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.

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.

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.

Regulatory T cells in erythema nodosum leprosum maintain anti-inflammatory function.

BACKGROUND: The numbers of circulating regulatory T cells (Tregs) are increased in lepromatous leprosy (LL) but reduced in erythema nodosum leprosum (ENL), the inflammatory complication of LL. It is unclear whether the suppressive function of Tregs is intact in both these conditions. METHODS: A longitudinal study recruited participants at ALERT Hospital, Ethiopia. Peripheral blood samples were obtained before and after 24 weeks of prednisolone treatment for ENL and multidrug therapy (MDT) for participants with LL. We evaluated the suppressive function of Tregs in the peripheral blood mononuclear cells (PBMCs) of participants with LL and ENL by analysis of TNFα, IFNγ and IL-10 responses to Mycobacterium leprae (M. leprae) stimulation before and after depletion of CD25+ cells. RESULTS: 30 LL participants with ENL and 30 LL participants without ENL were recruited. The depletion of CD25+ cells from PBMCs was associated with enhanced TNFα and IFNγ responses to M. leprae stimulation before and after 24 weeks treatment of LL with MDT and of ENL with prednisolone. The addition of autologous CD25+ cells to CD25+ depleted PBMCs abolished these responses. In both non-reactional LL and ENL groups mitogen (PHA)-induced TNFα and IFNγ responses were not affected by depletion of CD25+ cells either before or after treatment. Depleting CD25+ cells did not affect the IL-10 response to M. leprae before and after 24 weeks of MDT in participants with LL. However, depletion of CD25+ cells was associated with an enhanced IL-10 response on stimulation with M. leprae in untreated participants with ENL and reduced IL-10 responses in treated individuals with ENL. The enhanced IL-10 in untreated ENL and the reduced IL-10 response in prednisolone treated individuals with ENL was abolished by addition of autologous CD25+ cells. CONCLUSION: The findings support the hypothesis that the impaired cell-mediated immune response in individuals with LL is M. leprae antigen specific and the unresponsiveness can be reversed by depleting CD25+ cells. Our results suggest that the suppressive function of Tregs in ENL is intact despite ENL being associated with reduced numbers of Tregs. The lack of difference in IL-10 response in control PBMCs and CD25+ depleted PBMCs in individuals with LL and the increased IL-10 response following the depletion of CD25+ cells in individuals with untreated ENL suggest that the mechanism of immune regulation by Tregs in leprosy appears independent of IL-10 or that other cells may be responsible for IL-10 production in leprosy. The present findings highlight mechanisms of T cell regulation in LL and ENL and provide insights into the control of peripheral immune tolerance, identifying Tregs as a potential therapeutic target.

Leprosy as a Diagnostic Challenge in the United States.

A 63-year-old woman from Central Florida presented to an outside clinic with a 2-year history of a progressive, asymptomatic cutaneous eruption and arthralgias. Her past medical history was significant for reported seronegative rheumatoid arthritis, for which adalimumab, methotrexate, and low-dose prednisone therapy were initiated 5 years prior. The skin eruption occurred shortly after a 4-week hospitalization during which these medications were withheld. At her initial outside evaluation, a biopsy was performed and interpreted as subacute cutaneous lupus erythematosus (SCLE). She was treated with hydroxychloroquine without improvement. A repeat biopsy was reported as consistent with interstitial granulomatous dermatitis (IGD). There was no improvement with potent topical corticosteroids.

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.

Concomitant psoriasis and hidradenitis suppurativa responsive to adalimumab therapy: A case series.

Psoriasis and hidradenitis suppurativa are inflammatory dermatoses that have been associated with arthritis, metabolic syndrome, obesity, and smoking. They share common pathogenic mechanisms such as elevated levels of several proinflammatory cytokines including tumor necrosis factor (TNF), interleukin-17A, and impaired Notch pathway. Thus, treatments for both diseases are sometimes overlapping. Biological therapy such as adalimumab is effective for patients with hidradenitis suppurativa and psoriasis. Adalimumab is a monoclonal antibody that binds to TNF and inhibits the cytokine interaction with the TNF receptors, thus inhibiting the inflammatory cascade. Currently, data are lacking on the treatment for co-occurrence of psoriasis and hidradenitis suppurativa. This case series describes three patients with a diagnosis of concomitant psoriasis and hidradenitis suppurativa. In these cases, after 12 weeks of treatment with adalimumab 40 mg every other week, the average Psoriasis Area Severity Index score reduced from 21.4 to 2.9 for psoriasis, Hidradenitis Suppurativa-Physician's Global Assessment from 3.3 to 0.7, and pain Visual Analog Scale for hidradenitis suppurativa from 4.6 to 2. The results suggest that adalimumab is a treatment of choice for patients with concomitant hidradenitis suppurativa and psoriasis.

Target/therapies for chronic recurrent erythema nodosum leprosum.

A Type 2 lepra reaction or erythema nodosum leprosum is an anticipated complication in the lepromatous spectrum of leprosy cases. It is an example of an immune complex-mediated complement activated disease (Type III hypersensitivity reaction). Hence, we tried to target the inflammatory mediators and the mental stressors for the possible management strategies.

Lazarine leprosy: A unique phenomenon of leprosy.

Leprosy, a chronic granulomatous disease, has been known since ages but even today continues to baffle the clinicians with a wide spectrum of clinical, histopathological, and immunological characteristics. Leprosy reactions are mainly of two types, namely, Type 1 and Type 2. In Type 1 leprosy reaction, the preexisting lesions become erythematous, edematous, and rarely ulcerate. Ulcerating Type 1 reaction is called lazarine leprosy. Ulcerations may occur in borderline tuberculoid (BT) pole or borderline lepromatous pole but more common in BT pole. In this postelimination era of leprosy, we report an interesting case report of BT Hansen's disease with Type 1 lepra reaction with ulceration, namely, lazarine leprosy.

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.

A Case of Dapsone-induced Mild Methemoglobinemia with Dyspnea and Cyanosis.

Dear Editor, Dapsone is a dual-function drug with antimicrobial and antiprotozoal effects and anti-inflammatory features (1). In dermatology, it is a first choice for conditions such as leprosy, IgA pemphigus, dermatitis herpetiformis, and linear IgA bullous dermatosis, or an adjunctive treatment for, e.g. bullous pemphigoid (BP) and pemphigus vulgaris (1). However, dapsone is associated with some adverse effects, including methemoglobinemia (1). Methemoglobin (MetHb) concentrations of less than 15% usually cause no symptoms in patients with normal hemoglobin concentrations (2). Herein, we report the case of a patient with BP who developed dyspnea because of dapsone-induced methemoglobinemia that was as mild as 4.7%. A 93-year-old man was diagnosed with BP based on skin manifestations (Figure 1, a and b), histopathological findings (Figure 1, c and d), and anti-BP180 NC16A antibody titer determined by chemiluminescence enzyme immunoassay (279 U/mL) 3 years earlier. His comorbidities included diabetes mellitus, chronic heart failure, right pleural effusion, and brain infarction. The patient had been successfully treated with oral prednisolone, so the steroid was tapered to 4 mg/day. The blisters recurred, however, and new ones kept developing even though the prednisolone was increased to 25 mg/day. Dapsone (75 mg/day) was begun as adjunctive treatment, and new blister formation ceased. At one week from dapsone initiation, the patient developed dyspnea, and his oxygen saturation as measured by pulse oximetry decreased to 88% on room air. At presentation, his blood pressure was 118/78 mmHg, the heart rate was 95 beats/minute, and axillary temperature was 36.3 °C. Neurological examination and consciousness findings remained unchanged compared with findings before dyspnea onset. Chest examination showed normal breath and heart sounds, but lip and peripheral cyanosis was present. Blood tests revealed a white blood cell count of 12,920/µl; red blood cells, 370×104/µl; hemoglobin, 11.7 g/dl; and CMV antigenemia (or C7-HRP), negative. Chest CT and echocardiography indicated no remarkable change compared with imaging from one year earlier. Arterial blood gas analysis showed a pH of 7.454, PaO2 63.1 mmHg, PaCO2 35.4 mmHg, HCO3- 24.3 mmol/L, SaO2 92.4%, and MetHb of 4.7%. These findings indicated a saturation gap (difference between SpO2 and SaO2) induced by MetHb. Upon cessation of dapsone, MetHb levels and SpO2 returned to normal and the dyspnea resolved, implicating dapsone in the methemoglobinemia (Figure 1, e). Differential diagnoses were pulmonary disease, heart disease, neuromuscular disease, sepsis, and drug intoxication. These possibilities were ruled out by the physical examination, drug history, vital signs, blood tests, and chest CT and echocardiography. In normal individuals, MetHb levels are less than 1% (2). Healthy patients with normal hemoglobin concentrations develop cyanosis at MetHb level of 15-20%, dyspnea at 20-50%, and coma at 50-70%, and die at more than 70% (2). However, patients with hematologic disease, acidosis, or cardiopulmonary diseases, for example, present with symptoms even with MetHb levels less than 15% (2,3). We inferred that our patient presented with dyspnea even under mild methemoglobinemia because he had anemia, chronic heart failure, and right pleural effusion. The occurrence of dapsone-induced methemoglobinemia with obvious symptoms is rare (1,4). Clinicians should be aware that methemoglobinemia symptoms are influenced not only by MetHb concentrations but also by comorbidities.

Triamcinolone acetonide-loaded PLA/PEG-PDL microparticles for effective intra-articular delivery: synthesis, optimization, in vitro and in vivo evaluation.

Nowadays the use of sustainable polymers as poly-lactic acid (PLA) and poly-δ-decalactone (PDL) in drug delivery is advantageous compared to polymers derived from fossil fuels. The present work aimed to produce microparticles (MPs) derived from novel sustainable polymers, loaded with triamcinolone acetonide (TA) for treatment of rheumatoid arthritis via intra-articular (IA) delivery. PDL was synthesized from green δ-decalactone monomers and co-polymerized with methoxy-polyethylene glycol (mPEG) forming PEG-PDL with different molecular weights. The Hansen's solubility parameters were applied to select the most compatible polymer with the drug. An o/w emulsion/solvent evaporation technique was used for MPs fabrication, using 3 [3] full factorial design. Selection of the optimized MPs was performed using Expert Design® software's desirability function. The optimized formulations were characterized using scanning electron microscope, powder X-ray diffraction, differential scanning calorimetry, infrared spectroscopy and in vitro release studies. The inhibition percents of inflammation and histopathological studies were assessed in complete Freund's adjuvant-induced rats' knee joints evaluating the effect of IA injections of selected MPs compared to the free drug suspension. Solubility studies revealed high compatibility and miscibility between TA and PEG-PDL1700, which was blended with PLA for convenient MPs formation. The in vitro characterization studies confirmed the formation of drug-copolymer co-crystals. The in vivo studies ensured the superiority of the newly designed composite MPs in inflammation suppression, compared to the free drug suspension and PLA MPs as well. The present study proved the advantage of using sustainable polymers in a novel combination for effective drug delivery and suggesting its usefulness in designing versatile platforms for therapeutic applications.

Erythema Nodosum Leprosum: Update and challenges on the treatment of a neglected condition.

Erythema Nodosum Leprosum (ENL) occurs due to the immunological complication of multibacillary leprosy and is characterized by painful nodules and systemic compromising. It is usually recurrent and/or chronic and has both physical and economic impact on the patient, being a very important cause of disability. In addition, ENL is a major health problem in countries where leprosy is endemic. Therefore, adequate control of this condition is important. The management of ENL aims to control acute inflammation and neuritis and prevent the onset of new episodes. However, all currently available treatment modalities have one or two drawbacks and are not effective for all patients. Corticosteroid is the anti-inflammatory of choice in ENL but may cause dependence, especially for chronic patients. Thalidomide has a rapid action but its use is limited due the teratogenicity and neurotoxicity. Clofazimine and pentoxifylline have slow action and have important adverse effects. Finally, there is no pattern or guidelines for treating these patients, becoming more difficult to evaluate and to control this condition. This review aims to show the main drugs used in the treatment of ENL and the challenges in the management of the reaction.

Increased activated memory B-cells in the peripheral blood of patients with erythema nodosum leprosum reactions.

B-cells, in addition to antibody secretion, have emerged increasingly as effector and immunoregulatory cells in several chronic inflammatory diseases. Although Erythema Nodosum Leprosum (ENL) is an inflammatory complication of leprosy, the role of B- cell subsets has never been studied in this patient group. Therefore, it would be interesting to examine the contribution of B-cells in the pathogenesis of ENL. A case-control study design was used to recruit 30 untreated patients with ENL and 30 non-reactional lepromatous leprosy (LL) patient controls at ALERT Hospital, Ethiopia. Peripheral blood samples were obtained before, during and after treatment from each patient. Peripheral blood mononuclear cells (PBMCs) were isolated and used for immunophenotyping of B- cell subsets by flow cytometry. The kinetics of B-cells in patients with ENL before, during and after Prednisolone treatment of ENL was compared with LL patient controls as well as within ENL group. Total B-cells, mature B-cells and resting memory B-cells were not significantly different between patients with ENL reactions and LL controls before treatment. Interestingly, while the percentage of naive B-cells was significantly lower in untreated ENL patients than in LL patient controls, the percentage of activated memory B-cells was significantly higher in these untreated ENL patients than in LL controls. On the other hand, the percentage of tissue-like memory B-cells was considerably low in untreated ENL patients compared to LL controls. It appears that the lower frequency of tissue-like memory B-cells in untreated ENL could promote the B-cell/T-cell interaction in these patients through downregulation of inhibitory molecules unlike in LL patients. Conversely, the increased production of activated memory B-cells in ENL patients could imply the scale up of immune activation through antigen presentation to T-cells. However, the generation and differential function of these memory B-cells need further investigation. The finding of increased percentage of activated memory B-cells in untreated patients with ENL reactions suggests the association of these cells with the ENL pathology. The mechanism by which inflammatory reactions like ENL affecting these memory cells and contributing to the disease pathology is an interesting area to be explored for and could lead to the development of novel and highly efficacious drug for ENL treatment.