Alkaloids are nitrogenous compounds with various biological activities. Alkaloids with anti-inflammatory activity are commonly found in terrestrial plants, but there are few records of the identification and characterization of the activity of these compounds in marine organisms such as fungi, bacteria, sponges, ascidians, and cnidarians. Seaweed are a source of several already elucidated bioactive compounds, but few studies have described and characterized the activity of seaweed alkaloids with anti-inflammatory properties. In this review, we have gathered the current knowledge about marine alkaloids with anti-inflammatory activity and suggest future perspectives for the study and bioprospecting of these compounds.

Caulerpin (CLP), an alkaloid from algae of the genus Caulerpa, has shown anti-inflammatory activity. Therefore, this study aimed to analyze the effect of CLP in the murine model of peritonitis and ulcerative colitis. Firstly, the mice were submitted to peritonitis to evaluate which dose of CLP (40, 4, or 0.4 mg/kg) could decrease the inflammatory infiltration in the peritoneum. The most effective doses were 40 and 4 mg/kg. Then, C57BL/6 mice were submitted to colitis development with 3% dextran sulfate sodium (DSS) and treated with CLP at doses of 40 and 4 mg/kg. The disease development was analyzed through the disease activity index (DAI); furthermore, colonic tissue samples were submitted to histological analysis, NFκB determination, and in vitro culture for cytokines assay. Therefore, CLP at 4 mg/kg presented the best results, triggering improvement of DAI and attenuating the colon shortening and damage. This dose was able to reduce the TNF-α, IFN-γ, IL-6, IL-17, and NFκB p65 levels, and increased the levels of IL-10 in the colon tissue. Thus, CLP mice treatment at a dose of 4 mg/kg showed promising results in ameliorating the damage observed in the ulcerative colitis.

The regulation of the inflammatory response is essential to maintaining homeostasis. Several studies have investigated new drugs that may contribute to avoiding or minimizing excessive inflammatory process. The aim of this study was to evaluate the effect of extracts of green algae Caulerpa mexicana on models inflammation. In mice, the inflammatory peritonitis model is induced by zymosan. Previous treatment of mice with aqueous and methanolic extracts of C. mexicana was able to suppress the cell migration to the peritoneal cavity, in a time-dependent but not in a dose-dependent manner. The treatment of mice with C. mexicana extracts also decreased the xylene-induced ear edema, exerting strong inhibitory leukocyte migration elicited by zymosan into the air pouch. We concluded that administration of the extracts resulted in a reduction of cell migration to different sites as well as a decrease in edema formation induced by chemical irritants. This study demonstrates for the first time the anti-inflammatory effect of aqueous and methanolic extracts from the green marine algae Caulerpa mexicana.

Exploring therapeutic options is crucial in the ongoing COVID-19 pandemic caused by SARS-CoV-2. Nirmatrelvir, which is a potent inhibitor that targets the SARS-CoV-2 M^pro, shows promise as an antiviral treatment. Additionally, Ivermectin, which is a broad-spectrum antiparasitic drug, has demonstrated effectiveness against the virus in laboratory settings. However, its clinical implications are still debated. Using computational methods, such as molecular docking and 100 ns molecular dynamics simulations, we investigated how Nirmatrelvir and Ivermectin interacted with SARS-CoV-2 M^pro(A). Calculations using density functional theory were instrumental in elucidating the behavior of isolated molecules, primarily by analyzing the frontier molecular orbitals. Our analysis revealed distinct binding patterns: Nirmatrelvir formed strong interactions with amino acids, like MET49, MET165, HIS41, HIS163, HIS164, PHE140, CYS145, GLU166, and ASN142, showing stable binding, with a root-mean-square deviation (RMSD) of around 2.0 Å. On the other hand, Ivermectin interacted with THR237, THR239, LEU271, LEU272, and LEU287, displaying an RMSD of 1.87 Å, indicating enduring interactions. Both ligands stabilized M^pro(A), with Ivermectin showing stability and persistent interactions despite forming fewer hydrogen bonds. These findings offer detailed insights into how Nirmatrelvir and Ivermectin bind to the SARS-CoV-2 main protease, providing valuable information for potential therapeutic strategies against COVID-19.

Digestive and cardiodigestive forms of Chagas’ disease are observed in 2% to 27% of the patients, depending on their geographic location, Trypanosoma cruzi strain and immunopathological responses. The aim of this work was to evaluate the role of NOD2 innate immune receptor in the pathogenesis of the digestive system in Chagas’ disease. Patients with digestive form of the disease showed lower mRNA expression of NOD2, higher expression of RIP2 and α-defensin 6, compared to indeterminate form, detected by Real-time PCR in peripheral blood mononuclear cells. In addition, there was a negative correlation between the expression of NOD2 and the degree of dilation of the esophagus, sigmoid and rectum in those patients. The infection of NOD2^-/- mice with T. cruzi strain isolated from the digestive patient induced a decrease in intestinal motility. Histopathological analysis of the colon and jejunum of NOD2^-/- and wild type C57BL/6 animals revealed discrete inflammatory foci during the acute phase of infection. Interestingly, during the chronic phase of the infection there was inflammation and hypertrophy of the longitudinal and circular muscular layer more pronounced in the colon and jejunum from NOD2^-/- animals, when compared to wild type C57BL/6 mice. Together, our results suggest that NOD2 plays a protective role against the development of digestive form of Chagas’ disease. Chagas disease is caused by the protozoan Trypanosoma cruzi, during the chronic phase of infection 2–27% of patients develop digestive form of the disease (megaesophagus and megacolon) that contributes to patient morbidity and mortality, generating costs for public health services, and especially affecting significantly the life quality of the patients. Although is known that many factors inherent of the parasite (tropism, genetics, virulence and antigenicity), host (age, gender, nutritional status, genetics and immune response) and geographical distribution may influence the development of the different clinical forms of Chagas disease, the exact mechanism that leads to megacolon and megaesophagus development are unknown. Here we showed that patients with digestive form of Chagas’ disease do not express the innate immune receptor NOD2. By isolating a parasite from a digestive patient and infecting NOD2-deficient mice we observed a reduced intestinal motility, chronic development of colon and jejunum wall thickness associated with increased inflammatory mediators in the organ, when compared to wild type animals. Our results indicate that the NOD2 receptor protects against the development of the digestive form of Chagas disease and could be used as a biomarker for the development of gastrointestinal changes during T. cruzi infection in patients.

Fucans from marine algae have been the object of many studies that demonstrated a broad spectrum of biological activities, including anti-inflammatory effects. The aim of this study was to verify the protective effects of a fucan extracted from the brown algae Spatoglossum schröederi in animals submitted to a generalized inflammation model induced by zymosan (ZIGI). BALB/c mice were first submitted to zymosan-induced peritonitis to evaluate the treatment dose capable of inhibiting the induced cellular migration in a simple model of inflammation. Mice were treated by the intravenous route with three doses (20, 10, and 5 mg/kg) of our fucan and, 1 h later, were inoculated with an intraperitoneal dose of zymosan (40 mg/kg). Peritoneal exudate was collected 24 h later for the evaluation of leukocyte migration. Doses of the fucan of Spatoglossum schröederi at 20 and 10 mg/kg reduced peritoneal cellular migration and were selected to perform ZIGI experiments. In the ZIGI model, treatment was administered 1 h before and 6 h after the zymosan inoculation (500 mg/kg). Treatments and challenges were administered via intravenous and intraperitoneal routes, respectively. Systemic toxicity was assessed 6 h after inoculation, based on three clinical signs (bristly hair, prostration, and diarrhea). The peritoneal exudate was collected to assess cellular migration and IL-6 levels, while blood samples were collected to determine IL-6, ALT, and AST levels. Liver tissue was collected for histopathological analysis. In another experimental series, weight loss was evaluated for 15 days after zymosan inoculation and fucan treatment. The fucan treatment did not present any effect on ZIGI systemic toxicity; however, a fucan dose of 20 mg/kg was capable of reducing the weight loss in treated mice. The treatment with both doses also reduced the cellular migration and reduced IL-6 levels in peritoneal exudate and serum in doses of 20 and 10 mg/kg, respectively. They also presented a protective effect in the liver, with a reduction in hepatic transaminase levels in both doses of treatment and attenuated histological damage in the liver at a dose of 10 mg/kg. Fucan from S. schröederi presented a promising pharmacological activity upon the murine model of ZIGI, with potential anti-inflammatory and hepatic protective effects, and should be the target of profound and elucidative studies.