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• Age-standardized point prevalence of RHD was 388.9/100,000 in MENA in 2019. • Highest age-standardized DALY rate of RHD in 2019 was in Afghanistan. • Age-standardized point prevalence of RHD was highest in middle-age group. • Burden of RHD was negatively associated with the SDI over 1990–2019. Rheumatic heart disease (RHD) is a treatable and preventable condition resulting from acute rheumatic fever. To report the prevalence, mortality and disability-adjusted life-years (DALY) due to RHD in the Middle East and North Africa (MENA) region from 1990 to 2019, by sex, age group, country and sociodemographic index (SDI). Information on the prevalence, mortality and DALY associated with RHD were obtained from the Global Burden of Disease Study 2019. Data were gathered for all countries in the MENA region over the period 1990–2019. These data included counts and age-standardized rates per 100,000, accompanied by 95% uncertainty intervals (UIs). The MENA region had an age-standardized point prevalence of 388.9 per 100,000 in 2019, which was 5.4% higher than in 1990. The annual incidence rate was 1.6, which was 63.4% lower than in 1990. There were 379.4 thousand DALY attributable to RHD in 2019, with an age-standardized rate of 67.1, which was 61.3% lower than in 1990. In 2019, an estimated 7.4 thousand deaths were due to RHD, and the age-standardized death rate was 63.4% lower in 2019 than in 1990. DALY rates rose steadily with increasing age in both males and females. The SDI correlated negatively with the rate of DALY for RHD throughout the study period. The burden of RHD in MENA declined from 1990 to 2019, demonstrating the importance of regularly updating health data and identifying risk factors, and developing effective guidelines on prevention. [ABSTRACT FROM AUTHOR]

The use of 18F-FDG PET/CT in diagnostic algorithms for PVE has increased since publication of studies and guidelines advocating its use. The assessment of test accuracy has been limited by small study sizes. We undertook a systematic review using individual patient data (IPD) meta-analysis techniques. To estimate the summary sensitivity and specificity of 18F-FDG PET/CT in diagnosing PVE. We also assessed the effect of patient factors on test accuracy as defined by changes in the odds ratios associated with each factor. The effect of the PET/CT study on the final diagnosis was also assessed when compared to the preliminary Duke classification to determine in which patient group 18F-FDG PET/CT had the greatest utility. Studies were included if PET/CT was performed for suspicion of PVE and IPD of both the PET/CT result and final diagnosis defined by a gold-standard assessment was available. There were 3 possible final diagnoses ("definite PVE," "possible PVE," and "rejected PVE"). Seventeen studies were included with IPD available for 537 patients (from 538 scans). The summary sensitivity and specificity were 85% (95% CI 74.2%–91.8%) and 86.5% (95% CI 75.8%–92.9%) respectively when patients with final diagnosis of "possible PVE" were classified as positive for PVE. When this group was classified as negative for PVE, sensitivity was 87.4% (95% CI 80.4%–92.1%) and specificity was 84.9% (95% CI 71.5%–92.6%). Patients with a known pathogen (especially coagulase negative staphylococcal species), elevated CRP, a biological or aortic valve infection appeared more likely to have an accurate PET/CT diagnosis. Those with a mechanical valve, prior antibiotic treatment or a transcatheter aortic valve replacement valve were less likely to have an accurate test. Time since valve implantation and the presence of surgical adhesive did not appear to affect test accuracy. Of the patients with a preliminary Duke classification of "possible PVE," 84% received a more conclusive final diagnosis of "definite" or "rejected" PVE after the PET/CT study. 18F-FDG PET/CT has high sensitivity and specificity in diagnosing PVE and the diagnostic utility is greatest in patients with a preliminary Duke classification of "possible PVE." Some patient factors appear to affect test accuracy, though these results should be interpreted with caution given low patient numbers for subgroup analyses. [Display omitted] [ABSTRACT FROM AUTHOR]

COVID-19 caused by SARS-CoV-2 is an ongoing global pandemic. SARS-CoV-2 affects the human respiratory tract's epithelial cells, leading to a proinflammatory cytokine storm and chronic lung inflammation. With numerous patients dying daily, a vaccine and specific antiviral drug regimens are being explored. Probiotics are live microorganisms with proven beneficial effects on human health. While probiotics as nutritional supplements are long practiced in different cuisines across various countries, the emerging scientific evidence supports the antiviral and general immune-strengthening health effects of the probiotics. Here, we present an overview of the experimental studies published in the last 10 years that provide a scientific basis for unexplored probiotics as a preventive approach to respiratory viral infections. Based on collated insights from these experimental data, we identify promising microbial strains that may serve as lead prophylactic and immune-boosting probiotics in COVID-19 management. [ABSTRACT FROM AUTHOR]

Understanding the unique metabolic pathway of L. donovani is crucial for comprehending its biology under oxidative stress conditions. The de novo cysteine biosynthetic pathway of L. donovani is absent in humans and its product, cysteine regulates the downstream components of trypanothione-based thiol metabolism, important for maintaining cellular redox homeostasis. The role of serine o -acetyl transferase (SAT), the first enzyme of this pathway remains unexplored. In order to investigate the role of SAT protein, we cloned SAT gene into pXG-GFP+ vector for episomal expression of SAT in Amphotericin B sensitive L. donovani promastigotes. The SAT overexpression was confirmed by SAT enzymatic assay, GFP fluorescence, immunoblotting and PCR. Our study unveiled an upregulated expression of both LdSAT and LdCS of cysteine biosynthetic pathway and other downstream thiol pathway proteins in LdSAT-OE promastigotes. Additionally, there was an increase in enzymatic activities of LdSAT and LdCS proteins in LdSAT-OE, which was found similar to the Amp B resistant parasites, indicating a potential role of SAT protein in modulating drug resistance. We observed that the overexpression of SAT in Amp B sensitive parasites increases tolerance to drug pressure and oxidative stress via trypanothione-dependent antioxidant mechanism. Moreover, the in vitro J774A.1 macrophage infectivity assessment showed that SAT overexpression augments parasite infectivity. In LdSAT-OE promastigotes, antioxidant enzyme activities like APx and SOD were upregulated, intracellular reactive oxygen species were reduced with a corresponding increase in thiol level, emphasizing SAT's role in stress tolerance and enhanced infectivity. Additionally, the ROS mediated upregulation in the expression of LdSAT, LdCS, LdTryS and LdcTXNPx proteins reveals an essential cross talk between SAT and proteins of thiol metabolism in combating oxidative stress and maintaining redox homeostasis. Taken together, our results provide the first insight into the role of SAT protein in parasite infectivity and survival under drug pressure and oxidative stress. [Display omitted] • SAT is involved in trypanothione-based redox metabolism. • SAT overexpression increases tolerance to oxidative stress. • SAT overexpression confers resistance to Amp B and miltefosine. • SAT overexpression augments antioxidant activities of APx and SOD. • SAT overexpression enhances parasite infectivity and survival under oxidative stress conditions. [ABSTRACT FROM AUTHOR]

Globalisation has seen a shift towards international multicentre randomised controlled trials (RCTs). The amalgamation of heterogenous patient populations is thought to be responsible for the geographic variation in treatment effect noted in recent trials. Furthermore, there is significant underrepresentation of lower- income countries in cardiovascular disease (CVD) research. These issues raise important questions about the generalisability of these trial results. Given the central role of statin therapy in CVD risk reduction, we evaluated for geographic variation in treatment effect in the primary and secondary prevention statin RCTs. We conducted a comprehensive literature search using the terms: "statin", "coronary disease", "reduce" and "cholesterol". We included statin RCTs with >1000 participants, therapy >2 years and CVD outcomes. We analysed each study for regional recruitment data and geographic subgroup analysis. From an initial 2154 studies, we identified 20 eligible for inclusion. This amounted to 138,612 participants across multiple continents including Europe 69,086 (49.8%), Asia 14,672 (10.6%), South America 5128 (3.7%), North America 33,393 (24.1%), Oceania 9445 (6.8%) and Africa 2801 (2%). Data were unavailable for 4087 (2.9%) participants. Despite together comprising 35% of the world's population, China and India represented only 2.7% and 1.3% of the studied population respectively. None of the 6 multi-continent trials provided regional analysis. We were unable to identify significant geographic variation in the outcomes of the statin RCTs, primarily due to a lack of data. We also observed regarding statin RCT data, there is limited involvement of countries with the greatest burden of CVD. • Approximately 73.9% of RCT data for statin therapy is based on European and North American populations. • Despite together comprising 35% of the world's population, China and India represent only 2.7% and 1.3% of the studied population respectively. • There is very limited evidence regarding the efficacy and dosage of statins in lower- income regions known to be at very high-risk for coronary disease. [ABSTRACT FROM AUTHOR]

Leishmania possess a unique trypanothione redox metabolism with undebated roles in protection from oxidative damage and drug resistance. The biosynthesis of trypanothione depends on l -cysteine bioavailability which is regulated by cysteine biosynthesis pathway. The de novo cysteine biosynthesis pathway is comprised of serine O -acetyltransferase (SAT) and cysteine synthase (CS) enzymes which sequentially mediate two consecutive steps of cysteine biosynthesis, and is absent in mammalian host. However, despite the apparent dependency of redox metabolism on cysteine biosynthesis pathway, the role of SAT and CS in redox homeostasis has been unexplored in Leishmania parasites. Herein, we have characterized CS and SAT to investigate their interaction and relative abundance of these proteins in promastigote vs. amastigote growth stages of L. donovani . CS and SAT genes of L. donovani (LdCS and LdSAT) were cloned, expressed, and fusion proteins purified to homogeneity with affinity column chromatography. Purified LdCS contains PLP as cofactor and showed optimum enzymatic activity at pH 7.5. Enzyme kinetics showed that LdCS catalyses the synthesis of cysteine using O -acetylserine and sulfide with a K m of 15.86 mM and 0.17 mM, respectively. Digitonin fractionation and indirect immunofluorescence microscopy showed that LdCS and LdSAT are localized in the cytoplasm of promastigotes. Size exclusion chromatography, co-purification, pull down and immuno-precipitation assays demonstrated a stable complex formation between LdCS and LdSAT proteins. Furthermore, LdCS and LdSAT proteins expression/activity was upregulated in amastigote growth stage of the parasite. Thus, the stage specific differential expression of LdCS and LdSAT suggests that it may have a role in the redox homeostasis of Leishmania . [ABSTRACT FROM AUTHOR]

In the recently published MATRIX (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX) trial, the use of transradial access (TRA) compared to transfemoral access (TFA) during percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) was associated with a reduction in net adverse cardiovascular events. However, the results of MATRIX must be interpreted with caution due to several limitations including the strong modulating effect of operator/center experience on the relative efficacy of TRA and the inclusion of 2 distinct patient populations (ST-segment elevation and non-ST-segment elevation ACS). Therefore, although important, the results of MATRIX have strong limitations and are not sufficient to definitively identify an approach of choice during PCI for ACS. Further research is needed before strong, evidence-based recommendations regarding the approach of choice during PCI for ACS can be made. [ABSTRACT FROM AUTHOR]

Cardiac arrest (CA) is relatively rare but lethal complication of takotsubo cardiomyopathy (TTC). In most instances, patients are diagnosed with TTC after CA, making it difficult to distinguish if TTC is the precipitant or the consequence of the index event. In this systematic review, patient-level data were obtained to seek out the characteristics of patients in whom the underlying cause of CA is TTC. A comprehensive search of 4 major databases (Embase, Ovid MEDLINE, PubMed, and Google Scholar) was performed from their inception to the last week of September 2014. Of 186 citations, 62 case studies were included in the analysis, providing patient-level data on 77 patients. In 60 patients (78%), the diagnosis of TTC was made after CA. Patients presenting with CA were younger (mean age 49.5 ± 16 vs 64.9 ± 11 years, p <0.0001) and had relatively shorter corrected QT interval (mean 530 ± 101 vs 616 ± 140 ms) on electrocardiography. TTC-related hypotension was the major cause of CA in the acute phase, while a long corrected QT interval triggered CA in the subacute (24- to 72-hour) phase. In 11 patients, CA was not directly instigated by TTC despite a left ventricular appearance matching TTC. In conclusion, in TTC, CA typically develops within the first 3 days of presentation and is the result of long corrected QT intervaleinduced polymorphic ventricular tachycardia. Secondary TTC, in which patients present with typical left ventricular features after CA, likely represents a distinct cohort in which identifiable inheritable arrhythmias or structural heart disease should be sought. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Takotsubo cardiomyopathy (TTC) is a disorder of myocardial inflammation induced by high catecholamine levels and is associated with acute complications. In the long-term TTC is associated with a risk of single or multiple recurrences, but risk of such occurrences is not clear. We performed a systematic review and meta-analysis to identify and consolidate the evidence on the incidence and clinical correlates of cases of TTC recurrence. Methods: A comprehensive search of four major databases (EMBASE, OVID Medline, PubMed and Google Scholar) was performed from their inception to first week of Jan 2014. We included original research studies, recruiting ≥5 participants, with ≥3months follow-up, published in English language that reported data on recurrence in patients with TTC. Results: Out of 298 studies searched, 31 cohorts (1664 TTC patients) were included in the analyses. Out of 74 cases of recurrence, with a mean follow-up of 24.5months (95% CI, 19.3 to 33months), extensive recurrence data were available for 23 cases. Cumulative incidence of recurrence was approximately 5% at 6years. Annual rate of recurrence was approximately 1.5%. Furthermore, 14% of cases had recurrent chest pain and 11% reported dyspnea without definite evidence of recurrent TTC. Discharge medications at index admission included β-adrenoceptor antagonists (BB) in 66.8% and ACE inhibitors (ACEi) and ARB in 67.4%. Recurrence rate was independent of clinic utilization of BB prescription, but inversely correlated (r =−0.45, p =0.016) with ACEi/ARB prescription. Patients with severe TTC at index admission were noted to have more recurrences. Conclusions: (1) TTC is associated with only 1–2% annual recurrence rate but substantially greater frequency of ongoing symptoms. (2) ACEi/ARB rather than BB may reduce risk of recurrence. [Copyright &y& Elsevier]

The incidence and clinical correlates of acute in-hospital mortality of takotsubo cardiomyopathy (TTC) are not clear. We performed a systematic review and meta-analysis to consolidate the current evidence on acute mortality in TTC.We then assessed the impact of "secondary" TTC, male gender, advancing age, and catecholamine use on mortality. A comprehensive search of 4 major databases (EMBASE, Ovid MEDLINE, PubMed, and Google Scholar) was performed from their inception to the first week of July 2013. We included original research studies, recruiting ‡10 participants, published in English language, and those that reported data on mortality and cause of death in patients with TTC. Of 382 citations, 37 studies (2,120 patients with TTC) from 11 different countries were included in the analyses. The mean age of the cohort was 68 years (95% confidence interval [CI] 67 to 69) with female predominance (87%). The in-hospital mortality rate among patients with TTC was 4.5% (95% CI 3.1 to 6.2, I² = 60.8%). Among all deaths, 38% were directly related to TTC complications and rest to underlying noncardiac conditions. Male gender was associated with higher TTC mortality rate (odds ratio 2.6, 95% CI 1.5 to 4.6, p = 0.0008, I² = 0%) so was "secondary" TTC (risk difference -0.11, 95% CI -0.18 to L0.04, p = 0.003, I² = 84%). The mean age of patients dying tended to be greater than that in the whole cohort (72 ± 7 vs 65 ± 7 years). In conclusion, TTC is not as benign as once thought. To reduce the mortality rate, greater efforts need to be directed to the diagnosis, treatment, and ultimately prevention of "secondary" TTC. [ABSTRACT FROM AUTHOR]

Takotsubo cardiomyopathy (TTC) is a well-known condition, which leads to sudden transient regional systolic dysfunction. It mostly affects aging women and is usually precipitated by emotional or physical stress. Despite the tremendous amount of literature on TTC, cardiac sympathetic hyperactivity is the only thing known to be associated with pathogenesis. In our case, an elderly woman presented with an acute episode of TTC 24 hours after anti-influenza vaccination without any obvious stressor for sudden rise in the catecholamine level. Sudden postvaccination change in the cardiac sympathetic discharge is the most likely precipitant of TTC in this case. [ABSTRACT FROM AUTHOR]

• Leishmaniasis is a neglected tropical disease and remains a global concern for the healthcare sector. • Different causative species exhibit various clinical manifestations ranging from skin ulcers to systemic infections. • Leishmania parasite modulates host immune responses to survive in a hostile host environment. • Understanding of immunological factors accountable for parasite survival within the host is crucial for unraveling novel therapies. Leishmaniasis, a neglected tropical disease, still remains a global concern for the healthcare sector. The primary causative agents of the disease comprise diverse leishmanial species, leading to recurring failures in disease diagnosis and delaying the initiation of appropriate chemotherapy. Various species of the Leishmania parasite cause diverse clinical manifestations ranging from skin ulcers to systemic infections. Therefore, host immunity in response to different forms of infecting species of Leishmania becomes pivotal in disease progression or regression. Thus, understanding the paradox of immune arsenals during host and parasite interface becomes crucial to eliminate this deadly disease. In the present review, we have elaborated on the immunological perspectives of the disease and discussed primary host immune cells that form a defense line to counteract parasite infection. Furthermore, we also have shed light on the immune cells and effector molecules responsible for parasite survival in host lethal milieu/ environment. Next, we have highlighted recent molecules/compounds showing potent leishmanicidal activities pertaining to their pro-oxidant and immuno-modulatory mechanisms. This review addresses an immuno-biological overview of the factors influencing the parasitic disease, as this knowledge can aid in the unraveling/ identification of potential biomarkers, novel therapeutics, and vaccine candidates against leishmaniasis. [ABSTRACT FROM AUTHOR]

We prospectively investigated the effect of a 3-wk course of parenteral nutrition with 20% glucose, 4.25% amino acids, and 10% Intralipid® on plasma lipids and lipoproteins in a cohort of 12 nutritionally replete patients with inflammatory bowel disease. Mean total serum cholesterol and mean total serum phospholipids increased in parallel throughout the study; density gradient ultracentrifugation demonstrated these increases were due to the appearance of lipoprotein-X. The mean low-density lipoprotein (LDL) mass on the density gradients decreased during the study and high-density lipoprotein (HDL) cholesterol levels decreased by 28% by the end of the third week. Plasma free fatty acids decreased by 42%. These results demonstrate that the glucose and 10% Intralipid® regimen caused modest decreases in serum HDL cholesterol and LDL mass and the prompt appearance of lipoprotein-X with attendant hypercholesterolemia and hyperphospholipidemia. Patients undergoing long-term treatment with glucose and Intralipid® should be closely monitored for the occurrence of significant dyslipoproteinemia. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "Natural history of cardiac arrest in patients with Takotsubo cardiomyopathy" by K. Singh and colleagues and a response to the same are presented.

Takotsubo cardiomyopathy (TTC) is uncommon emergency condition usually precipitated by emotional or physical stress and is characterized by near-normal coronary arteries and regional wall motion abnormalities that extend beyond a single coronary vascular territory. Variants of TTC include classic apical ballooning syndrome and less commonly, mid, basal, and biventricular variants. Cardiac arrest is an uncommon complication of TTC. In the convalescence phase of TTC, prolonged QTc interval may cause cardiac arrest, but the reason for cardiac arrest in the acute phase when QTc interval is normal is unclear. We report 3 cases of mid ventricular TTC, with out-of-hospital cardiac arrest as the presenting feature. All 3 patients had normal QTc interval and were found to have normal coronary arteries on cardiac catheterization at presentation. Mid ventricular TTC was confirmed on contrast left ventriculography and echocardiography. Cardiac arrest myocarditis was ruled out by myocardial biopsy in 2 deceased patients and by cardiac magnetic resonance imaging in the one who survived. [ABSTRACT FROM AUTHOR]

Takotsubo cardiomyopathy (TTC) has generally been regarded as a relatively transient disorder, characterized by reversible regional left ventricular systolic dysfunction. However, most patients with TTC experience prolonged lassitude or dyspnea after acute attacks. Although this might reflect continued emotional stress, myocardial inflammation and accentuated brain-type natriuretic peptide (BNP) release persist for at least 3 months. We therefore tested the hypotheses that this continued inflammation is associated with (1) persistent contractile dysfunction and (2) consequent impairment of quality of life. Echocardiographic parameters (global longitudinal strain [GLS], longitudinal strain rate [LSR], and peak apical twist [AT]) were compared acutely and after 3 months in 36 female patients with TTC and 19 age-matched female controls. Furthermore, correlations were sought between putative functional anomalies, inflammatory markers (T2 score on cardiovascular magnetic resonance, plasma NT-proBNP, and high-sensitivity C-reactive protein levels), and the physical composite component of SF36 score (SF36-PCS). In TTC cases, left ventricular ejection fraction returned to normal within 3 months. GLS, LSR, and AT improved significantly over 3-month recovery, but GLS remained reduced compared to controls even at follow-up (−17.9 ± 3.1% vs −20.0 ± 1.8%, p = 0.003). Impaired GLS at 3 months was associated with both persistent NT-proBNP elevation (p = 0.03) and reduced SF36-PCS at ≥3 months (p = 0.04). In conclusion, despite normalization of left ventricular ejection fraction, GLS remains impaired for at least 3 months, possibly as a result of residual myocardial inflammation. Furthermore, perception of impaired physical exercise capacity ≥3 months after TTC may be explained by persistent myocardial dysfunction. [ABSTRACT FROM AUTHOR]

The emergence of drug resistance continues to afflict TB control where drug resistant strains have become a global health concern. Contrary to drug-sensitive TB, the treatment of MDR/XDR-TB is more complicated requiring the administration of second-line drugs that are inefficient than the first line drugs and are associated with greater side effects. The emergence of drug resistant Mtb strains had coincided with an innovation void in the field of drug discovery of anti-mycobacterials. However, the approval of bedaquiline and delamanid recently for use in MDR/XDR-TB has given an impetus to the TB drug discovery. The review discusses the drug discovery efforts in the field of tuberculosis with a focus on the strategies adopted and challenges confronted by TB research community. Here, we discuss the diverse clinical candidates in the current TB drug discovery pipeline. There is an urgent need to combat the current TB menace through multidisciplinary approaches and strategies making use of the recent advances in understanding the molecular biology and pathogenesis of Mtb. The review highlights the recent advances in drug discovery, with the host directed therapeutics and nanoparticles-drug delivery coming up as important tools to fight tuberculosis in the future. [Display omitted] • Drug discovery for Tuberculosis has resuscitated after a four decades of inactivity with the new FDA approved drugs, bedaquiline and delamanid. • Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) challenge the public health system with limited drug options. • The TB drug pipeline has adequate number of compounds that are under phase I/II/III clinical trials for their safety, efficacy and tolerability on the TB patients. • Repurposing FDA approved drugs being used in other disease interventions can help in shortening the course of drug discovery as the potential hits can jump directly to phase II clinical trials. • Effective strategies including nanotechnology, gene-editing tools, host-directed bacterial killing should be utilized to better exploit the diverse chemical space for TB drug discovery. [ABSTRACT FROM AUTHOR]

The pathogenicity of protozoan parasites is frequently attributed to their ability to circumvent the deleterious effects of ROS and Fe-S clusters are among their susceptible targets with paramount importance for parasite survival. The biogenesis of Fe-S clusters is orchestrated by ISC system; the sulfur donor IscS and scaffold protein IscU being its core components. However, among protozoan parasites including Leishmania , no information is available regarding biochemical aspect of IscU, its interaction partners and regulation. Here, we show that Leishmania donovani IscU homolog, LdIscU, readily assembles [2Fe-2S] clusters and, interestingly, follows Michaelis-Menten enzyme kinetics. It is localized in the mitochondria of the parasite and interacts with LdIscS to form a stable complex. Additionally, LdIscU and Fe-S proteins activity is significantly upregulated in resistant isolates and during stationary growth stage indicating an association between them. The differential expression of LdIscU modulated by Fe-S proteins demand suggests its potential role in parasite survival and drug resistance. Thus, our study provides novel insight into the Fe-S scaffold protein of a protozoan parasite. [ABSTRACT FROM AUTHOR]

Leishmania is a unicellular protozoan parasite which causes leishmaniasis, a neglected tropical disease. It possess a unique thiol metabolism comprising of several proteins among which, tryparedoxin (cTXN) and tryparedoxin peroxidase (cTXNPx), function in concert as oxidoreductases, utilizing trypanothione as a source of electrons to reduce the hydroperoxides produced by macrophages during infection. This detoxification pathway is unique and essential for the survival of Leishmania . Herein, we report the functional characterization of Leishmania donovani cTXN and its interaction with cTXNPx. The full length recombinant cTXN and cTXNPx proteins were purified in the native state and biochemical analysis showed that the cTXN-cTXNPx coupled system efficiently degraded hydrogen peroxide and tert-butyl hydroperoxide by transferring reducing equivalents from trypanothione. In silico investigation of the potential interaction between cTXN and cTXNPx proteins showed strong interaction of model structures with amino acids Ile109, Thr132, Glu107, Trp70, Trp39, Cys40 and His129 of Ld-cTXN and Thr54, Lys93, Arg128 and Asn152 of Ld-cTXNPx predicted to be involved in interaction. Moreover, co-purification, pull down assay and immunoprecipitation studies confirmed the interaction between Ld-cTXN and Ld-cTXNPx proteins. In addition, for the first time, we demonstrated at the translational level that Ld-cTXN protein is upregulated in Amp B resistant isolates accompanied by enhanced peroxidase activity, as compared to sensitive strains. Thus, our results show that Ld-cTXN and Ld-cTXNPx proteins acts in concert by physical interaction to form a strong peroxide stress detoxification system in Leishmania and their upregulation in Amp B resistant isolates imparts better stress tolerance, and hence fitter pathogens, as compared to sensitive strains. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a neglected tropical disease and remains a global concern for healthcare. It is caused by an opportunistic protozoan parasite belonging to the genus Leishmania and affects millions worldwide. This disease is mainly prevalent in tropical and subtropical regions and is associated with a high risk of public morbidity and mortality if left untreated. Transmission of this deadly disease is aggravated by the bite of female sand-fly vectors (Phlebotomus and Lutzomyia). With time, significant advancement in leishmaniasis-related research has been carried out to cope with the disease burden. Still, the Leishmania parasite has also co-evolved with its host and adapted successfully within the host's lethal milieu/environment. Thus, understanding and knowledge of various leishmanial virulence factors responsible for the parasitic infection are essential for exploring drug targets and vaccine candidates. The present review elucidates the importance of virulence factors in pathogenesis and summarizes the major leishmanial virulence molecules contributing to the parasitic infection during host-pathogen interaction. Furthermore, we have also elaborated on the potential contribution of leishmanial virulence proteins in developing vaccine candidates and exploring novel therapeutics against this parasitic disease. We aim to represent a clearer picture of parasite pathogenesis within the human host that can further aid in unraveling new strategies to fight against the deadly infection of leishmaniasis. [Display omitted] • Leishmaniasis is a neglected tropical disease caused by the protozoan parasite of the genus Leishmania. • Leishmania is an opportunistic and evolving parasite that modulates host immune responses for survival. • Leishmanial virulence factors play a decisive role in establishing parasitic infection. • Identifying and mapping virulence factors is pivotal for exploring drug targets and vaccine candidates. [ABSTRACT FROM AUTHOR]

Leishmania donovani is a unicellular protozoon parasite that causes visceral leishmaniasis (VL), which is a fatal disease if left untreated. Certain Fe–S proteins of the TCA cycle and respiratory chain have been found in the Leishmania parasite but the precise mechanisms for their biogenesis and the maturation of Fe–S clusters remains unknown. Fe–S clusters are ubiquitous cofactors of proteins that perform critical cellular functions. The clusters are biosynthesized by the mitochondrial I ron– S ulphur C luster (ISC) machinery with core protein components that include the catalytic cysteine desulphurase IscS, the scaffold proteins IscU and IscA, and frataxin as an iron carrier/donor. However, no information regarding frataxin, its regulation, or its role in drug resistance is available for the Leishmania parasite. In this study, we characterized Ld-frataxin to investigate its role in the ISC machinery of L. donovani . We expressed and purified the recombinant Ld-frataxin protein and observed its interaction with Ld-IscU by co-purification and pull-down assay. Furthermore, we observed that the cysteine desulphurase activity of the purified Ld-IscS protein was stimulated in the presence of Ld-frataxin and Ld-IscU, particularly in the presence of iron; neither Ld-frataxin nor Ld-IscU alone had significant effects on Ld-IscS activity. Interestingly, RT-PCR and western blotting showed that Ld-frataxin is upregulated in AmpB-resistant isolates compared to sensitive strains, which may support higher Fe–S protein activity in AmpB-resistant L. donovani . Additionally, Ld-frataxin was localized in the mitochondria, as revealed by digitonin fractionation and indirect immunofluorescence. Thus, our results suggest the role of Ld-frataxin as an iron binding/carrier protein for Fe–S cluster biogenesis that physically interacts with other core components of the ISC machinery within the mitochondria. [ABSTRACT FROM AUTHOR]

Leishmaniasis is regarded as a neglected tropical disease by World Health Organization (WHO) and is ranked next to malaria as the deadliest protozoan disease. The primary causative agents of the disease comprise of diverse leishmanial species sharing clinical features ranging from skin abrasions to lethal infection in the visceral organs. As several Leishmania species are involved in infection, the role of accurate diagnosis becomes pivotal in adding new dimensions to anti-leishmanial therapy. Diagnostic methods must be fast, reliable, easy to perform, highly sensitive, and specific to differentiate among similar parasitic diseases. Herein, we present the conventional and recent approaches impended for the disease diagnosis and their sensitivity, specificity, and clinical application in parasite detection. Furthermore, we have also elaborated various new methods to cure leishmaniasis, which include host-directed therapies, drug repurposing, nanotechnology, and combinational therapy. This review addresses novel techniques and innovations in leishmaniasis, which can aid in unraveling new strategies to fight against the deadly infection. •Leishmaniasis is a neglected tropical disease and is regarded as a global health issue by WHO •Fast and accurate diagnosis of this deadly disease is essential to reduce morbidity and mortality •Recent diagnostic approaches such as proteomics, flow cytometry, nano-diagnosis, and advanced molecular techniques have proved to be revolutionary •Novel treatment strategies such as host-directed therapy, drug repurposing, and nanotechnology are the future of leishmaniasis treatment [ABSTRACT FROM AUTHOR]