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Cysteine proteases play a crucial role in the development of the human malaria parasites Plasmodium falciparum and Plasmodium vivax. Our earlier studies demonstrated that these enzymes are equipped with specific domains for defined functions and further suggested the mechanism of activation of cysteine proteases. The activities of these proteases are regulated by a new class of endogenous inhibitors of cysteine proteases (ICPs). Structural studies of the ICPs of Trypanosoma cruzi (chagasin) and Plasmodium berghei (PbICP) indicated that three loops (termed BC, DE, and FG) are crucial for binding to target proteases. Falstatin, an ICP of P. falciparum, appears to play a crucial role in invasion of erythrocytes and hepatocytes. However, the mechanism of inhibition of cysteine proteases by falstatin has not been established. Our study suggests that falstatin is the first known ICP to function as a multimeric protein. Using site-directed mutagenesis, hemoglobin hydrolysis assays and peptide inhibition studies, we demonstrate that the BC loop, but not the DE or FG loops, inhibits cysteine proteases of P. falciparum and P. vivax via hydrogen bonds. These results suggest that the BC loop of falstatin acts as a hot-spot target for inhibiting malarial cysteine proteases. This finding suggests new strategies for the development of anti-malarial agents based on protease-inhibitor interactions.

We present two cases which underwent complex ocular surface reconstruction to achieve a stable ocular surface. Conjunctival autograft (CAG) procedure was required more than once, in addition to simple limbal epithelial transplantation to address extensive symblepharon in the eyes with total unilateral limbal stem cell deficiency secondary to acid ocular burns. These cases demonstrate that multiple CAGs may be harvested from the contralateral unaffected eye to correct recurrent symblepharon without any donor site complications if the correct surgical technique is adopted. [ABSTRACT FROM AUTHOR]

Angiosperms and bryophytes, though distantly related plant groups, have many similar ecological and economic implications, including medicinal value. Therefore, this study aimed to analyse the phenolic and flavonoids composition and antioxidant and antimicrobial activities of Helianthus annuus L. (Angiosperms-Asteraceae) and another plant, a moss (Bryophyta), Hyophila involuta (Hook.) Jaeg., aerial parts (leaves), prepared in four different extracts (methanol, chloroform, distilled water, and petroleum ether). Phytochemical screening was conducted using standard methods of precipitation and colouration reactions. The Folin-Ciocalteu method was employed to determine the total phenol content, while the Aluminium Chloride Colorimetric method was used for flavonoid content determination. The antioxidant activity was measured through two methods: DPPH and NOSA scavenging activity. The phytochemical screening detected the presence and absence of fixed oils and fats, flavonoids, saponins, terpenoids, tannins, polyphenols, carbohydrates, and glycosides in both plants. The antibacterial and antifungal activity of both plants' methanolic extracts was examined against bacterial and fungal pathogens, i.e., Escherichia coli and Bacillus subtilis and fungal strains, i.e., Fusarium oxysporum and Aspergillus niger. The results were compared to a regular antibiotic disc and negative control that served as a methanol solvent. The methanolic extract of H. annuus has higher total phenol and flavonoid content, as well as antioxidant and antimicrobial activity, than H. involuta. Based on these data, it can be concluded that, while H. annuus is more effective than H. involuta, both distantly related plant species have similar phytochemical profiles and should be included equally in future herbal compositions. [ABSTRACT FROM AUTHOR]

Indolyl thioethers and indolin‐2‐one motifs are extremely common in pharmaceuticals and organic materials, therefore developing a method to create these scaffolds is considered to be a vital endeavour in the chemical sciences. Here we have reported a unified strategy developed by the fine‐tuning of catalyst‐solvent combination [SOCl2 /AlCl3 in CHCl3 and SOCl2/DMSO (1 : 1) in CHCl3 at 25 °C] towards selective functionalization of Indole to synthesize 2,2′‐thiobisindoles and 3‐chloro‐3‐alkyl substituted oxindoles selectively in one‐pot manner with good to satisfactory yield (52‐86 %; 26 Examples). In application, reactions of 3‐subsituted indole and isatin derivatives produced the 1‐(chloromethyl) indoline‐2,3‐diones by just changing the reaction condition (60 °C), which shows the synthetic utility of the developed method. [ABSTRACT FROM AUTHOR]

Objective: Status epilepticus (SE) requires rapid intervention to prevent cerebral injury and mortality. The ketogenic diet, which bypasses glycolysis, is a promising remedy for patients with refractory SE. We tested the role of glycolytic lactate production in sustaining SE. Methods: Extracellular lactate and glucose concentration during a seizure and SE in vivo was measured using lactate and glucose biosensors. A lactate dehydrogenase inhibitor, oxamate, blocked pyruvate to lactate conversion during SE. Video‐EEG recordings evaluated seizure duration, severity, and immunohistochemistry was used to determine neuronal loss. Genetically encoded calcium indicator GCaMP7 was used to study the effect of oxamate on CA1 pyramidal neurons in vitro. Spontaneous excitatory postsynaptic currents (sEPSCs) were recorded from CA1 neurons to study oxamate's impact on neurotransmission. Results: The extracellular glucose concentration dropped rapidly during seizures, and lactate accumulated in the extracellular space. Inhibition of pyruvate to lactate conversion with oxamate terminated SE in mice. There was less neuronal loss in treated compared to control mice. Oxamate perfusion decreased tonic and phasic neuronal activity of GCaMP7‐expressing CA1 pyramidal neurons in vitro. Oxamate application reduced the frequency, but not amplitude of sEPSCs recorded from CA1 neurons, suggesting an effect on the presynaptic glutamatergic neurotransmission. Interpretation: A single seizure and SE stimulate lactate production. Diminishing pyruvate to lactate conversion with oxamate terminated SE and reduced associated neuronal death. Oxamate reduced neuronal excitability and excitatory neurotransmission at the presynaptic terminal. Glycolytic lactate production sustains SE and is an attractive therapeutic target. [ABSTRACT FROM AUTHOR]