Genus Physalis L.: A review of resources and cultivation, chemical composition, pharmacological effects and applications.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Physalis L. (Solanaceae) is commonly used in the treatment of dermatitis, leprosy, bronchitis, pneumonia, hepatitis and rheumatism in China and other Asian countries. AIM OF THE REVIEW: This article reviews the resources, cultivation, phytochemistry, pharmacological properties, and applications of Physalis L., and proposes further research strategies to enhance its therapeutic potential in treating various human diseases. MATERIALS AND METHODS: We conducted a systematic search of electronic databases, including CNKI, SciFinder and PubMed, using the term "Physalis L." to collect information on the resources, phytochemistry, pharmacological activities, and applications of Physalis L. in China during the past ten years (2013.1-2023.1). RESULTS: So far, a variety of chemical constituents have been isolated and identified from Physalis L. mainly including steroids, flavonoids, and so on. Various pharmacological activities were evaluated by studying different extracts of Physalis L., these activities include anti-inflammatory, antibacterial, antioxidant, antiviral, antineoplastic, and other aspects. CONCLUSION: Physalis L. occupies an important position in the traditional medical system. It is cost-effective and is a significant plant with therapeutic applications in modern medicine. However, further in-depth studies are needed to determine the medical use of this plant resources and cultivation, chemical composition, pharmacological effects and applications.

The traditional utilization, biological activity and chemical composition of edible fern species.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferns form an important part of the human diet. Young fern fiddleheads are mostly consumed as vegetables, while the rhizomes are often extracted for starch. These edible ferns are also often employed in traditional medicine, where all parts of the plant are used, mostly to prepare extracts. These extracts are applied either externally as lotions and baths or internally as potions, decoctions and teas. Ailments traditionally treated with ferns include coughs, colds, fevers, pain, burns and wounds, asthma, rheumatism, diarrhoea, or skin diseases (eczema, rashes, itching, leprosy). AIM OF THE REVIEW: This review aims to compile the worldwide knowledge on the traditional medicinal uses of edible fern species correlating to reported biological activities and isolated bioactive compounds. MATERIALS AND METHODS: The articles and books published on edible fern species were searched through the online databases Web of Science, Pubmed and Google Scholar, with critical evaluation of the hits. The time period up to the end of 2022 was included. RESULTS: First, the edible fern species were identified based on the literature data. A total of 90 fern species were identified that are eaten around the world and are also used in traditional medicine. Ailments treated are often associated with inflammation or bacterial infection. However, only the most common and well-known fern species, were investigated for their biological activity. The most studied species are Blechnum orientale L., Cibotium barometz (L.) J. Sm., Diplazium esculentum (Retz.) Sw., Marsilea minuta L., Osmunda japonica Thunb., Polypodium vulgare L., and Stenochlaena palustris (Burm.) Bedd. Most of the fern extracts have been studied for their antioxidant, anti-inflammatory and antimicrobial activities. Not surprisingly, antioxidant capacity has been the most studied, with results reported for 28 edible fern species. Ferns have been found to be very rich sources of flavonoids, polyphenols, polyunsaturated fatty acids, carotenoids, terpenoids and steroids and most of these compounds are remarkable free radical scavengers responsible for the outstanding antioxidant capacity of fern extracts. As far as clinical trials are concerned, extracts from only three edible fern species have been evaluated. CONCLUSIONS: The extracts of edible fern species exert antioxidant anti-inflammatory and related biological activities, which is consistent with their traditional medicinal use in the treatment of wounds, burns, colds, coughs, skin diseases and intestinal diseases. However, studies to prove pharmacological activities are scarce, and require chemical-biological standardization. Furthermore, correct botanical classification needs to be included in publications to simplify data acquisition. Finally, more in-depth phytochemical studies, allowing the linking of traditional use to pharmacological relevance are needed to be done in a standardized way.

Anti-Inflammatory, Barrier Maintenance, and Gut Microbiome Modulation Effects of Saccharomyces cerevisiae QHNLD8L1 on DSS-Induced Ulcerative Colitis in Mice.

The use of probiotics has been considered as a new therapy option for ulcerative colitis (UC), and yeast has recently received widespread recommendation for human health. In this study, the probiotic characteristics of four yeast strains, Saccharomyces boulardii CNCMI-745, Kluyveromyces marxianus QHBYC4L2, Saccharomyces cerevisiae QHNLD8L1, and Debaryomyces hansenii QSCLS6L3, were evaluated in vitro; their ability to ameliorate dextran sulfate sodium (DSS)-induced colitis was investigated. Among these, S. cerevisiae QHNLD8L1 protected against colitis, which was reflected by increased body weight, colon length, histological injury relief, decreased gut inflammation markers, and intestinal barrier restoration. The abundance of the pathogenic bacteria Escherichia-Shigella and Enterococcaceae in mice with colitis decreased after S. cerevisiae QHNLD8L1 treatment. Moreover, S. cerevisiae QHNLD8L1 enriched beneficial bacteria Lactobacillus, Faecalibaculum, and Butyricimonas, enhanced carbon metabolism and fatty acid biosynthesis function, and increased short chain fatty acid (SCFAs) production. Taken together, our results indicate the great potential of S. cerevisiae QHNLD8L1 supplementation for the prevention and alleviation of UC.

Phytochemical analysis, anti-inflammatory, antioxidant activity of Calotropis gigantea and its therapeutic applications.

ETHNOPHARMACOLOGICAL RELEVANCE: Herbal remedies can be used to treat a variety of chronic inflammatory illnesses, like rheumatoid arthritis and leprosy. The plant Calotropis gigantea (C. gigantea) belongs to the family Apocynaceae. To treat numerous contagious diseases, C. gigantea is utilized alone or combine with certain medicinal herbs. Traditional Asian and African practitioners employed C. gigantea to treat a variety of inflammatory conditions like boils, rheumatoid arthritis, gout, leprosy and other disorders. AIM OF THE STUDY: The goal of this study is to examine the anti-inflammatory and antioxidant activities of C. gigantea leaf extracts extracted using methanol, petroleum ether, and water. MATERIALS AND METHODS: The leaf extracts of C. gigantea were obtained using the Soxhlet extraction technique. The phytoconstituents present in all three C. gigantea leaf extracts were confirmed by qualitative analysis, and the amounts of the alkaloids, flavonoids, terpenoids and phenols found in the extracts were quantified. C. gigantea crude extracts were subjected to a nitric oxide scavenging experiment to assess their free radical scavenging activities. Protein denaturation and proteinase inhibition assays were used to investigate the effectiveness of extracts to restrict denaturation of protein and to inhibit key enzymes responsible for tissue damage. Further, the membrane stabilization efficacy of plant extracts were examined by the heat-induced hemolysis method. The DPPH and FRAP experiments were performed to determine the antioxidant effectiveness of phytoconstituents extracted using different solvents. The GC-MS study of plant C. gigantea methanolic, aqueous and petroleum ether extracts displayed a broad range of compounds that possess beneficial therapeutic effects. RESULTS: This study reveals that the methanolic extract of C. gigantea provides significantly more anti-inflammatory and antioxidant activity than other extracts. CONCLUSION: Compared to the aqueous and petroleum ether extracts, the methanolic leaf extract of C. gigantea demonstrated greater in vitro anti-inflammatory and antioxidant properties.

A comprehensive insight into the anti-inflammatory properties of dapsone.

The 4,4'-diaminodiphenyl sulfone (DDS), also known as dapsone, is traditionally used as a potent anti-bacterial agent in clinical management of leprosy. For decades, dapsone has been among the first-line medications used in multidrug treatment of leprosy recommended by the World Health Organization (WHO). Shortly after dapsone's discovery as an antibiotic in 1937, the dual function of dapsone (anti-microbial and anti-inflammatory) was elucidated. Dapsone exerts its anti-bacterial effects by inhibiting dihydrofolic acid synthesis, leading to inhibition of bacterial growth, while its anti-inflammatory properties are triggered by inhibiting reactive oxygen species (ROS) production, reducing the effect of eosinophil peroxidase on mast cells and downregulating neutrophil-mediated inflammatory responses. Among the leading mechanisms associated with its anti-microbial/anti-protozoal effects, dapsone clearly has multiple antioxidant, anti-inflammatory, and anti-apoptotic functions. In this regard, it has been described in treating a wide variety of inflammatory and infectious skin conditions. Previous reports have explored different molecular targets for dapsone and provided insight into the anti-inflammatory mechanism of dapsone. This article reviews several basic, experimental, and clinical approaches on anti-inflammatory effect of dapsone.

Pharmacological potential of the triterpene 3ß,6ß,16ß-trihidroxilup-20 (29)-ene isolated from Combretum leprosum: A literature review.

Globally, plant-derived medicines have been playing an increasing and relevant role in the treatment of several diseases, thus fostering the search for new bioactive substances. Among the various families of plants studied, those of the Combretum genus can be highlighted since they are widely used in folk medicine for the treatment of hepatitis, malaria, respiratory infections, cancer, skin hemorrhage, and anxiety. Phytochemical studies carried out on species of the Combretum genus demonstrated the presence of several classes of bioactive chemical compounds, including the triterpene 3ß,6ß,16ß-trihydroxilup-20(29)-ene (CLF-1). In this perspective, the objective of this review was to gather all pharmacological activities attributed to the CLF-1 triterpene, highlighting its importance for the pharmaceutical industry. The research was performed in scientific databases such as PubMed, SciELO, LILACS, SciFinder and Science Direct. The literature indicates a great pharmacological potential of CLF-1, evidencing its antioxidant, anti-inflammatory, antiviral, antiparasitic, antinociceptive, healing, and antibacterial action, antinociceptive and antitumor effect. Therefore, based on the different research above, it is plausible to consider CLF-1, obtained from different parts of the C. leprosum plant, as a molecule with biotechnological potential that may contribute to the development of new drugs and, consequently, in the treatment of various human pathologies.

Humulus japonicus rescues autistic­like behaviours in the BTBR T+ Itpr3tf/J mouse model of autism.

Humulus japonicus (HJ) is a traditional herbal medicine that exhibits anti­inflammatory, antimicrobial and anti­tumor effects that is used for the treatment of hypertension, pulmonary disease and leprosy. Recently, it has also been reported that HJ demonstrates neuroprotective properties in animal models of neurodegenerative diseases. The current study hypothesised that the administration of HJ would exhibit therapeutic effects in autism spectrum disorder (ASD), a neurodevelopmental disorder with lifelong consequences. The BTBR T+ Itpr3tf/J mouse model of ASD was used to investigate the anti­autistic like behavioural effects of HJ. Chronic oral administration of the ethanolic extract of HJ significantly increased social interaction, attenuated repetitive grooming behaviour and improved novel­object recognition in BTBR mice. Anti­inflammatory effects of HJ in the brain were analysed using immunohistochemistry and reverse­transcription quantitative PCR analysis. Microglia activation was markedly decreased in the striatum and hippocampus, and pro­inflammatory cytokines, including C­C Motif Chemokine Ligand 2, interleukin (IL)­1ß and IL­6, were significantly reduced in the hippocampus following HJ treatment. Moreover, HJ treatment normalised the phosphorylation levels of: N­methyl­D­aspartate receptor subtype 2B and calcium/calmodulin­dependent protein kinase type II subunit α in the hippocampus of BTBR mice. The results of the present study demonstrated that the administration of HJ may have beneficial potential for ameliorating behavioural deficits and neuroinflammation in ASD.

Ethnopharmacology, Biological Activity and Phytochemistry of Scaevola spinescens.

Scaevola spinescens is endemic to Australia and has traditionally been used by Aboriginal and Torres Strait Islander communities to treat a variety of conditions including colds, flu, fever, stomach pain, urinary disorders, sores, tinea, leprosy, and cancer. Extracts prepared from S. spinescens are non-toxic and have been linked with various medicinal properties including antiviral, antibacterial, anti-inflammatory, and anticancer activities. These studies support the ethnopharmacological use of S. spinescens by Indigenous peoples of Australia and highlight the need for further investigations on the plant for potential use in pharmaceutical and food applications. This review provides a comprehensive, up-to-date review of the literature on S. spinescens focusing on the traditional use, medicinal properties, phytochemicals, and factors that affect their composition during pre-treatment and extraction, as well as providing a framework for future studies of the plant.

Clofazimine broadly inhibits coronaviruses including SARS-CoV-2.

The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.

Update on the use of dapsone in dermatology.

Dapsone (4,4'-diaminodiphenylsulfone) is the only remaining sulfone used in anthropoid therapeutics and is commercially available as an oral formulation, an inhaled preparation, and a 5% or 7.5% cream. Dapsone has antimicrobial effects stemming from its sulfonamide-like ability to inhibit the synthesis of dihydrofolic acid. It also has anti-inflammatory properties such as inhibiting the production of reactive oxygen species, reducing the effect of eosinophil peroxidase on mast cells and down-regulating neutrophil-mediated inflammatory responses. This allows for its use in the treatment of a wide variety of inflammatory and infectious skin conditions. Currently in dermatology, the US Food and Drug Administration (FDA)-approved indications for dapsone are leprosy, dermatitis herpetiformis, and acne vulgaris. However, it proved itself as an adjunctive therapeutic agent to many other skin disorders. In this review, we discuss existing evidence on the mechanisms of action of dapsone, its FDA-approved indications, off-label uses, and side effects.

Cardioprotective effects of dapsone against doxorubicin-induced cardiotoxicity in rats.

PURPOSE: It has been supposed that cardiac toxicity of doxorubicin is due to its production of free radicals and inflammatory cytokines. Dapsone, an antibiotic drug which is the principal in a multidrug regimen for the treatment of leprosy, is a sulfone with anti-inflammatory and antioxidant immunosuppressive properties. Therefore, we designed this study to investigate the possible effects of dapsone on doxorubicin-induced cardiotoxicity. METHODS: Male rats were administrated doxorubicin (2.5 mg/kg) and dapsone (1, 3, 10 mg/kg) intraperitoneally six times in 2 weeks. Then electrocardiographic (ECG) parameters (QRS complexes, RR and QT intervals) alternation, papillary muscle contraction and excitation, and histopathological changes were assessed. Also, the heart tissue levels of malondialdehyde (MDA) as oxidant factor and superoxide dismutase (SOD) as antioxidant enzyme, tumor necrosis factor-alpha (TNF-α) and serum level of CK-MB were analyzed. RESULTS: Administration of dapsone with doxorubicin significantly reversed alterations induced by doxorubicin in serum levels of CK-MB, ECG parameters, papillary muscle contractility and excitation. Furthermore, the measurement of MDA, SOD and TNF-α tissue level indicated that dapsone significantly reduced oxidative stress and inflammation. These findings were consistent with histopathological analysis. CONCLUSION: Dapsone exerts cardioprotective effects on doxorubicin-induced cardiotoxicity through its anti-inflammatory and antioxidant mechanism.

A Brighter Side to Thalidomide: Its Potential Use in Immunological Disorders.

Thalidomide and its derivatives are immunomodulatory drugs (IMiDs) known for their sedative, teratogenic, anti-angiogenic, and anti-inflammatory properties. Commonly used in the treatment of cancers such as multiple myeloma and myelodysplastic syndrome (MDS), IMiDs have also been used in the treatment of an inflammatory skin pathology associated with Hansen's disease/leprosy. They have also shown promise in the treatment of autoimmune disorders including systemic lupus erythmatosus (SLE) and inflammatory bowel disease (IBD). Recent structural and experimental observations have revolutionized our understanding of these properties by revealing the fundamental molecular events underpinning IMiD activity. We review these findings, their relevance to IMiD therapy in immunological disorders, and discuss how further research might unlock the vast clinical potential of these compounds.

Anti-proliferative and anti-inflammatory effects of 3ß,6ß,16ß-Trihydroxylup-20(29)-ene on cutaneous inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: 3ß,6ß,16ß-Trihydroxylup-20(29)-ene (TTHL) is a triterpene isolated from the flowers of Combretum leprosum, a plant used in folk medicine in the north of Brazil for the treatment of skin disorders. AIM OF THE STUDY: In the present study, TTHL was evaluated as a potential topical anti-inflammatory and anti-proliferative agent through in vivo and in vitro models. MATERIAL AND METHODS: Anti-inflammmatory and anti-proliferative effects of TTHL were assessed using Swiss mice in acute and chronic models of skin inflammation induced by 12-O-tetradecanoylphorbol-acetate (TPA) application. Anti-proliferative activity was proved through in vitro experiments with the HaCaT human keratinocyte cell line. RESULTS: Treatment with TTHL inhibited inflammatory parameters such as oedema formation and cellular infiltration in acute and chronic models. In the chronic model, TTHL also inhibited epidermal hyperproliferation, as evidenced by reduction of epidermis thickness and proliferating cell nuclear antigen expression. The anti-proliferative effect was confirmed by the capability of TTHL in reducing the proliferation and inducing cell apoptosis of HaCaT cells. Suggesting a mechanism of action, TTHL showed activation of corticosteroid receptors, but without the induction of corticosteroid-related cutaneous side effects. CONCLUSION: Our results demonstrate consistent anti-inflammatory and anti-proliferative activity and assign TTHL as a valuable tool in the development of a new treatment for skin inflammatory and proliferative diseases, such as psoriasis.

In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems.

Thalidomide, a drug known for its teratogenic side-effects, is used successfully to treat a variety of clinical conditions including leprosy and multiple myeloma. Intense efforts are underway to synthesize and identify safer, clinically relevant analogs. Here, we conduct a preliminary in vivo screen of a library of new thalidomide analogs to determine which agents demonstrate activity, and describe a cohort of compounds with anti-angiogenic properties, anti-inflammatory properties and some compounds which exhibited both. The combination of the in vivo zebrafish and chicken embryo model systems allows for the accelerated discovery of new, potential therapies for cancerous and inflammatory conditions.

Clofazimine Biocrystal Accumulation in Macrophages Upregulates Interleukin 1 Receptor Antagonist Production To Induce a Systemic Anti-Inflammatory State.

Clofazimine (CFZ) is a poorly soluble antibiotic and anti-inflammatory drug indicated for the treatment of leprosy. In spite of its therapeutic value, CFZ therapy is accompanied by the formation of drug biocrystals that accumulate within resident tissue macrophages, without obvious toxicological manifestations. Therefore, to specifically elucidate the off-target consequences of drug bioaccumulation in macrophages, we compared the level of inflammasome activation in CFZ-accumulating organs (spleen, liver and lung) in mice after 2 and 8 weeks of CFZ treatment when the drug exists in soluble and insoluble (biocrystalline) forms, respectively. Surprisingly, the results showed a drastic reduction in caspase 1 and interleukin-1ß (IL-1ß) cleavage in the livers of mice treated with CFZ for 8 weeks (8-week-CFZ-treated mice) compared to 2-week-CFZ-treated and control mice, which was accompanied by a 3-fold increase in hepatic IL-1 receptor antagonist (IL-1RA) production and a 21-fold increase in serum IL-1RA levels. In the lung and spleen, IL-1ß cleavage and tumor necrosis factor alpha expression were unaffected by soluble or biocrystal CFZ forms. Functionally, there was a drastic reduction of carrageenan- and lipopolysaccharide-induced inflammation in the footpads and lungs, respectively, of 8-week-CFZ-treated mice. This immunomodulatory activity of CFZ biocrystal accumulation was attributable to the upregulation of IL-1RA, since CFZ accumulation had minimal effect in IL-1RA knockout mice or 2-week-CFZ-treated mice. In conclusion, CFZ accumulation and biocrystal formation in resident tissue macrophages profoundly altered the host's immune system and prompted an IL-1RA-dependent, systemic anti-inflammatory response.

Methylprednisolone sodium succinate reduces spinal cord swelling but does not affect recovery of dogs with surgically treated thoracolumbar intervertebral disk herniation.

The effect of methylprednisolone sodium succinate (MPSS) therapy was studied in 50 dogs with surgically treated Hansen type I thoracolumbar intervertebral disk herniation (TL-IVDH). Administration of MPSS significantly reduced the swelling of the spinal cord. The sensitivity of localization of disk extrusion using myelography in the MPSS group was 92.3%, and in the non-administration group was 83.3%. No significant difference in recovery rate or length of recovery time was found between the two groups. Administration of MPSS reduced spinal cord swelling, but has no effect on recovery in dogs after surgery for TL-IVDH.

Anti-inflammatory sesquiterpenes from Costus speciosus rhizomes.

ETHNOPHARMACOLOGICAL RELEVANCE: Costus speciosus (Koen ex. Retz.) Sm. (crepe ginger, family Costaceae) is an ornamental plant used in traditional medicine for the treatment of inflammation, rheumatism, bronchitis, fever, headache, asthma, flatulence, constipation, helminthiasis, leprosy, skin diseases, hiccough, anemia, as well as burning sensation on urination. AIM OF THE STUDY: The present study is designed to isolate and identify the active compounds from C. speciosus rhizomes and measure their anti-inflammatory activities. MATERIALS AND METHODS: The n-hexane-CHCl3 soluble fraction of the MeOH extract of C. speciosus rhizomes has been subjected to a repeated column chromatography, including normal silica gel and RP-18 column to give eight compounds. The structures of these compounds were established by UV, IR, 1D ((1)H and (13)C), and 2D ((1)H-(1)H COSY, NOESY, HSQC, and HMBC) NMR experiments and HRESIMS data. In addition, the anti-inflammatory activity of compounds 1-8 was evaluated by measuring the levels IL-6, IL-1ß, TNF-α, COX-2, lipoxgenase-5, and PGE2 using enzyme-linked immunosorbent assay. RESULTS: The n-hexane-CHCl3 soluble fraction afforded a new eudesmane acid, specioic acid (8), along with seven known compounds, 22,23-dihydrospinasterone (1), dehydrodihydrocostus lactone (mokko lactone) (2), dehydrocostus lactone (3), stigmasterol (4), arbusculin A (5), santamarine (douglanin) (6), and reynosin (7). Compounds 1, 4, and 5-7 were isolated for the first time C. speciosus. Compounds 1-4 displayed potent anti-inflammatory activity, while 7 and 8 showed moderate activity. Compounds 1-8 exhibited a concentration-related decrease in the levels of IL-1ß, IL-6, TNF-α, PGE2, lipoxgenase-5, and COX-2. Compounds 5 and 6 did not significantly decrease levels of different cytokines, PGE2, lipoxgenase-5, and COX-2 from PHA treatment at 1 µM. However, all tested compounds significantly decreased cytokines, PGE2, lipoxgenase-5, and COX-2 levels at concentration 100 µM. It is noteworthy that compounds 1-4 had the highest activity, where it lowered levels of cytokines, PGE2, lipoxgenase-5, and COX-2 to the extent that was no statistical difference from the control group. Thus, they decreased proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) with decreased level of the target enzymes (COX-2 and lipoxgenase-5) and subsequent reduction of its inflammatory product (PGE2). CONCLUSION: Good anti-inflammatory activities exhibited of the isolated compounds from C. speciosus corroborate the usefulness of this plant in the traditional treatment of inflammation and related symptoms.

The effect of 3ß, 6ß, 16ß-trihydroxylup-20(29)-ene lupane compound isolated from Combretum leprosum Mart. on peripheral blood mononuclear cells.

BACKGROUND: The Combretum leprosum Mart. plant, popularly known as mofumbo, is used in folk medicine for inflammation, pain and treatment of wounds. From this species, it is possible to isolate three triterpenes: (3ß, 6ß, 16ß-trihydroxylup-20(29)-ene) called lupane, arjunolic acid and molic acid. In this study, through preclinical tests, the effect of lupane was evaluated on the cytotoxicity and on the ability to activate cellular function by the production of TNF-α, an inflammatory cytokine, and IL-10, an immuno regulatory cytokine was assessed. The effect of lupane on the enzymes topoisomerase I and II was also evaluated. METHODS: For this reason, peripheral blood mononuclear cells (PBMCs) were obtained and cytotoxicity was assessed by the MTT method at three different times (1, 15 and 24 h), and different concentrations of lupane (0.3, 0.7, 1.5, 6, 3 and 12 µg/mL). The cell function was assessed by the production of TNF-α and IL-10 by PBMCs quantified by specific enzyme immunoassay (ELISA). The activity of topoisomerases was assayed by in vitro biological assays and in silico molecular docking. RESULTS: The results obtained showed that lupane at concentrations below 1.5 µg/mL was not toxic to the cells. Moreover, lupane was not able to activate cellular functions and did not alter the production of IL-10 and TNF-α. Furthermore, the data showed that lupane has neither interfered in the action of topoisomerase I nor in the action of topoisomerase II. CONCLUSION: Based on preclinical results obtained in this study, we highlight that the compound studied (lupane) has moderate cytotoxicity, does not induce the production of TNF-α and IL-10, and does not act on human topoisomerases. Based on the results of this study and taking into consideration the reports about the anti-inflammatory and leishmanicidal activity of 3ß, 6ß, 16ß-trihydroxylup-20(29)-ene, we suggest that this compound may serve as a biotechnological tool for the treatment of leishmaniasis in the future.

Novel insight into drug repositioning: Methylthiouracil as a case in point.

Drug repositioning refers to the development of existing drugs for new indications. These drugs may have (I) failed to show efficacy in late stage clinical trials without safety issues; (II) stalled in the development for commercial reasons; (III) passed the point of patent expiry; or (IV) are being explored in new geographic markets. Over the past decade, pressure on the pharmaceutical industry caused by the 'innovation gap' owing to rising development costs and stagnant product output have become major reasons for the growing interest in drug repositioning. Companies that offer a variety of broad platforms for identifying new indications have emerged; some have been successful in building their own pipelines of candidates with reduced risks and timelines associated with further clinical development. The business models and platforms offered by these companies will be validated if they are able to generate positive proof-of-concept clinical data for their repositioned compounds. This review describes the strategy of biomarker-guided repositioning of chemotherapeutic drugs for inflammation therapy, considering the repositioning of methylthiouracil (MTU), an antithyroid drug, as a potential anti-inflammatory reagent.

Phagocytosed Clofazimine Biocrystals Can Modulate Innate Immune Signaling by Inhibiting TNFα and Boosting IL-1RA Secretion.

Clofazimine (CFZ) is an FDA-approved leprostatic and anti-inflammatory drug that massively accumulates in macrophages, forming insoluble, intracellular crystal-like drug inclusions (CLDIs) during long-term oral dosing. Interestingly, when added to cells in vitro, soluble CFZ is cytotoxic because it depolarizes mitochondria and induces apoptosis. Accordingly, we hypothesized that, in vivo, macrophages detoxify CFZ by sequestering it in CLDIs. To test this hypothesis, CLDIs of CFZ-treated mice were biochemically isolated and then incubated with macrophages in vitro. The cell biological effects of phagocytosed CLDIs were compared to those of soluble CFZ. Unlike soluble CFZ, phagocytosis of CLDIs did not lead to mitochondrial destabilization or apoptosis. Rather, CLDIs altered immune signaling response pathways downstream of Toll-like receptor (TLR) ligation, leading to enhanced interleukin-1 receptor antagonist (IL-1RA) production, dampened NF-κB activation and tissue necrosis factor alpha (TNFα) production, and ultimately decreased TLR expression levels. In aggregate, our results constitute evidence that macrophages detoxify soluble CFZ by sequestering it in a biocompatible, insoluble form. The altered cellular response to TLR ligation suggests that CLDI formation may also underlie CFZ's anti-inflammatory activity.