Benzothiazole benzimidazole (S)-isothiazolidinone derivatives as protein tyrosine phosphatase-1B inhibitors

Benzothiazole benzimidazole (S)-isothiazolidinone ((S)-IZD) derivatives 5 were discovered through a peptidomimetic modification of the tripeptide (S)-IZD protein tyrosine phosphatase 1B (PTP1B) inhibitor 1. These derivatives are potent, competitive, and reversible inhibitors of PTP1B with improved caco-2 permeability. An X-ray co-crystal structure of inhibitor 5/PTP1B at 2.2A resolution demonstrated that the benzothiazole benzimidazole forms bi-dentate H-bonds to Asp48, and the benzothiazole interacts with the surface of the protein in a solvent exposed region towards the C-site. The design, synthesis, and SAR of this novel series of benzothiazole benzimidazole containing (S)-IZD inhibitors of PTP1B are presented herein.     

Synthesis and trypanocidal activity of ent-kaurane glycosides

Novel ent-kaurane glucosides were synthezised by a Koenigs-Knorr reaction between C17 and C19 alcohols derived from kaurenoic acid and 2,3,4,6-tetra-O-acetyl-glucopyranosyl bromide, followed by the hydrolysis of the acetates. Main products were assayed in vitro and in vivo against blood trypomastigote forms of Trypanosoma cruzi, the aetiological agent of Chagas' disease (American trypanosomiasis). The results allowed to establish structure-activity relationships among these derivatives, as well as pointed out the C19-methylester-C17-O-glucoside as a potential trypanocidal agent, whose trypanocidal profile was shown to be comparable to those of gentian violet and benznidazole.     

Structure-based drug design studies of the interactions of ent-kaurane diterpenes derived from Wedelia paludosa with the Plasmodium falciparum sarco/endoplasmic reticulum Ca2+-ATPase PfATP6

Malaria is responsible for more deaths around the world than any other parasitic disease. Due to the emergence of strains that are resistant to the current chemotherapeutic antimalarial arsenal, the search for new antimalarial drugs remains urgent though hampered by a lack of knowledge regarding the molecular mechanisms of artemisinin resistance. Semisynthetic compounds derived from diterpenes from the medicinal plant Wedelia paludosa were tested in silico against the Plasmodium falciparum Ca²⁺-ATPase, PfATP6. This protein was constructed by comparative modelling using the three-dimensional structure of a homologous protein, 1IWO, as a scaffold. Compound 21 showed the best docking scores, indicating a better interaction with PfATP6 than that of thapsigargin, the natural inhibitor. Inhibition of PfATP6 by diterpene compounds could promote a change in calcium homeostasis, leading to parasite death. These data suggest PfATP6 as a potential target for the antimalarial ent-kaurane diterpenes.     

Hepsin regulates TGFβ signaling via fibronectin proteolysis

Transforming growth factor‐beta (TGFβ) is a multifunctional cytokine with a well‐established role in mammary gland development and both oncogenic and tumor‐suppressive functions. The extracellular matrix (ECM) indirectly regulates TGFβ activity by acting as a storage compartment of latent‐TGFβ, but how TGFβ is released from the ECM via proteolytic mechanisms remains largely unknown. In this study, we demonstrate that hepsin, a type II transmembrane protease overexpressed in 70% of breast tumors, promotes canonical TGFβ signaling through the release of latent‐TGFβ from the ECM storage compartment. Mammary glands in hepsin CRISPR knockout mice showed reduced TGFβ signaling and increased epithelial branching, accompanied by increased levels of fibronectin and latent‐TGFβ1, while overexpression of hepsin in mammary tumors increased TGFβ signaling. Cell‐free and cell‐based experiments showed that hepsin is capable of direct proteolytic cleavage of fibronectin but not latent‐TGFβ and, importantly, that the ability of hepsin to activate TGFβ signaling is dependent on fibronectin. Altogether, this study demonstrates a role for hepsin as a regulator of the TGFβ pathway in the mammary gland via a novel mechanism involving proteolytic downmodulation of fibronectin.     

The Safety Assessment of Toxic Metals in Commonly Used Pharmaceutical Herbal Products and Traditional Herbs for Infants in Jordanian Market

The objective of this study was to assess the levels of contamination by toxic metals (Pb, Al, Ni, Cd and As) that may be present in 25 infant pharmaceutical herbal products and 15 traditional herbs in Jordan. Both products and medicinal herbs are currently prescribed by paediatricians. They are available as over-the-counter medicines and are sold the in herbal market, ensuring easy accessibility for parents. Inductively coupled plasma-optical emission spectroscopy (ICP-OES), with limit of detections (LODs) of 0.10, 1.00, 0.20, 0.15 and 2.00 mg.kg⁻¹ for Pb, Al, Ni, Cd and As respectively, was employed to measure the levels of toxic metals in the samples. Pb, Al and Ni were detected in 88, 76 and 4% of the analysed samples of pharmaceutical herbal products and in 93, 87 and 13% of the analysed samples of traditional herbs, respectively. Neither Cd or As were detected in all analysed samples. The data obtained were subsequently compared by referral to the acceptable limits of toxic heavy metals according to World Health Organisation (WHO) standards. Largely, the results showed acceptable toxic metal levels in the finished pharmaceutical products and the traditional medicinal herbs for infants. One exception to this was Persian Thyme (Satureja thymbra) with Pb content of 41.18 mg.kg⁻¹. Also, the daily intake of detected metals through pharmaceutical herbal products was found to be lower than the daily tolerable intake limit set by the regulatory bodies, except of 8% of products that exceeded the tolerable daily intake of Pb set by US FDA, as compared to traditional medicinal herbs, where the tolerable daily intake for Pb, Al and Ni were exceeded in 40, 60 and 8% of the analysed herbs, respectively. The results obtained revealed that the excessive use of medicinal plants as alternative medicine should be used with caution keeping in mind the safety factor in infants.

     

Bi-Functional Biobased Packing of the Cassava Starch,Glycerol, Licuri Nanocellulose and Red Propolis

The aim of this study was to characterize and determine the bi-functional efficacy of active packaging films produced with starch (4%) and glycerol (1.0%), reinforced with cellulose nanocrystals (0–1%) and activated with alcoholic extracts of red propolis (0.4 to 1.0%). The cellulose nanocrystals used in this study were extracted from licuri leaves. The films were characterized using moisture, water-activity analyses and water vapor-permeability tests and were tested regarding their total phenolic compounds and mechanical properties. The antimicrobial and antioxidant efficacy of the films were evaluated by monitoring the use of the active films for packaging cheese curds and butter, respectively. The cellulose nanocrystals increased the mechanical strength of the films and reduced the water permeability and water activity. The active film had an antimicrobial effect on coagulase-positive staphylococci in cheese curds and reduced the oxidation of butter during storage.     

Association of Empirically Derived Dietary Patterns with Cardiovascular Risk Factors: A Comparison of PCA and RRR Methods

IntroductionPrincipal component analysis is used to determine dietary behaviors of a population whereas reduced rank regression is used to construct disease-related dietary patterns. This study aimed to compare both types of DP and theirs associations with cardiovascular risk factors (CVRF).ResultsWe found that CVRF-related patterns also reflect eating behaviours of the population. Comparing concordant food groups between both dietary pattern methods, a diet high in fruits, oleaginous and dried fruits, vegetables, olive oil, fats rich in omega 6 and tea and low in fried foods, lean and fatty meat, processed meat, ready meal, soft drink and beer was associated with lower prevalence of CVRF. In the opposite, a pattern characterized by high intakes of fried foods, meat, offal, beer, wine and aperitifs and spirits, and low intakes of cereals, sugar and sweets and soft drinks was associated with higher prevalence of CVRF.ConclusionIn sum, we found that a “Prudent” and “Animal protein and alcohol” patterns were both associated with CVRF and behaviourally meaningful. Moreover, the relationships of those dietary patterns with lifestyle characteristics support the theory that food choices are part of a larger pattern of healthy lifestyle.     

A close‐up view of dynamic biomarkers in the setting of COVID‐19: Striking focus on cardiovascular system

Based on the recent reports, cardiovascular events encompass a large portion of the mortality caused by the COVID‐19 pandemic, which drawn cardiologists into the management of the admitted ill patients. Given that common laboratory values may provide key insights into the illness caused by the life‐threatening SARS‐CoV‐2 virus, it would be more helpful for screening, clinical management and on‐time therapeutic strategies. Commensurate with these issues, this review article aimed to discuss the dynamic changes of the common laboratory parameters during COVID‐19 and their association with cardiovascular diseases. Besides, the values that changed in the early stage of the disease were considered and monitored during the recovery process. The time required for returning biomarkers to basal levels was also discussed. Finally, of particular interest, we tended to abridge the latest updates regarding the cardiovascular biomarkers as prognostic and diagnostic criteria to determine the severity of COVID‐19.