SARS-CoV-2 Spike protein triggers gut impairment since mucosal barrier to innermost layers: From basic science to clinical relevance.

Studies have reported the occurrence of gastrointestinal (GI) symptoms, primarily diarrhea, in COVID-19. However, the pathobiology regarding COVID-19 in the GI tract remains limited. This work aimed to evaluate SARS-CoV-2 Spike protein interaction with gut lumen in different experimental approaches. Here, we present a novel experimental model with the inoculation of viral protein in the murine jejunal lumen, in vitro approach with human enterocytes, and molecular docking analysis. Spike protein led to increased intestinal fluid accompanied by Cl- secretion, followed by intestinal edema, leukocyte infiltration, reduced glutathione levels, and increased cytokine levels [interleukin (IL)-6, tumor necrosis factor-α, IL-1ß, IL-10], indicating inflammation. Additionally, the viral epitope caused disruption in the mucosal histoarchitecture with impairment in Paneth and goblet cells, including decreased lysozyme and mucin, respectively. Upregulation of toll-like receptor 2 and toll-like receptor 4 gene expression suggested potential activation of local innate immunity. Moreover, this experimental model exhibited reduced contractile responses in jejunal smooth muscle. In barrier function, there was a decrease in transepithelial electrical resistance and alterations in the expression of tight junction proteins in the murine jejunal epithelium. Additionally, paracellular intestinal permeability increased in human enterocytes. Finally, in silico data revealed that the Spike protein interacts with cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride conductance (CaCC), inferring its role in the secretory effect. Taken together, all the events observed point to gut impairment, affecting the mucosal barrier to the innermost layers, establishing a successful experimental model for studying COVID-19 in the GI context.

Arabinan-rich pectic polysaccharide fraction from Malpighia emarginata fruits alleviates inflammatory pain in mice.

Malpighia emarginata (Malpighiaceae), popularly known as "acerola", is a tropical and subtropical fruit native to the Americas. Despite its high vitamin C content, which gives it a high antioxidant property, soluble dietary fibers, such as polysaccharides, are also abundant constituents of acerola (10% of the dried fruit). The acerola cold-water soluble (ACWS) fraction presented anti-fatigue and antioxidant effects in vivo and in vitro. To infer further systemic effects of ACWS, this study aimed to investigate the antinociceptive, anti-inflammatory, and antioxidant effects of ACWS in murine models of pain. In formalin-induced nociception, ACWS (0.1, 1, and 10 mg/kg) reduced only the inflammatory phase, and also (10 and 30 mg/kg) attenuated the acetic acid-induced writhing and leukocyte migration in the peritoneal cavity. The mechanical allodynia and paw edema induced by intraplantar injection of carrageenan were greatly reduced by ACWS (10 mg/kg). At the inflammatory pick induced by carrageenan (4 h), ACWS significantly reduced myeloperoxidase activity, TNF-α, IL-1ß, and PGE2 levels, and restored IL-10 levels. ACWS also exhibited antioxidant properties by decreasing lipid hydroperoxides content, increasing GSH levels, and restoring superoxide dismutase and catalase activities in the carrageenan model and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay. Collectively, these results support the antinociceptive, anti-inflammatory, and antioxidant effects of ACWS and reveal a promising candidate for the treatment of inflammatory pain conditions.

CPW partially attenuates DSS-induced ulcerative colitis in mice.

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.

Analysis of the Effect of the TRPC4/TRPC5 Blocker, ML204, in Sucrose-Induced Metabolic Imbalance.

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.

Water-soluble polysaccharides from Piper regnellii (Pariparoba) leaves: Structural characterization and antinociceptive and anti-inflammatory activities.

Piper regnellii is a plant popularly known as "Pariparoba" and it is widely used in folk medicine to treat pain, inflammation, among others. This work presents the extraction, purification and characterization of polysaccharides present in the plant leaves and evaluation of their anti-inflammatory and antinociceptive activities. From the crude aqueous extract of P. regnellii leaves, a polysaccharide fraction named PR30R, predominantly constituted of arabinose, galactose and galacturonic acid monosaccharide units, was obtained. Methylation and NMR analysis showed that the main polysaccharides of PR30R are a type II arabinogalactan, formed by a ß-D-Galp-(1 â†’ 3) main chain, substituted at O-6 by side chains of ß-D-Galp-(1 â†’ 6), which are substituted at O-3 by non-reducing α-L-Araf ends, and a homogalacturonan, formed by →4)-α-D-GalpA-(1→ units. Intraperitoneal administration of the crude polysaccharide fraction PRSF reduced significantly nociception induced by acetic acid in mice at the doses tested, and the PR30R fraction, derived from PRSF, presented antinociceptive and anti-inflammatory effects at a dose of 0.1096 mg/kg (PRSF ED50). These data support the use of the plant leaves in folk medicine as an herbal tea to treat pain and inflammation.

Polysaccharides from Passion Fruit Peels: From an Agroindustrial By-Product to a Viable Option for 5-FU-Induced Intestinal Damage.

Gastrointestinal mucositis is a serious and dose-limiting toxic side effect of oncologic treatment. Interruption of cancer treatment due to gastrointestinal mucositis leads to a significant decrease in cure rates and consequently to the deterioration of a patient's quality of life. Natural polysaccharides show a variety of beneficial effects, including a gastroprotective effect. Treatment with soluble dietary fiber (SDF) from yellow passion fruit (Passiflora edulis) biomass residues protected the gastric and intestinal mucosa in models of gastrointestinal injury. In this study, we investigated the protective therapeutic effect of SDF on 5-FU-induced mucositis in male and female mice. Oral treatment of the animals with SDF did not prevent weight loss but reduced the disease activity index and preserved normal intestinal function by alleviating diarrhea and altered gastrointestinal transit. SDF preserved the length of the colon and histological damage caused by 5-FU. SDF significantly restored the oxidative stress and inflammation in the intestine and the enlargement and swelling of the spleen induced by 5-FU. In conclusion, SDF may be a promising adjuvant strategy for the prevention and treatment of intestinal mucositis induced by 5-FU.

Rodent models for anticancer toxicity studies: Contributions to drug development and future perspectives.

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.

Polysaccharide Fraction from Campomanesia adamantium and Campomanesia pubescens Attenuates 5-Fluorouracil-Induced Intestinal Mucosal Inflammation in Mice.

Gastrointestinal toxicity, including diarrhea and inflammation, is commonly observed with the use of 5-fluorouracil (5-FU). Several studies have shown that polysaccharides are interesting bioactive macromolecules for the treatment or prevention of gastrointestinal diseases. Therefore, in this study, the effect of a polysaccharide fraction from a mixture of two Guavira species (Campomanesia adamantium and Campomanesia pubescens), referred to here as CPW, on the development of intestinal mucositis was investigated. Intestinal mucositis was induced by a single injection of 5-FU (450 mg/kg), and various doses of CPW (3-100 mg/kg) were tested. CPW attenuated disease development and prevented small bowel dysmotility and colon shortening. CPW prevented the increase in villi width, crypt depth, and mucosal thickness in the duodenum, but not in the colon. Preservation of mucus, reduction of oxidative stress, inflammation, and prevention of the 5-FU-induced enlargement and swelling of the spleen were observed. In conclusion, this study demonstrated for the first time that CPW alleviates the intestinal damage induced by 5-FU and could be used as an adjuvant strategy during chemotherapy.

In Silico and In Vitro Analysis of Sulforaphane Anti-Candida Activity.

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.

Protective Effect of Dietary Polysaccharides from Yellow Passion Fruit Peel on DSS-Induced Colitis in Mice.

Inflammatory bowel disease (IBD) is a complex inflammatory disorder characterized by chronic and spontaneously relapsing inflammation of the gastrointestinal tract. IBD includes two idiopathic disorders: Crohn's disease (CD) and ulcerative colitis (UC). In particular, UC causes inflammation and ulceration of the colon and rectum. There is no cure for UC. The pharmacological treatment is aimed at controlling and/or reducing the inflammatory process and promoting disease remission. The present study investigated the possible protective effects of soluble dietary fiber (SDF) isolated from yellow passion fruit peel in the dextran sulfate sodium- (DSS-) induced colitis model in mice, induced by 5% of DSS. The animals were treated with SDF (10, 30, or 100 mg/kg (po)), and the disease activity index was monitored. Colon tissues were collected, measured, and prepared for oxidative stress, inflammation, and histology analysis. SDF improved body weight loss, colon length, and disease activity index and prevented colonic oxidative stress by regulating GSH levels and SOD activity. Furthermore, SDF reduced colonic MPO activity, TNF-α, and IL-1ß levels and increased IL-10 and IL-6 levels. As observed by histological analysis, SDF treatment preserved the colonic tissue, the mucus barrier, and reduced inflammatory cell infiltration. Although this is a preliminary study, taken together, our data indicate that SDF may improve the course of DSS-UC. More studies are needed to explore and understand how SDF promotes this protection.

Local effects of natural alkylamides from Acmella oleracea and synthetic isobutylalkyl amide on neuropathic and postoperative pain models in mice.

Neuropathic and postoperative pain are clinical conditions that impair the patient's quality of life. The current pharmacotherapy of both painful states is ineffective and accompanied by several side effects. In order to develop new therapeutics targets, the secondary metabolites of plants have been extensively studied. Acmella oleracea ("jambu") is a native plant from the Amazon region and rich in alkylamides, bioactive compounds responsible for inducing anesthetic and chemesthetic sensations. We previously demonstrated that the intraplantar administration of an hexanic fraction (HF) rich in alkylamides from jambu and the synthetic isobutylalkyl amide (IBA) at 0.1 µg/20 µL can promote antinociceptive and anti-inflammatory effects. Thus, this study aimed to evaluate the local effect of HF and IBA (0.1 µg/20 µL) on neuropathic (partial sciatic nerve ligation, PSNL) and postoperative pain (plantar incision surgery, PIS) models in mice. Seven days after the PSNL, the mechanical (von Frey test) and cold (acetone-evoked evaporative cooling) allodynia, and digital gait parameters were analyzed. The intraplantar HF and IBA treatments attenuated the mechanical and cold allodynia as well as the static (max. Contact and print area) and dynamic (stand duration) parameters of digital gait analyses. On the day after PIS, the mechanical allodynia, heat hyperalgesia (hot plate, 52 ± 0.1°C), and spontaneous nociception scores were evaluated. Topical treatment with HF reduced the mechanical allodynia, heat hyperalgesia, and spontaneous nociception scores. In contrast, IBA treatment only partially reduced the mechanical allodynia. In summary, the local treatment with HF was effective on both neuropathic and postoperative pain, as opposed to IBA, which only had an effect on neuropathic pain.

Dietary polysaccharides from guavira pomace, a co-product from the fruit pulp industry, display therapeutic application in gut disorders.

Inflammatory bowel disease (IBD) includes two distinct diseases: Crohn's disease (CD) and ulcerative colitis (UC). IBD is a chronic systemic disease of the gastrointestinal tract, characterized by an inflammatory process. The mechanisms by which diseases develop are still unknown, but it is known that it results from a complex interaction between genetic variability, the host's immune system, and environmental factors. One of the main complaints of patients is abdominal pain, which may be associated with the release of inflammatory mediators, changes in the normal motility of the digestive tract, and increased intestinal permeability. Currently available drugs for abdominal pain are not satisfactory, therefore, it is extremely necessary to seek new therapeutic options for the treatment of abdominal pain. Polysaccharides extracted from fruits have attracted interest, as these molecules protect the intestinal mucosa and promote wound healing, attenuating inflammation, pain, and altered intestinal motility. In this study, we investigated the ability of pectic polysaccharides obtained from guavira pomace, named CPW to reduce visceral hypersensitivity, regulate intestinal motility, and control diarrhea in mice. Acetic acid, capsaicin, or mustard oil were used to assess visceral pain in normal mice. CPW reduced abdominal writhing, cell migration, and capsaicin-induced visceral nociception. Furthermore, it regulated intestinal motility and all measured parameters of castor oil-induced diarrhea. CPW treatment reversed the increase in mucosal permeability, TEER, and tissue weight caused by acetic acid. In addition, molecular docking analysis showed that specific the CPW units binds to the 3N8V, 5COX, 2J67 and 6RBF proteins. Thus, the results suggest that CPW has attractive therapeutic characteristics for the treatment of abdominal pain and ulcerative colitis.

An Overview of the TRP-Oxidative Stress Axis in Metabolic Syndrome: Insights for Novel Therapeutic Approaches.

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.

Beneficial Effects of Polysaccharides on the Epithelial Barrier Function in Intestinal Mucositis.

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.

Polysaccharides with Antitumor Effect in Breast Cancer: A Systematic Review of Non-Clinical Studies.

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 ß-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.

Effectiveness of the polyphenols-rich Sedum dendroideum infusion on gastric ulcer healing in rats: Roles of protective endogenous factors and antioxidant and anti-inflammatory mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Peptic ulcer is an inflammatory disease that therapeutic options are mainly focused in antisecretory drugs. Sedum dendroideum Moc & Sessé ex DC (Crassulaceae) is employed in folk medicine for the treatment of gastric ulcers. Recently, our group demonstrated that Sedum dendroideum infusion (SDI) is rich in polyphenols (flavonol glycosides, myricetin, quercetin and kaempferol) and promoted gastroprotection against acute ulcer models, without changes gastric acid secretion. AIM OF THE STUDY: Here, we follow the investigation of the healing effects of SDI (ED50 = 191 mg/kg) in the chronic gastric ulcer model induced by 80% acetic acid in rats, elucidating underlying mechanisms. MATERIAL AND METHODS: Rats were orally treated with vehicle (water, 1 mL/kg), SDI (191 mg/kg), omeprazole (40 mg/kg) or sucralfate (100 mg/kg) twice daily for 5 days after ulcer induction. Following treatments, toxicological effects, macroscopic ulcer appearance, microscopic histological (HE, mucin PAS-staining) and immunohistochemical (PCNA and HSP70) analysis, inflammatory (MPO and NAG activity, cytokine levels measurements) and antioxidant (SOD and CAT) parameters were investigated in gastric ulcer tissues. RESULTS: Oral treatment with SDI accelerated gastric ulcer healing, maintained mucin content and promoted epithelial cell proliferation. SDI also reduced neutrophil and mononuclear leukocyte infiltration, TNF-α and IL-1ß levels and the oxidative stress, restoring SOD and CAT activities in the ulcer tissue. CONCLUSIONS: The gastric healing effect of SDI was mediated through endogenous protective events as well as due to the anti-inflammatory and antioxidant actions. Our observations support and reinforce the traditional utilize of Sedum dendroideum as a natural nontoxic therapeutic alternative for the treatment of gastric ulcers.

Susceptibility to SARS-CoV-2 infection in patients undergoing chemotherapy and radiation therapy.

The outbreak of the new coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a public health emergency of international concern, especially affecting the elderly people and patients with chronic disease, such as hypertension and respiratory syndromes. Patients undergoing chemotherapy treatment (e.g., bleomycin, cyclophosphamide, methotrexate, monoclonal antibodies, and paclitaxel therapy) are vulnerable to the development of respiratory syndromes induced by chemotherapeutic agents and are also more susceptible to viral infections as they are immunosuppressed. Neutropenia is an important risk factor for increased vulnerability to infections, as a respiratory syndrome involves an array of immune cells maintaining the balance between pathogen clearance and immunopathology. However, the differential diagnosis of pulmonary symptoms in cancer patients is broad, with complications being related to the malignancy itself, treatment toxicity, and infections. The risk factors depend on the specific type of cancer, chemotherapy, patient characteristics, and comorbidities. Thus, this review discusses the main events implicated in immunosuppression caused by chemotherapy and radiation therapy and the association of immunosuppression and other factors with SARS-CoV-2 infection susceptibility in cancer patients; and, importantly, how to deal with this situation in face of the current pandemic scenario.