Inhibition of Cysteine Proteases by 6,6'-Dihydroxythiobinupharidine (DTBN) from Nuphar lutea.

The specificity of inhibition by 6,6'-dihydroxythiobinupharidine (DTBN) on cysteine proteases was demonstrated in this work. There were differences in the extent of inhibition, reflecting active site structural-steric and biochemical differences. Cathepsin S (IC50 = 3.2 µM) was most sensitive to inhibition by DTBN compared to Cathepsin B, L and papain (IC50 = 1359.4, 13.2 and 70.4 µM respectively). DTBN is inactive for the inhibition of Mpro of SARS-CoV-2. Docking simulations suggested a mechanism of interaction that was further supported by the biochemical results. In the docking results, it was shown that the cysteine sulphur of Cathepsin S, L and B was in close proximity to the DTBN thiaspirane ring, potentially forming the necessary conditions for a nucleophilic attack to form a disulfide bond. Covalent docking and molecular dynamic simulations were performed to validate disulfide bond formation and to determine the stability of Cathepsins-DTBN complexes, respectively. The lack of reactivity of DTBN against SARS-CoV-2 Mpro was attributed to a mismatch of the binding conformation of DTBN to the catalytic binding site of Mpro. Thus, gradations in reactivity among the tested Cathepsins may be conducive for a mechanism-based search for derivatives of nupharidine against COVID-19. This could be an alternative strategy to the large-scale screening of electrophilic inhibitors.

Seahorses - a source of traditional medicine.

Wild marine organisms have been used in the discovery and development of traditional and allopathic medical treatments for a long time. Seahorses, a syngnathidae fish, are one of the important candidate organisms which have been used in Chinese traditional medicine from time immemorial. It is believed that seahorses have the potential to cure infertility, baldness, asthma and arthritis. An authentic research work on the biomedical validation of seahorses proved that they have the ability to cure arthritis and its associated inflammation. A Cathepsin-derived peptide from the seahorse species of Hippocampus kuda proved to be effective in chondrocyte cells and its associated impaired arthritis inflammation. Apart from this, seahorses have a putative free radical scavenging effect in controlling the ageing process. More authentic research is needed in order to validate the biomedical potential. This article highlights the role of seahorses' value in traditional medicine and their biomedical properties.

The relative merits of anabolics versus anti-resorptive compounds: where our targets should be, and whether we are addressing them.

Currently available results from fracture trials provide evidence that the most potent anti-resorptive agents reduce vertebral and non-vertebral fractures maximally by 61% and 51%, respectively. Results from the Phase III trial with denosumab, the human monoclonal antibody, are eagerly awaited. Denosumab leads to sustained 80-90% reduction of bone resorption markers, which is below the level commonly achieved with bisphosphonates, and it will be interesting to see whether this leads to an improvement in its anti-fracture efficacy over bisphosphonates. If the majority of the anti-fracture efficacy of anti-resorptive agents results from the reduction of the remodelling space (removal of stress raisers) and the conservation of structural integrity of cancellous bone, a further decrease in bone resorption might not be desirable, especially as suppression of the residual remodelling capacity could lead to an increased risk for accumulation of microdamage. In contrast to anti-resorptive agents, the bone anabolic parathyroid hormone activates modelling drifts, which act to increase trabecular thickness and add bone predominantly on the endocortical, and to a lesser degree the periosteal, surface. Despite its anabolic nature, reduction of vertebral and non-vertebral fractures is only marginally better than those achieved with anti-resorptive agents. Ageing compromises locomotor capacity and is associated with an increased risk of falls. Perhaps it is time to shift our attendance to the age-related deterioration of muscle or neuromuscular function as a target and add this 'adjuvant therapy' to the potent anti-remodelling and bone anabolic agents available for the treatment of osteoporosis if we truly want to reduce fracture incidence beyond what is possible today.

Determination of cysteine peptidases-like activity and their inhibitors in the serum of patients with ovarian cancer treated by conventional chemotherapy and vitamin E.

Enzymatic activity of cysteine peptidases (cathepsins B and L) --associated with carcinogenesis is controlled by their specific inhibitors. The study was objected to the effects enhanced by taxol and cisplatin in patients pretreated with the vitamin E, by determining the levels of cathepsins B and L in sera of patients with ovarian cancer. The activity of cysteine peptidase (CP) and their inhibitors (CPI) in serum from patients with ovarian cancer and noncancerous patients were measured by using fluorogenic substrate before and after the routine anticancer chemotherapy, and a complementary combination of chemotherapy with vitamin E. The cat B and L activities were significantly higher in patient sera with ovarian cancer than non-cancerous patients (0.0001 pounds sterling). The results shows that, inhibitory activity of CPI and complex form were significantly decreased from 4.6 mEU/mg protein in a group of non-cancerous patients to 0.7 mEU/mg protein in a group of patients with ovarian cancer (p < or = 0.0001). Supplementation with vitamin E after a cycle of therapy with toxic drugs caused a decrease of the cysteine peptidases activities, that is 2.8-fold in patients to whom 40 0mg of vitamin E per day was given in comparison with control, and 6-fold after the third course. The CPI and DCPI complex increased 3-fold and 2.3 fold respectively, as compared to a group of patients were vitamin E was not administered. We observed that vitamin E administered to the patients with ovarian cancer in periods between anticancer drugs therapy courses decreases the cysteine peptidases activity and increases the enzyme-inhibitor complexes level

[Effect of adjuvants on the cellular function of the monocytic phagocytosing system]. / Vliianie ad"iuvantov na funktsiiu kletok monotsitarnoi fagotsitiruiushchei sistemy

The authors studied the effect of adjuvants differing by origin and physico-chemical nature (complete Freund's adjuvant, S. typhi endoxin, cadmium sulfate, iron trichloride) on the ingestion and digestion of erythrocytes of the sheep by the cells of monocytic phagocytizing system, on the persistence of the antigen in these cells, its complexation with the RNA-macrophages and the function of their lysosomal apparatus. The adjuvants change the phagocytizing capacity of the macrophages only in their administration in vivo. Administration to the animals of Freund adjuvant and of the S. typhic endotoxin somewhat increased the ingestion of the antigens, whereas the administration of FeCl3 and CdSO4 failed to change it or even somewhat decreased it. The capacity of ingestion of the antigen in vitro in macrophages obtained from the animals treated with the adjuvants was changed in comparison with the normal. All the adjuvants tested produced a marked action on the lysosomal apparatus of the cells of the monocytic phagocytizing system: they changed the activity of catepsin, promoted the accumulation and the retention in the lysosomes of the highly immunogenic fractions of the antigen, and increased the permeability (except the CdSO4 of the lysosomal membranes in the cells of the antigen binding with the RNA of the cells of the peritoneal exudate or the splenic cells.