and there are reasons to be enthusiastic about the potential impact of this trend in the global scenario.

Ethnopharmacological Relevance: Babassu mesocarp, derived from the Attalea speciosa fruits, is used in folk medicine for infections, inflammatory diseases, and skin wounds., Aim of the Study: To investigate the antimicrobial and immunological effect of babassu mesocarp aqueous extract (BAE) in Swiss mice lethally infected with methicillin-resistant Staphylococcus aureus (MRSA)., Materials and Methods: The animals (n = 14/group) received an overload of MRSA (3.0 × 10 8  CFU/mL, via intraperitoneal) and were treated 6 h later with the BAE (125 and 250 mg/kg, subcutaneously). Two experiments were performed with four groups each (Control, ATB, BAE125 and BAE 250). The first was to determine the survival (n = 7 animals/group). The second is to evaluate 24h after infection the number of Colony Forming Units (CFU) and cells in the blood, peritoneum and bronchoalveolar fluid. Cytometric Bead Assay - CBA quantified the cytokines and flow cytometry to determine the cellular distribution in the mesenteric lymph node., Results: Treatment with BAE improved the survival (60%) in all groups, reduced the number of colony-forming units in the peritoneum and blood, the number of peritoneal and bronchoalveolar cells, and the levels of pro-inflammatory IL-6, TNF-α, and IL-17 cytokines. Additionally, BAE increased: IL-10 and INF-γ levels, nitric oxide release, CD4 + T helper cells, CD14+/IaIe + activated macrophages and Ly6G + neutrophils in the mesenteric lymph node., Conclusions: BAE can be used as a complementary treatment during infections due to its antimicrobial and immunomodulatory effect and the ability to protect animals from death after MRSA lethal infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

BACKGROUND Electrical storm is a rare but potentially life-threatening syndrome characterized by recurrent ventricular arrhythmias. Liver transplant recipients are at increased risk of developing electrical storms due to conditions that prolong QT intervals, such as cirrhotic cardiomyopathy. However, limited information exists on electrical storms in this specific population. This case report presents a patient who experienced 13 cardiac arrests during ventricular fibrillation following liver transplantation. CASE REPORT A 61-year-old woman with a medical history of diabetes, obesity, and cirrhosis due to non-alcoholic fatty liver disease underwent liver transplantation using a deceased donor's liver. Following the procedure, she developed a deterioration in her respiratory function, necessitating orotracheal intubation. Approximately 21 hours post-surgery, she experienced cardiac arrest during ventricular fibrillation, which was rapidly reversed with electrical defibrillation. However, the patient entered a state of electrical storm. Management involved antiarrhythmic medications and temporary transvenous cardiac pacing. She remained stable for 40 hours, but a dislodgment of the device triggered another episode of ventricular fibrillation, leading to her death. CONCLUSIONS This case report highlights the clinical presentation and challenges in managing electrical storms in liver transplant recipients. We hypothesize that cirrhotic cardiomyopathy could be the cause of her recurrent ventricular arrhythmias. Further studies are needed to better understand the underlying mechanisms and risk factors of this life-threatening syndrome in this population, which may enhance risk stratification and enable earlier intervention.

BACKGROUND Liver transplantation is a life-saving intervention for patients with a diagnosis of acute liver failure or end-stage liver disease. Despite advances in surgical techniques and immunosuppressive therapies, primary nonfunction remains a concern, often necessitating retransplantation. In these scenarios, the anhepatic state, achieved through total hepatectomy with a temporary portacaval shunt, serves as a bridge to retransplantation. However, the challenge lies in the uncertain survival period and several potential complications associated with this procedure. CASE REPORT We present a case of a 35-year-old male patient with autoimmune hepatitis who underwent liver transplantation from a deceased donor. Seven days later, he experienced acute liver failure, leading to an urgent listing for retransplantation. To prevent the intense systemic inflammatory response, the patient underwent a total hepatectomy with a temporary portacaval shunt while awaiting another graft and endured a 57-h anhepatic state. On day 17 following retransplantation, he had cerebral death due to a hemorrhagic stroke. CONCLUSIONS This case underscores one of the most prolonged periods of anhepatic state as a bridge to retransplantation, highlighting the complexities associated with this technique. The challenges include sepsis, hypotension, coagulopathy, metabolic acidosis, renal failure, electrolyte disturbances, hypoglycemia, and hypothermia. Vigilant monitoring and careful management are crucial to improve patient outcomes. Further research is needed to optimize the duration of the anhepatic state and minimize complications for liver transplantation recipients.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) of the gastrointestinal tract. The etiology is not fully understood, but environmental, microbial, and immunologic factors, as well as a genetic predisposition, play a role. UC is characterized by episodes of abdominal pain, diarrhea, bloody stools, weight loss, severe colonic inflammation, and ulceration. Despite the increase in the frequency of UC and the deterioration of the quality of life, there are still patients who do not respond well to available treatment options. Against this background, natural products such as polysaccharides are becoming increasingly important as they protect the intestinal mucosa, promote wound healing, relieve inflammation and pain, and restore intestinal motility. In this study, we investigated the effect of a polysaccharide isolated from the biomass of Campomanesia adamantium and Campomanesia pubescens (here referred to as CPW) in an experimental model of acute and chronic ulcerative colitis induced by dextran sulfate sodium (DSS). CPW reversed weight loss, increased disease activity index (DAI), bloody diarrhea, and colon shortening. In addition, CPW reduced visceral mechanical hypersensitivity, controlled oxidative stress and inflammation, and protected the mucosal barrier. CPW is not absorbed in the intestine, does not inhibit cytochrome P450 proteins, and does not exhibit AMES toxicity. These results suggest that CPW attenuates DSS-induced acute and chronic colitis in mice and may be a potential alternative treatment for UC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Many orthodontic patients request dental bleaching during orthodontic treatment to achieve a faster aesthetic resolution, however, no attention has been paid to the inflammatory processes that can occur when both therapies are indicated together. So, this clinical trial evaluated the inflammatory parameters and color alterations associated with dental bleaching in patients wearing a fixed orthodontic appliance., Methods: Thirty individuals aged between 18 and 40 years were equally and randomly allocated into three groups: FOA (fixed orthodontic appliance), BLE (dental bleaching), and FOA + BLE (fixed orthodontic appliance + dental bleaching). The orthodontic appliances and the bleaching procedures were performed in the maxillary premolars and molars. For dental bleaching a 35% hydrogen peroxide was used. The gingival crevicular fluid (GCF) and nitric oxide (NO - ) levels were evaluated at different time-points. Color evaluation was performed using an Easyshade spectrophotometer at baseline (FOA, FOA + BLE, BLE), one month after (FOA + BLE) and 21 days after appliance removing (FOA + BLE and FOA groups), in each tooth bleached. The ANOVA and Tukey's tests, with a significance level of 5%, were used for statistical analysis., Results: The GCF volume in the FOA + BLE and FOA groups significantly increased at the time points evaluated (p < 0.001); however, this did not occur in the BLE group (p > 0.05). On the other hand, NO - levels significantly decreased during dental bleaching with or without fixed orthodontic appliances (FOA + BLE and BLE groups; p < 0.05), while no significant changes were observed in the FOA group (p > 0.05). Significant changes in color were observed in the FOA + BLE and BLE groups compared to in the FOA group (p < 0.01). However, the presence of fixed orthodontic appliance (FOA + BLE) negatively affected the bleaching efficacy compared to BLE group (p < 0.01)., Conclusions: Dental bleaching did not increase the inflammatory parameters in patients wearing fixed orthodontic appliance. However, in the presence of orthodontic appliances, the bleaching efficacy was lower than that of bleaching teeth without orthodontic appliances., Trial Registration: RBR-3sqsh8 (first trial registration: 09/07/2018)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Sepsis is an organ dysfunction syndrome associated with high mortality. To date, no effective treatment is available to combat this disease. Punica granatum L. is a potential alternative treatment due to its anti-inflammatory, antimicrobial, and antioxidant properties. Thus, this study aimed to evaluate the effects of a hydroalcoholic crude extract from the peels of P. granatum (HCEPg) in mice with lethal sepsis. Lethal polymicrobial sepsis was induced in female Swiss mice via cecal ligation and puncture (CLP). Initially, the animals were divided into three groups: Sham (false-operated), CLP-control (phosphate-buffered saline), and CLP-HCEPg (single dose, 5 mg/kg, subcutaneous administration). Treatment was initiated immediately after the induction of sepsis, and survival was evaluated every 12 hr for 5 days. Those who survived were euthanized. Serum cytokine levels were measured using a cytometric bead array Mouse Inflammatory Cytokine Kit. The number of colony-forming units, as well as the number of cells in the lymphoid organs and their activation markers, were analyzed. Results showed that treatment with HCEPg increased lifespan and reduced bacterial counts in the peritoneum, bloodstream, and spleen. HCEPg also decreased hydrogen peroxide secretion by phagocytes and augmented serum IL-10 levels, indicating its systemic anti-inflammatory effects. Additionally, treatment with HCEPg attenuated infection-induced lung hemorrhage. Overall, P. granatum extract improved the lifespan of septic mice, possibly due to its antimicrobial, anti-inflammatory, and immunomodulatory effects, thereby regulating bacterial load and translocation, as well as controlling the systemic inflammation induced by sepsis., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Liana de O. Trovão et al.)

Sugar-induced metabolic imbalances are a major health problem since an excessive consumption of saccharides has been linked to greater obesity rates at a global level. Sucrose, a disaccharide composed of 50% glucose and 50% fructose, is commonly used in the food industry and found in a range of fast, restaurant, and processed foods. Herein, we investigated the effects of a TRPC4/TRPC5 blocker, ML204, in the metabolic imbalances triggered by early exposure to sucrose-enriched diet in mice. TRPC4 and TRPC5 belong to the family of non-selective Ca +2 channels known as transient receptor potential channels. High-sucrose (HS)-fed animals with hyperglycaemia and dyslipidaemia, were accompanied by increased body mass index. mesenteric adipose tissue accumulation with larger diameter cells and hepatic steatosis in comparison to those fed normal diet. HS mice also exhibited enhanced adipose, liver, and pancreas TNFα and VEGF levels. ML204 exacerbated hyperglycaemia, dyslipidaemia, fat tissue deposition, hepatic steatosis, and adipose tissue and liver TNFα in HS-fed mice. Normal mice treated with the blocker had greater hepatic steatosis and adipose tissue cell numbers/diameter than those receiving vehicle, but showed no significant changes in tissue inflammation, glucose, and lipid levels. The results indicate that TRPC4/TRPC5 protect against the metabolic imbalances caused by HS ingestion.

The ostrich oil (OO) has been topically used for decades to treat skin diseases. Its oral use has been encouraged through e-commerce advertising several health benefits to OO without scientific evidence on its safety or effectiveness. This study presents the chromatographic profile of a commercially available OO and its acute and 28-day repeated dose in vivo toxicological profiles. OO anti-inflammatory and antinociceptive effects were also investigated. Omega-9 (ω-9; oleic acid; 34.6%) and -6 (linoleic acid; 14.9%) were detected as OO main constituents. A high single dose of the OO (2 g/kg of ω-9) demonstrated no or low acute toxicity. However, when orally treated with OO (30-300 mg/kg of ω-9) for 28 consecutive days, mice exhibited altered locomotor and exploratory activities, hepatic damage, and increased hindpaw sensitivity accompanied by increased levels of cytokine and brain-derived neurotrophic factor in their spinal cords and brains. Lack of anti-inflammatory or antinociceptive activities was also evidenced in 15-day-OO treated mice. These results indicate that chronic consumption of OO induces hepatic injury, in addition to neuroinflammation and subsequent hypersensitivity and behavioural changes. Thus, there is no evidence to support OO use to treating illness in humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Antineoplastic treatment induces a type of gastrointestinal toxicity known as mucositis. Findings in animal models are usually easily reproducible, and standardized treatment regimens are often used, thus supporting translational science. Essential characteristics of mucositis, including intestinal permeability, inflammation, immune and oxidative responses, and tissue repair mechanisms, can be easily investigated in these models. Given the effects of mucositis on the quality of life of patients with cancer, and the importance of experimental models in the development of more effective new therapeutic alternatives, this review discusses progress and current challenges in using experimental models of mucositis in translational pharmacology research., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A majority of medical and lay articles regarding crucifixion, and specifically the crucifixion of Jesus Christ, now state that suffocation was the primary cause of death from crucifixion. An in-depth analysis reveals that this theory is based on a form of torture unrelated to crucifixion and that no evidence directly linking suffocation to crucifixion has been published. Indeed, a thorough review of available ancient evidence from literature, artwork, graffiti, and modern archeology and re-enactment studies reveals no evidence in favor of suffocation and much evidence against suffocation as the cause of death in typically-portrayed crucifixions, and particularly for the crucifixion of Jesus Christ. Researchers are encouraged to look elsewhere for the most likely cause or causes of death from crucifixion. It may be time to abandon the idea that suffocation was the primary cause of death in crucifixion., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© Catholic Medical Association 2022.)

Cinnamaldehyde is a natural product with anti-inflammatory and immune-modulatory properties, known to regulate host responses to bacterial stimuli. This study aimed to investigate the effects of cinnamaldehyde on ligature-induced periodontitis in rats, and its impact on the modulation of human peripheral blood mononuclear cells (PBMC). Male Wistar rats were assigned into three groups:i) control: no ligature + vehicle; ii) ligature: ligature + vehicle; and iii) ligature + cinnamaldehyde (50 mg/kg); all treatments by daily oral gavage. After 14 days of induced periodontitis, the hemimandibles were collected for bone loss evaluation. The gingival levels of IL-1β, MMP-9 and iNOS mRNA were evaluated. Nitric oxide (NO) was measured in both rat saliva and plasma. PBMC were stimulated with Aggregatibacter actinomycetemcomitans (Aa) in the presence or absence of cinnamaldehyde (5, 20 e 40 µM), and cytokine production was quantified in cell supernatant. Proliferating lymphocytes were taken for flow cytometer reading, while culture supernatants were used for IFN-γ and IL-10 assessment. The ligature group had both increased alveolar bone loss and gingival expression of IL-1β, MMP-9 and iNOS compared to the control group. All parameters were attenuated by cinnamaldehyde treatment. Lower salivary but not plasma NO was detected in the cinnamaldehyde compared to the ligature group. Aa-stimulated PBMCs treated with cinnamaldehyde produced less IL-1β; the compound also attenuated lymphocyte proliferation in a dose-dependent manner, as well as cell IL-10 production. Cinnamaldehyde treatment reduced periodontal bone loss, and downregulated key inflammatory mediators and human PBMC responses, pointing to novel potential therapeutic effects of this compound., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Oropharyngeal candidiasis/candidosis is a common and recurrent opportunistic fungal infection. Fluconazole (FLZ), one of the most used and effective antifungal agents, has been associated with a rise of resistant Candida species in immunocompromised patients undergoing prophylactic therapy. Sulforaphane (SFN), a compound from cruciferous vegetables, is an antimicrobial with yet controversial activities and mechanisms on fungi. Herein, the in silico and antifungal activities of SFN against C. albicans were investigated. In silico analyzes for the prediction of the biological activities and oral bioavailability of SFN, its possible toxicity and pharmacokinetic parameters, as well as the estimates of its gastrointestinal absorption, permeability to the blood-brain barrier and skin, and similarities to drugs, were performed by using different software. SFN in vitro anti- Candida activities alone and in combination with fluconazole (FLZ) were determined by the broth microdilution method and the checkerboard, biofilm and hyphae formation tests. Amongst the identified probable biological activities of SFN, nine indicated an antimicrobial potential. SFN was predicted to be highly absorbable by the gastrointestinal tract, to present good oral availability, and not to be irritant and/or hepatotoxic. SFN presented antifungal activity against C. albicans and prevented both biofilm and hyphae formation by this microorganism. SFN was additive/synergistic to FLZ. Overall, the data highlights the anti- Candida activity of SFN and its potential to be used as an adjuvant therapy to FLZ in clinical settings.

In folk medicine, Vismia guianensis is used to treat skin diseases and mycoses in the Amazon region. We evaluated the anti- Candida activity of the hydroalcoholic extract from the leaves of Vismia guianensis (EHVG). HPLC-PDA and FIA-ESI-IT-MS n were used to chemically characterize EHVG. The anti- Candida activity was determined in vitro by the minimum inhibitory concentrations (MIC) against Candida glabrata (ATCC-2001); Candida albicans (ATCC-90028, ATCC-14053, and ATCC-SC5314), and C. albicans clinical isolates. EHVG effects on adhesion, growth, and biofilm formation were also determined. Molecular docking was used to predict targets for EHVG compounds. The main compounds identified included anthraquinone, vismione D, kaempferol, quercetin, and vitexin. EHVG was fungicidal against all tested strains. C. albicans ATCC 14053 and C. glabrata ATCC 2001 were the most sensitive strains, as the extract inhibited their virulence factors. In silico analysis indicated that vismione D presented the best antifungal activity, since it was the most effective in inhibiting CaCYP51, and may act as anti-inflammatory and antioxidant agent, according to the online PASS prediction. Overall, the data demonstrate that EHVG has an anti- Candida effect by inhibiting virulence factors of the fungi. This activity may be related to its vismione D content, indicating this compound may represent a new perspective for treating diseases caused by Candida sp.

Schistosoma mansoni infections, particularly egg antigens, induce Th2-dominant granulomatous responses accompanied by remarkable immunoregulatory mechanisms that avoid intense fibrosis. Interleukin (IL)-33 is a cytokine that stimulates the early activation of Th2 responses, and its soluble ST2 receptor (sST2) avoids granulomatous response, as well as CXCL9 and CXCL10 chemokines that have antifibrotic activity. However, in schistosomiasis, these molecules have not been suitably studied. Therefore, this study aimed to measure IL-33 and sST2 RNA, cytokines, and chemokines in peripheral blood cultures from individuals living in schistosomiasis-endemic areas. Peripheral blood cells from individuals with S. mansoni (n = 34) and non-infected individuals (n = 31) were cultured under mitogen stimulation. Supernatant chemokines and cytokines were evaluated using a cytometric bead array, and IL-33 and sST2 mRNA expression was measured using qPCR. Infected individuals showed higher levels of CXCL8, CXCL9, CXCL10, IFN-γ, TNF-α, IL-6, IL-2, IL-4, and IL-10; there was a lower expression of IL-33 mRNA and similar expression of sST2mRNA in infected than non-infected individuals. In conclusion, for the first time, we demonstrated lower IL-33mRNA expression and high levels of the antifibrotic chemokines CXCL9 and CXCL10 in schistosomiasis mansoni, which could control exacerbations of the disease in individuals from endemic areas., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Metabolic syndrome (MS) is a complex pathology characterized by visceral adiposity, insulin resistance, arterial hypertension, and dyslipidaemia. It has become a global epidemic associated with increased consumption of high-calorie, low-fibre food and sedentary habits. Some of its underlying mechanisms have been identified, with hypoadiponectinemia, inflammation and oxidative stress as important factors for MS establishment and progression. Alterations in adipokine levels may favour glucotoxicity and lipotoxicity which, in turn, contribute to inflammation and cellular stress responses within the adipose, pancreatic and liver tissues, in addition to hepatic steatosis. The multiple mechanisms of MS make its clinical management difficult, involving both non-pharmacological and pharmacological interventions. Transient receptor potential (TRP) channels are non-selective calcium channels involved in a plethora of physiological events, including energy balance, inflammation and oxidative stress. Evidence from animal models of disease has contributed to identify their specific contributions to MS and may help to tailor clinical trials for the disease. In this context, the oxidative stress sensors TRPV1, TRPA1 and TRPC5, play major roles in regulating inflammatory responses, thermogenesis and energy expenditure. Here, the interplay between these TRP channels and oxidative stress in MS is discussed in the light of novel therapies to treat this syndrome.

The Chikungunya virus (CHIKV) can cause long lasting symptoms and manifestations. However, there is little information on which ocular ones are most frequent following infection. We performed a systematic review (registered in the International Prospective Register of Systematic Reviews; no CRD42020171928) to establish the most frequent ocular manifestations of CHIKV infection and their associations with gender and age. Articles published until September 2020 were selected from PubMed, Scielo, Cochrane and Scopus databases. Only studies with CHIKV-infected patients and eye alterations were included. Reviews, descriptive studies, or those not investigating the human ocular manifestations of CHIKV, those with patients with other diseases and infections, abstracts and studies without relevant data were excluded. Twenty-five studies were selected for inclusion. Their risk of bias was evaluated by a modified Newcastle-Ottawa scale. The most frequent ocular symptoms of CHIKV infection included ocular pain, inflammation and reduced visual acuity, whilst conjunctivitis and optic neuritis were the most common manifestations of the disease. These occurred mostly in individuals of 42 ± 9.5 years of age and woman. The few available reports on CHIKV-induced eye manifestations highlight the need for further research in the field to gather more substantial evidence linking CHIKV infection, the eye and age/gender. Nonetheless, the data emphasizes that ocular alterations are meaningful occurrences of CHIKV infection which can substantially affect quality of life.

Mucopolysaccharidosis (MPS) is a heterogeneous group of rare, chronic, progressive and systemic inherited disorders resulting from deficiency or lack of lysosomal enzymes responsible for the degradation of glycosaminoglycans. Products of nitrosative stress have been previously detected in blood and urine samples of patients with MPS. However, it is unclear whether they are present in the saliva of MPS patients and also if they correlate with salivary parameters such as flow and pH. This study compared the salivary levels of NOX (NO2- + NO3-), nitrite (NO2-), protein (albumin), erythrocyte and leukocyte numbers, as well as the salivary flow rate and pH values of samples obtained from 10 MPS patients and 10 healthy subjects. MPS patients exhibited higher salivary levels of NOX and NO2- when compared to healthy subjects (p < 0.05). Albumin was only detected in six saliva samples of MPS patients and, erythrocytes and leukocytes were detected in 60% and 40% of the MPS patients, respectively. In addition, salivary flow rate and pH averages were statistically lower in this group when compared to healthy samples (p < 0.05). Overall, the data indicates that the salivary levels of NO products can be used in combination with other heath indicators to monitor MPS disorders.

Objectives: This clinical trial evaluated the effects of red wine exposure on the effectiveness of at-home bleaching with 10% carbamide peroxide, degree of tooth sensitivity, and levels of periodontal inflammatory markers., Method and Materials: Eighty participants were assigned to two groups, namely, those who drank red wine (experimental group), and those who did not drink red wine (control group). The experimental group participants rinsed their mouths with 25 mL of red wine four times a day during the bleaching period. Shade evaluation was assessed visually by using the Vita Classical and Vita Easyshade techniques. Tooth sensitivity was evaluated by the numeric and visual analog scales, and the salivary and gingival crevicular fluids were collected for assessment of nitric oxide (NO) levels, a marker of inflammation. Differences in color change were analyzed by one-way analysis of variance (ANOVA). The absolute risks of tooth sensitivity were compared by the Fisher exact test. Tooth sensitivity intensity data sets for both the visual analog scale and the numeric rating scale were compared using the Wilcoxon signed rank test (α = .05). Repeated measures and two-way ANOVA followed by the Bonferroni test were used to assess time-course and differences between groups in NO production., Results: The bleaching technique was effective regardless of wine consumption (P > .05). Tooth sensitivity was classified as mild, with no differences between groups (P > .05). Red wine reduced both the gingival crevicular fluid and salivary levels of NO (P < .05)., Conclusion: Red wine does not interfere with the effectiveness and sensitivity of at-home teeth bleaching with 10% carbamide peroxide and protects against bleaching-induced inflammation.

In late 2019, an outbreak of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initiated in Wuhan, Hubei province, China. The major clinical symptoms described for coronavirus disease (COVID-19) include respiratory distress and pneumonia in severe cases, and some patients may experience gastrointestinal impairments. In accordance, viral RNA or live infectious virus have been detected in feces of patients with COVID-19. Binding of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) is a vital pathway for the virus entry into human cells, including those of the respiratory mucosa, esophageal epithelium as well as the absorptive enterocytes from ileum and colon. The interaction between SARS-CoV-2 and ACE2 receptor may decrease the receptor expression and disrupt the function of B0AT1 transporter influencing the diarrhea observed in COVID-19 patients. In this context, a fecal-oral transmission route has been considered and points out a role for the digestive tract in disease transmission and severity. Here, in order to further understand the impact of COVID-19 in human physiology, the cellular and molecular mechanisms of SARS-CoV-2 infection and disease severity are discussed in the context of gastrointestinal disturbances.

Limosilactobacillus fermentum (ATCC 23271) was originally isolated from the human intestine and has displayed antimicrobial activity, primarily against Candida species. Complete genome sequencing and comparative analyses were performed to elucidate the genetic basis underlying its probiotic potential. The ATCC 23271 genome was found to contain 2,193,335 bp, with 2123 protein-coding sequences. Phylogenetic analysis revealed that the ATCC 23271 strain shares 941 gene clusters with six other probiotic strains of L. fermentum . Putative genes known to confer probiotic properties have been identified in the genome, including genes related to adhesion, tolerance to acidic pH and bile salts, tolerance to oxidative stress, and metabolism and transport of sugars and other compounds. A search for bacteriocin genes revealed a sequence 48% similar to that of enterolysin A, a protein from Enterococcus faecalis . However, in vitro assays confirmed that the strain has inhibitory activity on the growth of Candida species and also interferes with their adhesion to HeLa cells. In silico analyses demonstrated a high probability of the protein with antimicrobial activity. Our data reveal the genome features of L. fermentum ATCC 23271, which may provide insight into its future use given the functional benefits, especially against Candida infections.

Intestinal mucositis is a clinically relevant side effect of anticancer therapies. It is experienced by 60-100% of patients undergoing treatment with high doses of chemotherapy, radiation therapy, and bone marrow transplantation. Intestinal mucositis can manifest as pain, weight loss, inflammation, diarrhea, rectal bleeding, and infection; affecting normal nutritional intake and intestinal function. It often impacts adherence to anticancer therapy as it frequently limits patient's ability to tolerate treatment, causing schedule delays, interruptions, or premature discontinuation. In some cases, local and systemic secondary infections are observed, increasing the costs toward medical care and hospitalization. Several strategies for managing mucositis are available which do not always halt this condition. In this context, new therapeutic strategies are under investigation to prevent or treat intestinal mucositis. Polysaccharides from natural resources have recently become promising molecules against intestinal damage due to their ability to promote mucosal healing and their anti-inflammatory actions. These effects are associated with the protection of intestinal mucosa and regulation of microbiota and immune system. This review aims to discuss the recent advances of polysaccharides from natural resources as potential therapies for intestinal mucositis. The source, species, doses, treatment schedules, and mechanisms of action of polysaccharides will be discussed in detail., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sauruk da Silva, Carla da Silveira, Bueno, Malaquias da Silva, da Silva Fonseca, Fernandes and Maria-Ferreira.)

Background: Solanum diploconos (Mart.) Bohs is a native Brazilian plant belonging to the Solanaceae family, popularly known as "tomatinho do mato" and poorly investigated. Herein, we presented for the first time evidence for the anti-inflammatory and wound healing activities of S. diploconos fruit hydroalcoholic extract. Material and Methods . In vitro fMLP-induced chemotaxis, LPS-induced inflammatory mediator levels (cytokines by ELISA and NO release by Griess reaction), and adhesion molecule expression (CD62L, CD49d, and CD18, by flow-cytometry) were assessed in neutrophils treated with different concentrations of the extract. Inflammation resolution was measured by the efferocytosis assay and the healing activity by in vivo and in vitro assays. The air pouch model of carrageenan-induced inflammation in Swiss mice was used to investigate the in vivo anti-inflammatory effects of the extract. Leukocyte influx (by optical microscopy) and cytokine release were quantified in the pouch exudates. Additionally, the acute and subacute toxic and genotoxic effects of the extract were evaluated., Results: In vitro , the extract impaired neutrophil chemotaxis and its ability to produce and/or release cytokines (TNF α , IL-1 β , and IL-6) and NO upon LPS stimuli ( p < 0.01). LPS-treated neutrophils incubated with the extract presented increased CD62L expression ( p < 0.01), indicating a reduced activation. An enhanced efferocytosis of apoptotic neutrophils by macrophages was observed and accompanied by higher IL-10 and decreased TNF α secretion ( p < 0.01). In vivo , similar results were noted, including reduction of neutrophil migration, protein exudation, and cytokine release ( p < 0.01). Also, the extract increased fibroblast proliferation and promoted skin wound healing ( p < 0.01). No signs of toxicity or genotoxicity were observed for the extract., Conclusion: S. diploconos fruit extract is anti-inflammatory by modulating neutrophil migration/activation as well macrophage-dependent efferocytosis and inflammatory mediator release. It also indicates its potential use as a healing agent. Finally, the absence of acute toxic and genotoxic effects reinforces its possible use as medicinal product., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Larissa Benvenutti et al.)

Purpose: To review the effects of polysaccharides and their proposed mechanisms of action in breast cancer experimental models. Data sources, selection, and extraction: Articles were selected by using PubMed, ScienceDirect, Scopus, and Medline, assessed from 1 May 2019 to 1 July 2020. The systematic review was registered in the International Prospective Register of Systematic Reviews (Prospero) under the number CRD42020169103. Results: Most of the studies explore algae polysaccharides (43.2%), followed by mushrooms (13.5%), plants (13.5%), fruits (10.8%), fungus (2.7%), bacteria, (2.7%), and sea animals (2.7%). A total of 8.1% investigated only in vitro models, 62.1% evaluated only in vivo models, and 29.7% evaluated in vitro and in vivo models. The mechanism of action involves apoptosis, inhibition of cellular proliferation, angiogenesis, and antimetastatic effects through multiple pathways. Conclusions: Findings included here support further investigations on the anti-tumor effect of polysaccharides. Some polysaccharides, such as fucoidan and β-glucans, deserve detailed and structured studies aiming at translational research on breast tumors, since they are already used in the clinical practice of other proposals of human health.

Competing Interests: None to declare.

Metabolic syndrome (MetS) and obesity are growing in many parts of the world, becoming public health problems. It is proposed that foods with functional properties can assist in the treatment of these diseases. Crude buriti pulp oil (BPO) is a food traditionally consumed by residents in the Pantanal, Cerrado and Brazilian Amazon. It is rich in oleic acid, tocopherols and carotenoids, emerging as a potential functional food. Thus, this study aimed to evaluate the effect of the supplementation of BPO on metabolic disorders caused by a high-fat diet. Four groups of C57BL6 mice were used, a lean group with AIN-93M diet and control oil supplementation, an obese group with a high-fat diet and control oil supplementation, and two obese groups with a high-fat diet and BPO supplementation in the amounts of 50 and 100 mg/kg. BPO worsened the metabolic state caused by the high-fat diet, worsening risk factors associated with MetS, as the abdominal circumference and retroperitoneal fat, serum levels of total cholesterol, uric acid, alanine transaminase, glucose and triglycerides, and renal fat, in addition to changes in glycaemic control and oxidative stress markers. C57BL/6 mice fed with a high-fat diet and supplemented with BPO presented a worsening in metabolic risk factors associated with MetS., (© 2020 Wiley-VCH GmbH.)

Rheumatoid arthritis (RA) is a painful inflammatory disease of the joints which affects a considerable proportion of the world population, mostly women. If not adequately treated, RA patients can become permanently disabled. Importantly, not all the patients respond to the available anti-rheumatic therapies, which also present diverse side effects. In this context, monitoring of treatment response is pivotal to avoid unnecessary side effects and costs towards an ineffective therapy. Herein, we performed a pilot study to investigate the potential use of flow cytometry and attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy as measures to identify responders and non-responders to leflunomide, a disease-modifying drug used in the treatment of RA patients. The evaluation of peripheral blood CD62L + polymorphonuclear cell numbers and ATR-FTIR vibrational modes in plasma were able to discriminate responders to leflunomide (LFN) three-months after therapy has started. Overall, the results indicate that both flow cytometry and ATR-FTIR can potentially be employed as additional measures to monitor early treatment response to LFN in RA patients.

Inflammatory arthritis, such as rheumatoid arthritis (RA), stands out as one of the main sources of pain and impairment to the quality of life. The use of hemopressin (PVNFKFLSH; Hp), an inverse agonist of type 1 cannabinoid receptor, has proven to be effective in producing analgesia in pain models, but its effect on neuro-inflammatory aspects of RA is limited. In this study, antigen-induced arthritis (AIA) was evoked by the intraarticular (i.art.) injection of methylated bovine serum albumin (mBSA) in male Sprague Dawley rats. Phosphate buffered saline (PBS)-injected ipsilateral knee joints or AIA contralateral were used as control. Nociceptive and inflammatory parameters such as knee joint oedema and leukocyte influx and histopathological changes were carried out in addition to the local measurement of interleukins (IL) IL-6, IL-1β, tumor necrosis factor-α and the immunoreactivity of the neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP) in the spinal cord (lumbar L3-5 segments) of AIA rats. For 4 days, AIA rats were treated daily with a single administration of saline, Hp injected (10 or 20 μg/day, i.art.), Hp given orally (20 μg/Kg, p.o.) or indomethacin (Indo; 5 mg/Kg, i.p.). In comparison to the PBS control group, the induction of AIA produced a significant and progressive mono-arthritis condition. The degree of AIA severity progressively compromised the normal walking pattern and impaired mobility over the next four days in relation to PBS-injected rats or contralateral knee joints. In AIA rats, the reduction of the distance between footprints and disturbances of gait evidenced signs of nociception. This response worsened at day 4, and a loss of footprint from the ipsilateral hind paw was evident. Daily treatment of the animals with Hp either i.art. (10 and 20 μg/knee) or p.o. (20 μg/Kg) as well as Indo (5 mg/Kg, i.p.) ameliorated the impaired mobility in a time-dependent manner (P < 0.05). In parallel, the AIA-injected ipsilateral knee joints reach a peak of swelling 24 h after AIA induction, which persisted over the next four days in relation to PBS-injected rats or contralateral knee joints. There was a significant but not dose-dependent inhibitory effect produced by all dosages and routes of Hp treatments on AIA-induced knee joint swelling (P < 0.05). In addition, the increased synovial levels of MPO activity, total leukocytes number and IL-6, but not IL-1β, were significantly reduced by the lower i.art. dose of Hp. In conclusion, these results successfully demonstrate that Hp may represent a novel therapeutic strategy to treat RA, an effect which is unrelated to the proinflammatory actions of the neuropeptides CGRP and SP., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The latex of Euphorbia tirucalli L. (LET) has great etnopharmacological relevance for several traditional communities. In this study, the in vitro and in vivo (using Tenebrio molitor larvae) antimicrobial effects of LET were evaluated. LET did not inhibit the growth of S. aureus , however, a reduction on staphyloxanthin production (an important virulence factor of S. aureus ) was observed. LET (at 10 μL/kg) was also able to enhance the survival of larvae infected with a lethal dose of S. aureus , an effect associated with reduction in the numbers of haemocytes. Furthermore, haemocytes from LET-treated larvae exhibited dysfunctional lysosome activity. These results indicate the effectiveness of LET as an anti-infective agent which could be useful as source of lead molecules for the development of new therapies against S. aureus -induced infections.

Taxane-derived drugs are antineoplastic agents used for the treatment of highly common malignancies. Paclitaxel and docetaxel are the most commonly used taxanes; however, other drugs and formulations have been used, such as cabazitaxel and nab-paclitaxel. Taxane treatment is associated with neurotoxicity, a well-known and relevant side effect, very prevalent amongst patients undergoing chemotherapy. Painful peripheral neuropathy is the most dose-limiting side effect of taxanes, affecting up to 97% of paclitaxel-treated patients. Central neurotoxicity is an emerging side effect of taxanes and it is characterized by cognitive impairment and encephalopathy. Besides impairing compliance to chemotherapy treatment, taxane-induced neurotoxicity (TIN) can adversely affect the patient's life quality on a long-term basis. Despite the clinical relevance, not many reviews have comprehensively addressed taxane-induced neurotoxicity when they are used therapeutically. This article provides an up-to-date review on the pathophysiology of TIN and the novel potential therapies to prevent or treat this side effect., (© 2020 The British Pharmacological Society.)

Objective: Portomesenteric vein thrombosis (PMVT) is a potentially severe complication that can occur after bariatric surgery. PMVT has gained importance because of the increasing number of bariatric surgeries being performed. to report a rare and severe complication after bariatric surgery, which is difficult to manage. To try to identify common characteristics among the cases and discuss potential causes comparing our data to the available literature., Methods: We describe six cases of PMVT in young women with different presentations., Results: All six cases occurred in young women 29-41 years old with obesity - body mass index - BMI: 36-39) and weighing 105-121 kg. The patients had few comorbidities (all of which were related to metabolic syndrome) and moderate hepatic steatosis with no sign of cirrhosis. Five patients used oral contraceptives until a few days before the operation. One patient tested positive for thrombophilia. Five patients underwent a laparoscopic sleeve gastrectomy and one underwent a gastric bypass with no complications during the operation (median operating time: 61.3 min, range 52-91 min). The mean duration of follow-up after hospitalization was 12.3 months (range: 7-18 months) and to-date only one patient has had no recanalization., Conclusion: The frequency of PMVT appears to be increased in woman and after sleeve gastrectomy. Our findings indicate that patients with abdominal pain weeks after bariatric surgery must be investigated.

There is currently a global effort to reduce malaria morbidity and mortality. However, malaria still results in the deaths of thousands of people every year. Malaria is caused by Plasmodium spp., parasites transmitted through the bite of an infected female Anopheles mosquito. Treatment timing plays a decisive role in reducing mortality and sequelae associated with the severe forms of the disease such as cerebral malaria (CM). The available antimalarial therapy is considered effective but parasite resistance to these drugs has been observed in some countries. Antimalarial drugs act by increasing parasite lysis, especially through targeting oxidative stress pathways. Here we discuss the roles of reactive oxygen species and reactive nitrogen intermediates in CM as a result of host-parasite interactions. We also present evidence of the potential contribution of oxidative and nitrosative stress-based antimalarial drugs to disease treatment and control., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: This study aimed to assess the effects of daily use of Cimicifuga racemosa on endothelial function through flow-mediated dilation of the brachial artery, when used for 28 days by healthy postmenopausal women. Methods: The double-blind, randomized, placebo-controlled study included two groups of postmenopausal women ( n  = 31 each). The subjects were clinically assessed and flow-mediated dilation of the brachial artery was measured before and after 28 days of treatment. Patients received dry extract corresponding to 160 mg C. racemosa (extract with 4 mg of triterpene glycosides) or placebo. Results: Mean age, time since menopause, and body mass index in the two groups were similar. The measurements of flow-mediated dilation of the brachial artery, pre and post treatment, respectively, showed a significant increase in patients who used C. racemosa ( p  = 0.006), unlike patients who used placebo, who did not present changes in the outcome of flow-mediated dilation of the brachial artery after 28 days of use ( p  ≥ 0.05). When comparing the number of women in both groups who showed an increase in flow-mediated dilation, a significant difference was found in the measurements of the treated group after the use of the medication ( p  = 0.018). Conclusions: Daily use of 160 mg C. racemosa extract by postmenopausal women for 28 days beneficially influences endothelial function by promoting elasticity of the brachial artery.

Escherichia coli and Staphylococcus aureus are important agents of urinary tract infections that can often evolve to severe infections. The rise of antibiotic-resistant strains has driven the search for novel therapies to replace the use or act as adjuvants of antibiotics. In this context, plant-derived compounds have been widely investigated. Cuminaldehyde is suggested as the major antimicrobial compound of the cumin seed essential oil. However, this effect is not fully understood. Herein, we investigated the in silico and in vitro activities of cuminaldehyde, as well as its ability to potentiate ciprofloxacin effects against S. aureus and E. coli. In silico analyses were performed by using different computational tools. The PASS online and SwissADME programmes were used for the prediction of biological activities and oral bioavailability of cuminaldehyde. For analysis of the possible toxic effects and the theoretical pharmacokinetic parameters of the compound, the Osiris, SwissADME and PROTOX programmes were used. Estimations of cuminaldehyde gastrointestinal absorption, blood brain barrier permeability and skin permeation by using SwissADME; and drug likeness and score by using Osiris, were also evaluated The in vitro antimicrobial effects of cuminaldehyde were determined by using microdilution, biofilm formation and time-kill assays. In silico analysis indicated that cuminaldehyde may act as an antimicrobial and as a membrane permeability enhancer. It was suggested to be highly absorbable by the gastrointestinal tract and likely to cross the blood brain barrier. Also, irritative and harmful effects were predicted for cuminaldehyde if swallowed at its LD50. Good oral bioavailability and drug score were also found for this compound. Cuminaldehyde presented antimicrobial and anti-biofilm effects against S. aureus and E. coli.. When co-incubated with ciprofloxacin, it enhanced the antibiotic antimicrobial and anti-biofilm actions. We suggest that cuminaldehyde may be useful as an adjuvant therapy to ciprofloxacin in S. aureus and E. coli-induced infections., Competing Interests: The authors have declared that no competing interests exist.

Parkinson's disease (PD) represents one of the most common multifactorial neurodegenerative disorders affecting the elderly population. It is associated with the aggregation of α-synuclein protein and the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The disease is mainly represented by motor symptoms, such as resting tremors, postural instability, rigidity, and bradykinesia, that develop slowly over time. Parkinson's disease can also manifest as disturbances in non-motor functions. Although the pathology of PD has not yet been fully understood, it has been suggested that the disruption of the cellular redox status may contribute to cellular oxidative stress and, thus, to cell death. The generation of reactive oxygen species and reactive nitrogen intermediates, as well as the dysfunction of dopamine metabolism, play important roles in the degeneration of dopaminergic neurons. In this context, the transient receptor potential channel canonical (TRPC) sub-family plays an important role in neuronal degeneration. Additionally, PD gene products, including DJ-1, SNCA, UCH-L1, PINK-1, and Parkin, also interfere with mitochondrial function leading to reactive oxygen species production and dopaminergic neuronal vulnerability to oxidative stress. Herein, we discuss the interplay between these various biochemical and molecular events that ultimately lead to dopaminergic signaling disruption, highlighting the recently identified roles of TRPC in PD., (Copyright © 2020 Maria-Ferreira, de Oliveira, da Silva and Fernandes.)

Phosphodiesterases (PDEs) form a superfamily of enzymes that catalyze the hydrolysis of cyclic nucleotides adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) to their inactive 5' monophosphates. cAMP plays a critical role as a second messenger in endocrine tissues, and activation of cAMP signaling has been reported in endocrine tumors. Germline variants in PDEs have been associated with benign cortisol-secreting adrenocortical adenomas and testicular germ cell cancer but not adrenocortical carcinoma. We performed whole genome sequencing (WGS) and whole exome sequencing (WES) of paired blood and tumor samples from 37 pediatric adrenocortical tumors (ACTs). Germline inactivating variants in PDEs were observed in 9 of 37 (24%) patients. Tumor DNA analysis revealed loss of heterozygosity, with maintenance of the mutated allele in all cases. Our results suggest that germline variants in PDEs and other regulators of the cAMP-signaling pathway may contribute to pediatric adrenocortical tumorigenesis, perhaps by cooperating with germline hypomorphic mutant TP53 alleles and uniparental disomy of chromosome 11p15 (Beckwith-Wiedemann syndrome).

Cryptococcus species are responsible for important systemic mycosis and are estimated to cause millions of new cases annually. The available therapy is limited due to the high toxicity and the increasing rates of yeast resistance to antifungal drugs. Popularly known as "sucará," Xylosma prockia (Turcz.) Turcz. (Salicaceae) is a native plant from Brazil with little information on its pharmacological potential. In this work, we evaluated in vitro anticryptococcal effects of the leaf ethanolic extract of X. prockia and its fractions against Cryptococcus gattii and Cryptococcus neoformans . We also evaluated phenotypic alterations caused by ethyl acetate fraction (EAF) (chosen according to its biological results). The liquid chromatography-mass spectrometry (LC-MS) analysis of EAF demonstrated the presence of phenolic metabolites that belong to three structurally related groups as majority compounds: caffeoylquinic acid, coumaroyl-glucoside, and caffeoyl-glucoside/deoxyhexosyl-caffeoyl glucoside derivatives. The minimum inhibitory concentration (MIC) values against C. gattii and C. neoformans ranged from 8 to 64 mg/L and from 0.5 to 8 mg/L, for ethanolic extract and EAF, respectively. The EAF triggered an oxidative burst and promoted lipid peroxidation. EAF also induced a reduction of ergosterol content in the pathogen cell membrane. These effects were not associated with alterations in the cell surface charge or in the thermodynamic fingerprint of the molecular interaction between EAF and the yeasts evaluated. Cytotoxic experiments with peripheral blood mononuclear cells (PBMCs) demonstrated that EAF was more selective for yeasts than was PBMCs. The results may provide evidence that X. prockia leaf extract might indeed be a potential source of antifungal agents., (Copyright © 2020 Folly, Ferreira, Salvador, Sathler, da Silva, Santos, dos Santos, Nunes Neto, Rodrigues, Fernandes, da Silva, de Freitas, Denadai, Rodrigues, Mendonça, Monteiro, Santos, Cabrera, Siless and Lang.)