Bio-Membrane Internalization Mechanisms of Arginine-Rich Cell-Penetrating Peptides in Various Species

Recently, membrane-active peptides or proteins that include antimicrobial peptides (AMPs), cytolytic proteins, and cell-penetrating peptides (CPPs) have attracted attention due to their potential applications in the biomedical field. Among them, CPPs have been regarded as a potent drug/molecules delivery system. Various cargoes, such as DNAs, RNAs, bioactive proteins/peptides, nanoparticles and drugs, can be carried by CPPs and delivered into cells in either covalent or noncovalent manners. Here, we focused on four arginine-rich CPPs and reviewed the mechanisms that these CPPs used for intracellular uptake across cellular plasma membranes. The varying transduction efficiencies of them alone or with cargoes were discussed, and the membrane permeability was also expounded for CPP/cargoes delivery in various species. Direct membrane translocation (penetration) and endocytosis are two principal mechanisms for arginine-rich CPPs mediated cargo delivery. Furthermore, the amino acid sequence is the primary key factor that determines the cellular internalization mechanism. Importantly, the non-cytotoxic nature and the wide applicability make CPPs a trending tool for cellular delivery.

The Anticancer Potential of Doxycycline and Minocycline—A Comparative Study on Amelanotic Melanoma Cell Lines

Malignant melanoma is still a serious medical problem. Relatively high mortality, a still-growing number of newly diagnosed cases, and insufficiently effective methods of therapy necessitate melanoma research. Tetracyclines are compounds with pleiotropic pharmacological properties. Previously published studies on melanotic melanoma cells ascertained that minocycline and doxycycline exerted an anti-melanoma effect. The purpose of the study was to assess the anti-melanoma potential and mechanisms of action of minocycline and doxycycline using A375 and C32 human amelanotic melanoma cell lines. The obtained results indicate that the tested drugs inhibited proliferation, decreased cell viability, and induced apoptosis in amelanotic melanoma cells. The treatment caused changes in the cell cycle profile and decreased the intracellular level of reduced thiols and mitochondrial membrane potential. The exposure of A375 and C32 cells to minocycline and doxycycline triggered the release of cytochrome c and activated initiator and effector caspases. The anti-melanoma effect of analyzed drugs appeared to be related to the up-regulation of ERK1/2 and MITF. Moreover, it was noticed that minocycline and doxycycline increased the level of LC3A/B, an autophagy marker, in A375 cells. In summary, the study showed the pleiotropic anti-cancer action of minocycline and doxycycline against amelanotic melanoma cells. Considering all results, it could be concluded that doxycycline was a more potent drug than minocycline.

A Panoramic Review of Benzimidazole Derivatives and Their Potential Biological Activity

The therapeutic potential of the benzimidazole nucleus dates back to 1944, being and important heterocycle system due to its presence in a wide range of bioactive compounds such as antiviral, anticancer, antibacterial, and so on, where optimization of substituents in this class of pharmacophore has resulted in many drugs. Its extensive biological activity is due to its physicochemical properties like hydrogen bond donor-acceptor capability,  stacking interactions, coordination bonds with metals as ligands and hydrophobic interactions; properties that allow them to easily bind with a series of biomolecules, including enzymes and nucleic acids, causing a growing interest in these types of molecules. This review aims to present an overview to leading benzimidazole derivatives, as well as to show the importance of the nature and type of substituents at the N1, C2, and C5(6) positions, when they are biologically evaluated, which can lead to obtaining potent drug candidate with significant range of biological activities.

A Computational Approach to Predict the Molecular Drug Targets Against Candida glabrata

Non- albicans Candida (NAC) species are responsible for 35-65% of all candidaemias in the general population and are associated with a high rate of morbidity and mortality (about 15% to 35%). The availability of few commercially used antifungal drugs against candidiasis and rapid emergences of antibiotic resistance among NAC species has significantly contributed to their increased global outbreak. Green tea is known for its multi-beneficial effects including antimicrobial potential against Candida. The present study investigated the molecular drug targets of green tea phytocompounds against inhibition of ergosterol biosynthesis in Candida glabrata using in silico tools.The molecular interaction was studied between ligands and essential proteins participating in ergosterol biosynthesis in C. glabrata using autodockvina software. The protein validation and homology modeling estimation were determined by the SWISS MODEL workspace. The Drug likeness study of all the test ligands was performed using SwissADME, while the toxicity of test compounds was analyzed using the admetSAR 2.0 version.The in silico analyses identified Rutin, Chlorogenic acid, Coumaroylquinic acid, Quercetin, Epigallocatechingallate as the potent phytocompounds with significant molecular binding with Erg 6, Erg 27, Erg 8, Erg 7, Erg 24 respectively. The ADMET data suggested an absence of the CYP2 inhibitors indicating the metabolism of all the tested drug candidates in the intestine and liver.The present study highlighted the possible drug targets of green tea phytocompounds against ergosterol biosynthesis protein in C. glabrata. It is pertinent that the current study has provided preliminary breakthroughs which could lead to exploring their avenues in potent drug development against NAC species.

A Case Report on Ayurvedic Management of Dushta Vrana

Dushta vrana is a commonly encountered problem in day-to-day practice. Contemporary progress in the field of surgery has reduced the incidence of wound infection to a great extent along with the use of antibiotics. But still the management of ulcer encounters many glitches. This case study discusses about a 58-year-old male patient who presented with a chronic non healing ulcer in the anterior aspect of the left ankle joint associated with pain, burning sensation, foul smelling and inflammation with no history of varicose veins. Patient was treated with Karaskara ksheera kashaya dhara followed by dressing with Jathyadi ghrta. Punarnavadi kashayam and Guggulupanchapala choornam was given internally for a period of 35days. Virechana with Avipathy Choornam was given once during the whole course of the treatment. Raktamokshana was done twice as Jaloukavacharana. In order to enhance the speedy recovery, traditional use of Kupeelu was considered. A highly potent drug among the Upavisha which is well known for properties like Vranahara, Soolahara, Kushtahara, Sothaghna etc. which augments the peripheral blood circulation, reduces pain, burning sensation and inflammation. The wound healed within a period of 35 days and got complete relief from pain, burning sensation and swelling. Thus, the patient was successfully treated with no complications.

Improved Anticancer Activities of a New Pentafluorothio-Substituted Vorinostat-Type Histone Deacetylase Inhibitor

The development of new anticancer drugs is necessary in order deal with the disease and with the drawbacks of currently applied drugs. Epigenetic dysregulations are a central hallmark of cancerogenesis and histone deacetylases (HDACs) emerged as promising anticancer targets. HDAC inhibitors are promising epigenetic anticancer drugs and new HDAC inhibitors are sought for in order to obtain potent drug candidates. The new HDAC inhibitor SF5-SAHA was synthesized and analyzed for its anticancer properties. The new compound SF5-SAHA showed strong inhibition of tumor cell growth with IC50 values similar to or lower than that of the clinically applied reference compound vorinostat/SAHA (suberoylanilide hydroxamic acid). Target specific HDAC inhibition was demonstrated by Western blot analyses. Unspecific cytotoxic effects were not observed in LDH-release measurements. Pro-apoptotic formation of reactive oxygen species (ROS) and caspase-3 activity induction in prostate carcinoma and hepatocellular carcinoma cell lines DU145 and Hep-G2 seem to be further aspects of the mode of action. Antiangiogenic activity of SF5-SAHA was observed on chorioallantoic membranes of fertilized chicken eggs (CAM assay). The presence of the pentafluorothio-substituent of SF5-SAHA increased the antiproliferative effects in both solid tumor and leukemia/lymphoma cell models when compared with its parent compound vorinostat. Based on this preliminary study, SF5-SAHA has the prerequisites to be further developed as a new HDAC inhibitory anticancer drug candidate.

A Comprehensive Review on the Chemical Composition and Pharmacological Activities of Acacia catechu (L.f.) Willd.

With the emergence of epidemics, pandemics, and infectious diseases, several research activities have been carried out on natural products to tackle them. As there are structural diversities in natural products, researchers are focused on exploring them for treatment and/or management of various infections and/or diseases. Acacia catechu (L.f.) Willd. belonging to the order Fabales and family Fabaceae shows a wide range of pharmacological functions in the management of diseases in humankind. This review was carried out to gather and provide information about the chemical constituents and pharmacological activities of A. catechu through the literature survey of scientific articles. On preliminary assessments, A. catechu is demonstrated as a significant wellspring of bioactive compounds with a wide range of biological and pharmaceutical applications such as antidiabetic, antioxidant, antimicrobial, anticancer, antidiarrheal, anti-inflammatory, antiviral, hepatoprotective, immunomodulatory, and so on. Although the metabolites from the plant are reported with diverse pharmacological applications, there is little information in regards to toxicity and clinical trials on bioactive compounds of this plant. Further research on diverse bioactive compounds from the plant is required to develop them as a successful potent drug.

MDR1 Drug Efflux Pump Promotes Intrinsic and Acquired Resistance to PROTACs in Cancer Cells

ABSTRACTPROTACs (Proteolysis-Targeting Chimeras) represent a promising new class of drugs that selectively degrade proteins of interest from cells. PROTACs targeting oncogenes are avidly being explored for cancer therapies, with several currently in clinical trials. Drug resistance represents a significant challenge in cancer therapies, and the mechanism by which cancer cells acquire resistance to PROTACs remains poorly understood. Using proteomics, we discovered acquired and intrinsic resistance to PROTACs in cancer cells can be mediated by upregulation of the drug efflux pump MDR1. PROTAC-resistant cells could be re-sensitized to PROTACs through co-administering MDR1 inhibitors. Notably, co-treatment of MDR1-overexpressing colorectal cancer cells with MEK1/2 or KRASG12C degraders and the dual ErbB receptor/MDR1 inhibitor lapatinib exhibited potent drug synergy due to simultaneous blockade of MDR1 and ErbB receptor activity. Together, our findings suggest that concurrent blockade of MDR1 will likely be required in combination with PROTACs to achieve durable protein degradation and therapeutic response in cancer.

Sanguiins—Promising Molecules with Broad Biological Potential

Compounds of natural origin, an infinite treasure of bioactive chemical entities, persist as an inexhaustible resource for discovering new medicines. In this review, we summarize the naturally occurring ellagitannins, sanguiins, which are bioactive constituents of various traditional medicinal plants, especially from the Rosaceae family. In-depth studies of sanguiin H-6 as an antimicrobial, antiviral, anticancer, anti-inflammatory, and osteoclastogenesis inhibitory agent have led to potent drug candidates. In addition, recently, virtual screening studies have suggested that sanguiin H-6 might increase resistance toward SARS-CoV-2 in the early stages of infection. Further experimental investigations on ADMET (absorption, distribution, metabolism, excretion, and toxicity) supplemented with molecular docking and molecular dynamics simulation are still needed to fully understand sanguiins’ mechanism of action. In sum, sanguiins appear to be promising compounds for additional studies, especially for their application in therapies for a multitude of common and debilitating ailments.