There are substantial shortcomings in the drugs currently available for treatment of type 2 diabetes mellitus. The global diabetic crisis has not abated despite the introduction of new types of drugs and targets. Persistent unaddressed patient needs remain a significant factor in the quest for new leads in routine studies. Drug discovery methods in this area have followed developments in the market, contributing to a recent rise in the number of molecules. Nevertheless, troubling developments and fresh challenges are still evident. Recently, metformin, the most widely used first-line drug for diabetes, was found to contain a carcinogenic contaminant known as N-nitroso dimethylamine (NDMA). Therefore, purity and toxicity are also a big challenge for drug discovery and development. Moreover, newer drug classes against SGLT-2 illustrate both progress and difficulties. The same was true previously in the case of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Furthermore, researchers must study the importance of mechanistic characteristics of novel compounds, as well as exposure-related hazardous aspects of current and newly identified protein targets, in order to identify new pharmacological molecules with improved selectivity and specificity.

Phosphorylated chitosan (PC), a water-soluble derivative of chitosan possesses several biological and chemical properties suitable for diabetic wound healing. In the present study, we report the synthesis and diabetic wound healing capabilities of PC. Elemental analysis, FT-IR, ¹³C-NMR and ³¹P-NMR techniques were employed for the chemical characterization of PC. In vitro, antioxidant properties of PC were determined in terms of Fe³⁺ reducing, metal chelating, lipid peroxidation and superoxide scavenging ability. The wound healing potential of PC was assessed in diabetic excisional wound rat model. PC exhibited good water solubility, and in vitro antioxidant capacity. Wound contraction was higher in PC-treated wounds (91.11%) as compared to untreated wounds (67.26%) on 14^th-day post wound creation. Histopathology of PC-treated wounds revealed improved tissue morphology with higher number of fibroblasts, a thicker epithelial layer, enhanced collagen deposits and angiogenesis as compared to untreated wounds. An overall increase of 57% and 25% in hydroxylamine and hexosamine content respectively were noted as compared to untreated wounds. A significant (P ≤ 0.05) increase in SOD activity and a significant (P ≤ 0.05) decrease in lipid peroxides were recorded in PC-treated wounds as compared to untreated wounds. These observations demonstrated that PC can be used as an effective agent in diabetic wound healing. Graphical Abstract Illustration of phosphorylated chitosan (PC) synthesis and its wound healing potential: Chitosan was phosphorylated to impart diabetic wound healing properties. Chemical characterizations such as elemental analysis, FT-IR and NMR confirmed successful phosphorylation of chitosan. PC exhibited good in vitro antioxidant properties. To assess the diabetic wound healing potential, an excisional wound model was developed in diabetic rats. PC treatment demonstrated accelerated wound healing.

Amoebiasis is a major public health problem in tropical and subtropical countries. Currently, metronidazole is the gold choice medication for the treatment of this disease. However, reports have indicated towards the possibility of development of metronidazole-resistance in Entamoeba strains in near future. In view of the emergence of this possibility, in addition to the associated side effects and mutagenic ability of the currently available anti-amoebic drugs, there is a need to explore newer therapeutics against this disease. In this context, the present study evaluated the amoebicidal potential of cryptdin-2 against E. histolytica. In the present study, cryptdin-2 exhibited potent in-vitro amoebicidal activity against E. histolytica in a concentration dependent manner at a minimum amoebicidal concentration (MAC) of 4 mg/L. Scanning electron microscopy as well as phase contrast microscopic investigations of cryptdin-2 treated trophozoites revealed that the peptide was able to induce significant morphological alterations in terms of membrane wrinkling, leakage of the cytoplasmic contents and damaged plasma membrane suggesting a possible membrane dependent amoebicidal activity. N-phenyl napthylamine (NPN) uptake assay in presence of sulethal, lethal as well as twice the lethal concentrations further confirmed the membrane-dependent mode of action of cryptdin-2 and suggested that the peptide could permeabilize the plasma membrane of E. histolytica. It was also found that cryptdin-2 interfered with DNA, RNA as well as protein synthesis of E. histolytica exerting the highest effect against DNA synthesis. Thus, the macromolecular synthesis studies correlated well with the observations of membrane permeabilization studies. The amoebicidal efficacy of cryptdin-2 suggests that it may be exploited as a promising option to combat amoebiasis or, at least, may act as an adjunct to metronidazole and/or other available anti-amoebic drugs. Intestinal amoebiasis, caused by Enatmoeba histolytica continues to be a major public health problem in tropical and subtropical countries and is considered to be the third principal parasitic disease responsible for mortality in the world. In addition to the mutagenic ability and known toxicity of conventional anti-amoebic drugs, there are reports indicating the emergence of treatment failures to these drugs. Therefore, there has been a considerable interest in exploring the potential of various antimicrobial peptides having higher efficacy and lower toxicity to combat such parasitic infections. Herein, we present the amoebicidal efficacy of cryptdin-2, a Paneth cell alpha-defensin against E. histolytica. Cryptdin-2 was found to decrease the number of trophozoites of E. histolytica in a concentration dependent manner. By and large, cryptdin-2 could retain its amoebicidal activity in the presence of cations, bile salts and at various pH values. Microscopic analysis and N-phenyl napthylamine (NPN) uptake assay revealed membrane dependent amoebicidal action of the peptide. It was also demonstrated that cryptdin-2 has the potential to target the intracellular macromolecular synthesis machinery of Entamoeba. Based on these results, cryptdin-2 seems to be a promising agent for the development of novel therapeutics against amoebiasis or at least may act as an adjunct to conventional antibiotics against E. histolytica.