Endogenous cysteine protease inhibitors in upmost pathogenic parasitic protozoa.

The regulation of the activity of proteases by endogenous inhibitors is a common trend in almost all forms of life. Here, we review the endogenous inhibitors of cysteine proteases of three major pathogenic parasitic protozoa. The review focuses on members of the genus Plasmodium, Entamoeba, and Leishmania. Research in this domain has revealed the presence of only chagasin-like inhibitors of cysteine proteases that house a ß-barrel immunoglobulin-fold and inhibit the target proteases using a 3-loop inhibitory mechanism in these pathogens. Inhibitors of cysteine proteases are highly evolvable enzymes that target a broad spectrum of pathogenic cysteine proteases with a proclivity for those involved in host-parasite interactions. A common trend reflects a limited sequence homology between cysteine proteases and their inhibitors. The inhibitors are also known to participate in other housekeeping functions of the parasites. Generalizations about their roles are thus best avoided. In this review, the reader will find comprehensive information on the cellular localization of inhibitors of cysteine proteases, their structure, function, and the associated mechanisms of action. The reader will also find a thorough analysis of the role of these inhibitors in parasite pathology and the common trends interlinking them with parasite biology and evolution.

Exosomes, extracellular vesicles and the eye.

Exosomes are a subset of extracellular vesicles which accommodate a cargo of bioactive biomolecules that generally includes proteins, nucleic acids, lipids, sugars, and related conjugates depicting the cellular environment and are known to mediate a wide array of biological functions, like cellular communication, cellular differentiation, immunomodulation, neovascularization, and cellular waste management. The exponential implication of exosomes in the pathological development and progression of various disorders including neurodegenerative diseases, cardiovascular diseases, and cancer has offered a tremendous opportunity for exploring their role in ocular conditions. Ocular diseases such as age-related macular disease, glaucoma, infectious endophthalmitis, diabetic retinopathy, autoimmune uveitis etc face various challenges in their early diagnosis and treatments due to contributing factors such as delay in the onset of symptoms, microbial identification, difficulty in obtaining samples for biopsy or being diagnosed as masquerade syndromes. Studies have reported unique exosomal cargos that are involved in successful delivery of miRNA or proteins to recipient cells to express desired expression or exploited as a diagnostic marker for various diseases. Furthermore, engineered exosomes can be used for targeted delivery of therapeutics and exosomes being natural nanoparticles found in all types of cells, host may not elicit an immune response against it. With the rapid advancement of opting personalized therapeutics, extending exosomal research to sight-threatening ocular infections can possibly advance the current diagnostic and therapeutic approaches. This review briefs about the current knowledge of exosomes in visual systems, advancements in exosomal and ophthalmic research, participation of exosomes in the pathogenesis of common ocular diseases, the challenges for exosomal therapies along with the future of this promising domain of research for diseases that fatally threaten billions of people worldwide.

Cysteine proteases: Battling pathogenic parasitic protozoans with omnipresent enzymes.

Millions of people worldwide lie at the risk of parasitic protozoic infections that kill over a million people each year. The rising inefficacy of conventional therapeutics to combat these diseases, mainly due to the development of drug resistance to a handful of available licensed options contributes substantially to the rising burden of these ailments. Cysteine proteases are omnipresent enzymes that are critically implicated in the pathogenesis of protozoic infections. Despite their significance and druggability, cysteine proteases as therapeutic targets have not yet been translated into the clinic. The review presents the significance of cysteine proteases of members of the genera Plasmodium, Entamoeba, and Leishmania, known to cause Malaria, Amoebiasis, and Leishmaniasis, respectively, the protozoic diseases with the highest morbidity and mortality. Further, projecting them as targets for molecular tools like the CRISPR-Cas technology for favorable manipulation, exploration of obscure genomes, and achieving a better insight into protozoic functioning. Overcoming the hurdles that prevent us from gaining a better insight into the functioning of these enzymes in protozoic systems is a necessity. Managing the burden of parasitic protozoic infections pivotally depends upon the betterment of molecular tools and therapeutic concepts that will pave the path to an array of diagnostic and therapeutic applications.

Averting transmission: A pivotal target to manage amoebiasis.

Amoebiasis is a parasitic infectious disease caused by the enteric protozoan Entamoeba histolytica, a leading basis of deaths accounted to parasites, succeeding malaria and schistosomiasis. Conventional treatment methodologies used to deal with amoebiasis mainly rely on the administration of anti-amoebic compounds and vaccines but are often linked with substantial side-effects on the patient. Besides, cases of development of drug resistance in protozoans have been recorded, contributing further to the reduction in the efficiency of the treatment. Loopholes in the efficacious management of the disease call for the development of novel methodologies to manage amoebiasis. A way to achieve this is by targeting the essential metabolic processes of 'encystation' and 'excystation', and the associated biomolecules, thus interrupting the biphasic life cycle of the parasite. Technologies like the CRISPR-Cas9 system can efficiently be exploited to discover novel and essential molecules that regulate the protozoan's metabolism, while efficiently manipulating and managing the known drug targets, leading to an effective halt and forestall to the enteric infection. This review presents a perspective on these essential metabolic processes and the associated molecules that can be targeted efficaciously to prevent the transmission of amoebiasis, thus managing the disease and proving to be a fruitful endeavour.