Synergistic activity of crocin and crocin loaded in niosomes alone and in combination with fluconazole against Candida albicans isolates: In vitro and in silico study.

INTRODUCTION: Since the drug resistance in Candida species is becoming a serious clinical challenge, novel alternative therapeutic options, particularly herbal medicine, have attracted increasing interest. This study aimed to pinpoint the potential antifungal activity of crocin (Cro), the efficacy of the niosomal formulation of Cro (NCro), and the synergistic activity of both formulations in combination with fluconazole (FLC) against susceptible and resistant C. albicans isolates. MATERIAL AND METHODS: NCro was formulated using the heating method. The in vitro antimycotic activity of Cro, NCro, and FLC was evaluated. Checkerboard and isobologram assays evaluated the interaction between both formulations of Cro and FLC. Necrotic and apoptotic effects of different agents were analyzed using the flow cytometry method. In silico study was performed to examine the interactions between Lanosterol 14 alpha-demethylase and Cro as a part of our screening compounds with antifungal properties. RESULTS: NCro exhibited high entrapment efficiency up to 99.73 ± 0.54, and the mean size at 5.224 ± 0.618 µm (mean ± SD, n = 3). Both formulations of Cro were shown to display good anticandidal activity against isolates. The synergistic effect of the NCro in combination with FLC is comparable to Cro (P-value =0.03). Apoptotic indicators confirmed that tested compounds caused cell death in isolates. The docking study indicated that Cro has interactivity with the protein residue of 14α-demethylase. CONCLUSION: The results showed a remarkable antifungal effect by NCro combined with FLC. Natural compounds, particularly nano-sized carrier systems, can act as an effective therapeutic option for further optimizing fungal infection treatment.

Global Dilemma and Needs Assessment Toward Achieving Sustainable Development Goals in Controlling Leishmaniasis.

Leishmaniasis is a disease of poverty that imposes a devastating medical, social, and economic burden on over 1 billion people nationwide. To date, no in-depth study to analyze the major global challenges and needs assessment has been carried out. This investigation aimed to explore a comprehensive narrative review of leishmaniasis's main challenges and initially highlight obstacles that might impede the implementation of control measures. Also, we propose a specific list of priorities for needs assessment. The presence of socioeconomic factors, multiple clinical and epidemiological forms, various Leishmania species, the complexity of the life cycle, the absence of effective drugs and vaccines, and the lack of efficient vector and reservoir control make this organism unique and sophisticated in playing a tangled role to react tricky with its surrounding environments, despite extensive efforts and implementation of all-inclusive former control measures. These facts indicate that the previous strategic plans, financial support, and basic infrastructures connected to leishmaniasis surveillance are still insufficient. Strengthening the leishmaniasis framework in a context of accelerated programmatic action and intensification of cross-cutting activities along with other neglected tropical diseases (NTDs) is confidently expected to result in greater effectiveness, cost-benefit, and fruitful management. Sensitive diagnostics, effective therapeutics, and efficacious vaccines are vital to accelerating advancement toward elimination, and reducing morbidity/mortality and program costs. Collective actions devoted by all sectors and policy-makers can hopefully overcome technical and operational barriers to guarantee that effective and coordinated implementation plans are sustained to meet the road map for NTDs 2021- 2030 goals.

Cutaneous Leishmaniasis Hampers COVID-19: A Controlled Cross-Sectional Study in High-Burden Endemic Areas of Iran.

INTRODUCTION: Emerging infectious diseases such as SARS-CoV-2 can cause pandemics and create a critical risk for humans. In a previous pilot study, we reported that the immunological responses induced by cutaneous leishmaniasis (CL) could decrease the incidence and severity of COVID-19. In this large-scale case-control study, we assessed the possible relationship between mortality and morbidity of COVID-19 in healed CL persons suffering scars compared to cases without CL history. METHODS: This controlled cross-sectional study was conducted between July 2020 and December 2022 in the endemic and high-burden areas of CL in southeastern Iran. In the study, 1400 previous CL cases with scars and 1,521,329 subjects who had no previous CL were analyzed. We used R 4.0.2 to analyze the data. Firth's bias reduction approach corresponding to the penalization of likelihood logistic regression by Jeffreys was also employed to influence the variables in the dataset. Also, a Bayesian ordinal logistic regression model was performed to explore the COVID-19 severity in both case and referent groups. RESULTS: The occurrence and severity rate of COVID-19 in CL scar cases are significantly less than in the non-CL control group, while in the CL scar subjects, patients with critical conditions and mortality were not observed. The morbidity (OR = 0.11, CI 0.06-0.20 and P < 0.001) and severity of COVID-19 in previous cases with CL scars were significantly diminished than that in the control group (credible interval - 2.57, - 1.62). CONCLUSIONS: The results represented a durable negative relationship between cured CL and COVID-19 incidence and severity. Additional studies seem necessary and should be designed to further validate the true impact and underlying mechanistic action of CL on COVID-19.

Comparison of cytotoxicity of Miltefosine and its niosomal form on chick embryo model.

Various drugs have been used for the treatment of leishmaniasis, but they often have adverse effects on the body's organs. In this study, we aimed to explore the effects of one type of drug, Miltefosine (MIL), and its analogue or modifier, liposomal Miltefosine (NMIL), on several fetal organs using both in silico analysis and practical tests on chicken embryos. Our in silico approach involved predicting the affinities of MIL and NMIL to critical proteins involved in leishmaniasis, including Vascular Endothelial Growth Factor A (VEGF-A), the Kinase insert domain receptor (KDR1), and apoptotic-regulator proteins (Bcl-2-associate). We then validated and supported these predictions through in vivo investigations, analyzing gene expression and pathological changes in angiogenesis and apoptotic mediators in MIL- and NMIL-treated chicken embryos. The results showed that NMIL had a more effective action towards VEGF-A and KDR1 in leishmaniasis, making it a better candidate for potential operative treatment during pregnancy than MIL alone. In vivo, studies also showed that chicken embryos under MIL treatment displayed less vascular mass and more degenerative and apoptotic changes than those treated with NMIL. These results suggest that NMIL could be a better treatment option for leishmaniasis during pregnancy.

A prospective longitudinal study on the elimination trend of rural cutaneous leishmaniasis in southeastern Iran: Climate change, population displacement, and agricultural transition from 1991 to 2021.

Leishmaniasis is a complex disease. Any change in weather conditions affects the humans' social and agricultural expansion and, consequently, the parasite's life cycle in terms of ecology, biodiversity, social stigma, and exclusion. This population-based prospective longitudinal investigation was conducted between 1991 and 2021 in a well-defined CL (cutaneous leishmaniasis) focus in Bam County, southeastern Iran. A robust health clinic and health surveillance system were responsible for the ongoing systematic documentation, detection, identification, and management of CL cases. The exponential smoothing method via the state space model was used in the univariate time series. The TTR, smooth, and forecast packages were used in R software. Landsat satellite images from 1991, 2001, 2011, and 2021 were employed in the physical development. During this period, the temperature increased while the rainfall and humidity decreased. The findings showed a downward trend in the standardized drought index. Also, the results showed that climate warming and ecological changes profoundly affected the area's agricultural patterns and topographical features. Furthermore, the last three decades witnessed an elimination trend for zoonotic CL (ZCL) and the predominance of anthroponotic CL (ACL). The present findings showed that the critical factors in the predominance of ACL and elimination of ZCL were rising temperature, drought, migration, unplanned urbanization, earthquake, and agrarian reform. The wall-enclosed palm tree gardens excluded the primary ZCL reservoir host. They controlled the disease while providing suitable conditions for the emergence/re-emergence of ACL in the newly established settlements and the unplanned ecozone. Therefore, robust health infrastructures, sustained financial support, and evidence-based research studies are crucial to facilitating the necessary surveillance, monitoring, and evaluation to control and eliminate the disease.

In silico and in vitro potentials of crocin and amphotericin B on Leishmania major: Multiple synergistic mechanisms of actions.

A significant barrier to optimal antileishmanial treatment is low efficacy and the emergence of drug resistance. Multiple approaches were used to monitor and assess crocin (a central component of saffron) mixed with amphotericin B (AmpB) potential in silico and in vitro consequences. The binding behavior of crocin and iNOS was the purpose of molecular docking. The results showed that crocin coupled with AmpB demonstrated a safe combination, extremely antileishmanial, suppressed Leishmania arginase absorption, and increased parasite death. This natural flower component is a robust antioxidant, significantly promoting the expression of the Th1-connected cytokines (IL12p40, IFN-γ, and TNF- α), iNOS, and transcription factors (Elk-1, c-Fos, and STAT-1). In comparison, the expression of the Th2-associated phenotypes (IL-10, IL-4, and TGF-ß) was significantly reduced. The leishmanicidal effect of this combination was also mediated through programmed cell death (PCD), as confirmed by the manifestation of phosphatidylserine and cell cycle detention at the sub-GO/G1 phase. In conclusion, crocin with AmpB synergistically exerted in vitro antileishmanial action, generated nitric oxide and reactive oxygen species, modulated Th1, and Th2 phenotypes and transfer factors, enhanced PCD profile and arrested the cell cycle of Leishmania major promastigotes. The main action of crocin and AmpB involved wide-ranging mechanistic insights for conducting other clinical settings as promising drug candidates for cutaneous leishmaniasis. Therefore, this combination could be esteemed as a basis for a potential bioactive component and a logical source for leishmanicidal drug development against CL in future advanced clinical settings.

Antileishmanial potentials of azacitidine and along with meglumine antimoniate on Leishmania major: In silico prediction and in vitro analysis.

This study aimed to investigate the in vitro and in silico antileishmanial activity of azacitidine (AZA) on Leishmania major promastigotes and amastigotes. The in silico method was used to evaluate the possibility of the interaction of AZA into the binding pocket of inducible nitric oxide synthase (iNOS), a leading defensive oxidative metabolite. Following that, in vitro anti-promastigote, and anti-amastigote activity of AZA was determined using an MTT assay and a macrophage model, respectively. Cytotoxic effects of AZA and meglumine antimoniate (MA) were also assessed by MTT assay on murine macrophages. All experiments were performed in triplicate. The results showed that AZA interacted with Ser133, Gln134, and Lys13 amino acids of iNOS, and the molecular docking score was obtained at -241.053 kcal/mol. AZA in combination with MA significantly (P<0.001) inhibited the growth rate of nonclinical promastigote (IC50 247.6±7.3 µM) and 8.5-fold higher of clinical intramacrophage amastigote stage (29.8±5.3 µM), compared to the untreated group. A significant upsurge of Th1 subsets and transcription genes and a meaningful decline in Th2 cytokines subclasses at the equivalent concentrations of AZA and MA was observed (P<0.001). The apoptosis effect of AZA along with MA was significantly induced on L. major in a dose-dependent manner (P<0.001). The present study demonstrated that AZA possesses antileishmanial activity in in vitro and in silico models. However, AZA combined with MA was more effective than AZA alone in inhibiting the growth rate of promastigotes and amastigotes of L. major. This study indicates that AZA in combination with MA demonstrated a potent antileishmanial mechanism, promoting immune response and enhancing an immunomodulatory role toward the Th1 pathway. This experimental study is a basic study for applying more knowledge about the mechanisms of AZA along with MA in animal models in the future.

Monitoring of airborne fungi during the second wave of COVID-19 in selected wards of the referral university hospital in southeastern Iran.

Microbiological monitoring of the air hospital is essential for prevention and control, due to the possible airborne route of infection transmission, especially in high-risk wards. This study aimed to monitor the airborne fungi during the second wave of the COVID-19 pandemic in selected wards of the biggest university educational hospital in Kerman, southeastern Iran. This study was conducted in 11 different wards, separated into the patient room and nursing station, of the Afzalipour hospital from May to August 2021. Fungal isolates were characterized to the species level by conventional and sequencing methods. Out of 93 obtained fungal colonies, 70 (75.3%) isolates were filamentous and 23 (24.7%) isolates were yeast. Aspergillus species were the predominant fungal isolates among the filamentous colonies (n=19; 27.1%), and Naganishia albida (formerly Cryptococcus albidus) was identified as the most common yeast isolate (n=13/23; 56.8%). The infectious ward was the most contaminated unit (n=19/93), while the least contaminated units were the neonatal intensive care unit (n=3/93), and oncology (n=3/93). The statistical findings displayed that the number of fungal isolates in patients' rooms is significantly higher than in nurses' stations (p-value=0.013). Our study demonstrated the presence of diverse fungal species in all wards of the hospital. Considering the presence of airborne fungi in hospitals and related public health problems is one of the critical issues for health systems management. In this regard, efficient monitoring of airborne fungi might play an influential role in hospital infection control and surveillance, particularly in high-risk hospitalization patients in critical wards.

Nasopharyngeal myiasis due to Cephalopina titillator in Southeastern Iran: a prevalence, histopathological, and molecular assessment.

The Cephalopina titillator is one of the most important causative agents of nasal myiasis in camels. This study aimed to explore the prevalence, histopathological effects, and molecular identification of C. titillator infestation in camels of Kerman province, South-Eastern Iran, between 2019 and 2021. The larvae were placed in 10% formalin for histopathological evaluation and species identification. Pieces of larval abdominal segments of C. titillator were selected for extraction of DNA. Partial mitochondrial CO1 genes were sequenced for final analysis. Out of the 870 camels examined, 339 (38.9%) were infested with larval stages of C. titillator. There was a significant difference between age and infection rate (P = 0.001), while no association between males and females (P = 0.074) was found. The infection rate was significantly higher in the winter (P < 0.001) than in the other seasons. In this study, different lesions depending on duration, locations, and the depth of larval adhesion notably degeneration changes, necrosis, and ulceration were observed. Also, in chronic cases, granulation tissue reactions were organized. Cephalopina titillator was confirmed by PCR sequencing analysis using mitochondrial CO1 region. A 582 bp nucleotide sequence was deposited in GenBank under the MW136151 accession number. Phylogenetic analysis of CO1 produced a single uniform sister clade to MZ209004 and MW167083 records from China and Iraq, respectively. The high prevalence of C. titillator in camels in this region and other areas of Iran declares that the country is in an endemic status and displays the existence of the potential risk for camels.

Cutaneous leishmaniasis situation analysis in the Islamic Republic of Iran in preparation for an elimination plan.

Iran has invariably been under the growing public health threat of cutaneous leishmaniasis (CL), a significant barrier to local development that hinders the prevention and control efforts toward eliminating the disease. So far, no comprehensive and in-depth epidemiological analysis of the CL situation has been carried out nationwide. This study aimed to employ advanced statistical models to analyze the data collected through the Center for Diseases Control and Prevention of Communicable Diseases during 1989-2020. However, we emphasized the current trends, 2013-2020, to study temporal and spatial CL patterns. In the country, the epidemiology of CL is incredibly intricate due to various factors. This fact indicates that the basic infrastructure, the preceding supports, and the implementation plan related to preventive and therapeutic measures need crucial support. The leishmaniasis situation analysis is consistent with desperate requirements for efficient information on the control program in the area. This review provides evidence of temporally regressive and spatially expanding incidence of CL with characteristic geographical patterns and disease hotspots, signifying an urgent need for comprehensive control strategies. This information could be a suitable model and practical experience in the Eastern Mediterranean Region, where over 80% of CL is reported.

Poor adherence is a major barrier to the proper treatment of cutaneous leishmaniasis: A case-control field assessment in Iran.

Leishmaniasis is an overlooked, poverty-stricken, and complex disease with growing social and public health problems. In general, leishmaniasis is a curable disease; however, there is an expansion of unresponsive cases to treatment in cutaneous leishmaniasis (CL). One of the effective and ignored determinants in the treatment outcome of CL is poor treatment adherence (PTA). PTA is an overlooked and widespread phenomenon to proper Leishmania treatment. This study aimed to explore the effect of poor adherence in unresponsiveness to treatment in patients with anthroponotic CL (ACL) by comparing conventional statistical modalities and machine learning analyses in Iran. Overall, 190 cases consisting of 50 unresponsive patients (case group), and 140 responsive patients (control group) with ACL were randomly selected. The data collecting form that included 25 queries (Q) was recorded for each case and analyzed by R software and genetic algorithm (GA) approaches. Complex treatment regimens (Q11), cultural and lay views about the disease and therapy (Q8), life stress, hopelessness and negative feelings (Q22), adverse effects of treatment (Q13), and long duration of the lesion (Q12) were the most prevalent significant variables that inhibited effective treatment adherence by the two methods, in decreasing order of significance. In the inherent algorithm approach, similar to the statistical approach, the most significant feature was complex treatment regimens (Q11). Providing essential knowledge about ACL and treatment of patients with chronic diseases and patients with misconceptions about chemical drugs are important issues directly related to the disease's unresponsiveness. Furthermore, early detection of patients to prevent the long duration of the disease and the process of treatment, efforts to minimize side effects of treatment, induction of positive thinking, and giving hope to patients with stress and anxiety by medical staff, and family can help patients adhere to the treatment.

Vulvovaginal candidiasis in Iranian women: Molecular identification and antifungal susceptibility pattern.

AIM: Vulvovaginal candidiasis (VVC), is a common fungal infection that remains a global concern. The objectives of this study were molecular identification and assessment of the antifungal susceptibility profile of Candida species, causing VVC in southeast Iran. METHODS: A cross-sectional investigation was carried out on 119 nonpregnant females suspected of VVC between February 2019 and May 2021. Yeast samples were characterized to the species level by conventional and molecular methods. All Candida isolates were examined for in vitro susceptibility profile to six conventional antifungal drugs using Clinical and Laboratory Standards Institute guidelines. RESULTS: Out of 119 subjects, 52 (43.7%) cases were affected by VVC, out of whom 11 (21.15%) cases had recurrent vulvovaginal candidiasis (RVVC). The species distribution was as follows; Candida albicans (n = 21; 40.4%), C. glabrata (n = 11; 21.2%), C. tropicalis (n = 9; 17.3%), C. parapsilosis (n = 5; 9.7%), C. africana (n = 3; 5.7%), C. famata (n = 1; 1.9%), C. lusitaniae (n = 1; 1.9%), and C. dubliniensis (n = 1; 1.9%). The resistance rate of Candida isolates to fluconazole, itraconazole, and voriconazole were 15.38%, 11.5%, and 3.8%, respectively. Resistance to fluconazole was obtained in 46% (5/11) of RVVC cases but only in 7% (3/41) of VVC cases. CONCLUSION: This study demonstrated that the majority of VVC cases were caused by non-albicans Candida species which also were resistant to some antifungal agents. Hence, our findings revealed the importance of conducting periodical epidemiological studies to determine changes in species distribution. Moreover, for effective management of treatment and infection, it is imperative to evaluate the susceptibility profiles of Candida species isolated from VVC patients.

Global distribution of treatment resistance gene markers for leishmaniasis.

BACKGROUND: Pentavalent antimonials (Sb(V)) such as meglumine antimoniate (Glucantime®) and sodium stibogluconate (Pentostam®) are used as first-line treatments for leishmaniasis, either alone or in combination with second-line drugs such as amphotericin B (Amp B), miltefosine (MIL), methotrexate (MTX), or cryotherapy. Therapeutic aspects of these drugs are now challenged because of clinical resistance worldwide. METHODS: We reviewedthe recent original studies were assessed by searching in electronic databases such as Scopus, Pubmed, Embase, and Web of Science. RESULTS: Studies on molecular biomarkers involved in drug resistance are essential for monitoring the disease. We reviewed genes and mechanisms of resistance to leishmaniasis, and the geographical distribution of these biomarkers in each country has also been thoroughly investigated. CONCLUSION: Due to the emergence of resistant genes mainly in anthroponotic Leishmania species such as L. donovani and L. tropica, as the causative agents of ACL and AVL, respectively, selection of an appropriate treatment modality is essential. Physicians should be aware of the presence of such resistance for the selection of proper treatment modalities in endemic countries.

A novel rapid LAMP test for identification of cutaneous leishmaniasis: An evaluation and comparative analysis of three molecular methods.

Leishmaniasis is a neglected and widespread parasitic disease that can lead to serious health problems. The conventional method in diagnostic health clinics is direct smear preparation of the lesion and staining with standard Giemsa to visualize the amastigote stage and by culturing the organism in an NNN (Novy-MacNeal-Nicolle) to observe the promastigote form of the parasite. In the case of urban-type leishmaniasis, microscopic diagnosis is sometimes not possible due to the reduction of amastigotes in patients' wounds. Because most endemic areas are located in regions that do not have access to laboratories equipped with molecular tools, access to a rapid test to diagnose the disease is essential. In this study, for the first time for DNA extraction, the scalpel used for sampling was washed and extracted by boiling method. Also, the LAMP technique in this study was modified so that the test can be performed in 10 min and the results can be recognized by color. We used four microscopic methods, conventional PCR, real-time PCR, and LAMP, to diagnose urban-type leishmaniasis and compared the results of these methods with each other. The sensitivity and specificity of LAMP were higher than other techniques used. Therefore, it allows rapid diagnosis for timely treatment of the disease to control the primary reservoir host more quickly in ACL as humans are the principal source of infection. This test is performed at a high-speed and is cost-effective. For its convenience, this test is highly recommended to be used in endemic areas.

Cytotoxicity of Amphotericin B and AmBisome: In Silico and In Vivo Evaluation Employing the Chick Embryo Model.

Leishmaniasis has been identified as a significant disease in tropical and subtropical regions of the world, with Iran being one of the disease-endemic areas. Various treatments have been applied for this disease, and amphotericin B (Amp B) is the second line of treatment. Side effects of this drug have been reported in various organs. The present study investigated the effects of different types of Amp B on fetal organs using in silico and in vivo assays (chicken embryos). In vivo analysis was done by checking pathological changes, angiogenesis, and apoptosis alterations on eggs treated by Amp B and AmBisome. In silico approach was employed to predict the affinity of Amp B and AmBisome to the vascular endothelial growth factor A (VEGF-A), its receptor (KDR1), apoptotic-regulator proteins (Bcl-2-associated X protein (Bax), B-cell lymphoma (Bcl-2), and Caspase-8. The ADME-toxicity prediction reveals that AmBisome possesses a superior pharmacological effect to Amp B. The best result of all the dockings in the Molegro Virtual Docker (MVD) was obtained between Bax, Bcl-2, Caspase-8, KDR1, and VEGF-A targets. Due to the lower Egap (HOMO-LUMO) of AmBisome, the chemical reactivity of AmBisome was higher than that of Amp B. In vivo analysis showed that embryos that received Amp B exhibited less vascular density than AmBisome. Amp B alone significantly increased the expression of apoptosis and decreased angiogenesis genes compared to AmBisome. The histopathology analysis of the treated embryos showed a reduction in the blood vessel collapse and an increase in degenerative and apoptotic-necrotic changes in the embryonic tissues. Overall, the results suggest the potential benefits of AmBisome over Amp B, which might be a better treatment strategy to treat leishmaniasis during pregnancy.

Fifty years of struggle to control cutaneous leishmaniasis in the highest endemic county in Iran: A longitudinal observation inferred with interrupted time series model.

Negligible data are available following major social activities and environmental changes on leishmaniasis. Therefore, how interactions between these events influence cutaneous leishmaniasis (CL) risk is not well-known. This longitudinal study was undertaken to explore the impact of interventions conducted between 1971 and 2020 in Bam county, which has had the highest disease burden in Iran. Only confirmed CL cases during this period were taken into account. Data were analyzed by SPSS 22 using the X2 test to assess the significance of the difference between proportions. Moreover, we used interrupted time series (ITS) to assess the impact of three environmental events during this period. Overall, 40,164 cases of CL occurred in the past five decades. Multiple complex factors were among the leading causes that synergistically induced the emergence/re-emergence of CL outbreaks in Bam. The main factors attributed negatively to CL control were cessation of malaria spraying activity, expansion of the city spaces, and a massive earthquake creating new breeding potentials for the vectors. The highest impact on CL incidence during these years was related to the earthquake [coefficient = 17.8 (95% CI: 11.3, 22.7); p-value < 0.001]. Many factors can contribute to CL outbreaks in endemic foci. They also can cause new foci in new areas. Since humans are the single reservoir for CL in this area, early detection and effective management significantly contribute to controlling CL to reduce the disease burden. However, essential evidence gaps remain, and new tools are crucial before the disease can ultimately be controlled. Nevertheless, sustained funding and more trained task forces are essential to strengthen surveillance and case management and monitor the interventions' impact.

Antiproliferative properties of Turmerone on Leishmania major: Modes of action confirmed by antioxidative and immunomodulatory roles.

Treatment of leishmaniasis by conventional synthetic compounds has faced a serious challenge worldwide. This study was performed to evaluate the effect and modes of action of aromatic Turmerone on the Leishmania major intra-macrophage amastigotes, the causative agent of zoonotic cutaneous leishmaniasis in the Old World. In the findings, the mean numbers of L. major amastigotes in macrophages were significantly decreased in exposure to Turmerone plus meglumine antimoniate (Glucantime®; MA) than MA alone, especially at 50 µg/mL. In addition, Turmerone demonstrated no cytotoxicity as the selectivity index (SI) was 21.1; while it induced significant apoptosis in a dose-dependent manner on L. major promastigotes. In silico molecular docking analyses indicated an affinity of Turmerone to IL-12, with the MolDock score of - 96.8 kcal/mol; which may explain the increased levels of Th1 cytokines and decreased level of IL-10. The main mechanism of action is more likely associated with stimulating a powerful antioxidant and promoting the immunomodulatory roles in the killing of the target organism.

Prophylactic effect of cutaneous leishmaniasis against COVID-19: a case-control field assessment.

INTRODUCTION: We assessed the potential relationship between COVID-19 and laboratory-confirmed cutaneous leishmaniasis (CL)-registered cases with a history of scarring, compared with volunteer participants without history of CL. METHODS: This case-control retrospective study was conducted in southeastern Iran with a high anthroponotic cutaneous leishmaniasis (ACL) burden. RESULTS: Overall, n=1010 CL cases (n=479 male, n=531 female) were evaluated for infection with SARS-CoV-2. In the CL case group, 2 men and 1 woman (0.3% in total) had a mild form of COVID-19 disease; none were hospitalized or died. In contrast, of n=2020 participants without history of CL, n=57 (2.9%) contracted laboratory-confirmed COVID-19, including mild (66.7%), hospitalized (26.3%), critical (3.5%) and fatal (3.5%). There was a strong negative association between CL infection and COVID-19. The burden of COVID-19 in CL-cured participants significantly reduced the morbidity (odds ratio: 0.12; CI: 0.03-0.30; P <0.001) and mortality (percentile: -4.10, -0.02). CONCLUSION: Participants with a history of CL scar had significantly reduced incidence of COVID-19 morbidity and mortality. The cross-protection mediated by CL may retard COVID-19 in endemic countries. However, further longitudinal studies are needed to explore the potential profile and duration of this protection offered by CL against COVID-19.

The impact of diabetes on cutaneous leishmaniasis: a case-control field assessment.

This study aimed to assess the associated-risk determinants for cutaneous leishmaniasis (CL) in patients with diabetes mellitus (DM) compared to patients without DM. This case-control study was performed between 2017 and 2019 in southeastern Iran. Overall, 206 participants were selected from patients with DM without CL (11.2%), patients with CL without DM (6.2%), and DM patients concomitance with CL (27.6%) as case groups and healthy individuals as a control group 64 (76%). These cases were compared for parasitological, immunological, biochemical, and hematological parameters. The findings demonstrated that parasitological factors regarding the number, duration, and size of the lesion in CL patients showed a significant difference among patients with and without DM (p < 0.05). Data analysis showed that six major risk factors, including female (odds ratio (OR) = 3.47, confidence interval (CI) = 1.84-6.53, p < 0.001), total protein in CL group (OR = 4.9, CI = 2.3-10.44, p < 0.001), alanine aminotransferase (ALT) concentration in CL group (OR = 0.87, CI = 0.81-0.93, p < 0.001) and DM co-infected with CL group (OR = 0.8, CI = 0.72-0.88, p < 0.001) than healthy group, aspartate aminotransferase (AST) concentration in DM group (OR = 0.86, CI = 0.76-0.98, p = 0.02), transforming growth factor beta)TGF-ß( level in the CL group (OR = 1.03, CI = 1.003-1.05, p = 0.02), and presence of diabetes disease (OR = 2.07, CI = 1.16-3.7, p < 0.05), were significantly linked with the induction of CL lesion. The findings demonstrated a significant relationship between DM and CL in distinct risk determinants. Also, the study revealed that DM enhanced the severity of active CL.

In vitro and in vivo therapeutic potentials of 6-gingerol in combination with amphotericin B for treatment of Leishmania major infection: Powerful synergistic and multifunctional effects.

The ongoing conventional drugs for leishmaniasis treatment are insufficient. The present study aimed to assess 6-gingerol alone and in combination with amphotericin B on Leishmania major stages using experimental and in vivo murine models. Here, arrays of experimental approaches were designed to monitor and evaluate the 6-gingerol potential therapeutic outcomes. The binding affinity of 6-gingerol and IFN-γ was the basis for docking conformations. 6-Gingerol combined with amphotericin B represented a safe mixture, extremely leishmanicidal, a potent antioxidant, induced a remarkable apoptotic index, significantly increased the expression of the Th1-related cytokines (IL-12p40, IFN-γ, and TNF- α), iNOS, and transcription factors (STAT1, c-Fos, and Elk-1). In contrast, the expression of the Th2-related cytokines was significantly downregulated (p < 0.001). This combination was also potent when the lesion appearance was evaluated following three weeks of treatment. The histopathological and immunohistochemical patterns of the murine model represented clusters of CD4+ and CD8+ T lymphocytes which compressed and deteriorated the macrophages harboring Leishman bodies. The primary mode of action of 6-gingerol and amphotericin B involved broad mechanistic insights providing a coherent basis for further clinical study as a potential drug candidate for CL. In conclusion, 6-gingerol with amphotericin B synergistically exerted anti-leishmanial activity in vitro and in vivo and potentiated macrophages' leishmanicidal activity, modulated Th1- and Th2-related phenotypes improved the histopathological changes in the BALB/c mice infected with L. major. They elevated the leukocyte infiltration into the lesions. Therefore, this combination should be considered for treating volunteer patients with CL in clinical studies.