Current Pharmaceutical Design - Volume 27, Issue 28, 2021

Valeriana officinalis L. (Valerianaceae) is one of the most reputed ancient medicinal plants used in modern phytotherapy and traditional medicine. Its root extract is one of the most effective herbal sedatives and tranquilizers, where the plant is also used for the treatment of gastrointestinal spasms. V. officinalis has complex phytochemistry consisting of the esterified iridoid derivatives known as valepotriates (e.g., valtrate, didrovaltrate, isovalerenic acid), sesquiterpenes (e.g., valerenic acid), flavonoids (e.g., linarin, apigenin), lignans (e.g., pinoresinol, hydroxypinoresinol), alkaloids (e.g., actinidine, valerine), triterpenes (e.g., ursolic acid), monoterpenes (e.g., borneol, bornyl acetate). Among them, valerenic acid is a marker compound for standardization of the root extracts of the plant and has been reported in many in vitro/in vivo studies to be responsible for anxiolytic action of the plant. Although modulation of gamma-aminobutyric acid (GABA) receptors has been revealed to be the leading mechanism of the plant-based on the existence of valerenic acid, several studies described the interaction of valerenic acid with glutamergic receptors. In addition to valerenic acid, isovaleric acid, didrovaltrate, borneol, and some lignans have also been proposed to contribute to the anxiolytic effect of the plant. In the current review, the data selectively scrutinized from the in vitro/in vivo studies about identifying anxiolytic molecular mechanisms of V. officinalis is focused.

Background: In the late 20th century, the leading role of signaling pathways in various cancers is revealed via some genome's systematic investigations. The Akt/GSK-3 signaling pathway is one of the critical signaling pathways dysregulated in numerous human cancers. The Akt cascade acts in the cancer process by regulating apoptosis, cell cycle, metabolism, and cells' longevity. The GSK-3 is downstream of Akt, which has an opposite role in cancer progression. Objective: Attending to the importance of the Akt/GSK-3 pathway in cancer progression and the positive result of natural products in cancer treatment, this research is designed to review effective herbal medicines in one of the involvement critical signal pathways of cancer for developing novel anticancer drugs. Method: Keywords "plant", "natural", "cancer", "AKT", and "GSK" were searched through the "Scopus" and "Google scholar" databases up to 30th August 2020. Papers linking to pharmacology, toxicology, and pharmaceutics were collected and discussed. Results and Conclusion: The Akt/GSK-3 signaling pathway plays a prominent role in cancer. Although the effect of GSK-3 in cancer cells is depended on the type and contents of cells, the inhibition of Akt/GSK-3 mostly is led to three primary outcomes in cancer cells, including (1) apoptotic activity and autophagy induction, (2) anti-proliferative and growth inhibitory effects, and (3) anti-metastatic and angiogenesis effects. As the tendency to use natural products increases, we gathered 64 plants or bioactive components with the anticancer activity via the Akt/GSK-3 signaling pathway. Since most of these investigations have been conducted on cell lines, these plants can be the right candidate to be evaluated in human trials.

Background: Despite the great interest and numerous studies, there is currently no unified standard describing the sequential manipulation with cells to obtain exosomes for clinical use.The use of exosomes has become an attractive alternative to cell therapy, since the flexible nature of these biological vesicles allows scientists to manipulate their composition to produce the desired exosomes carrying specific drugs, RNA and proteins. This study aimed to analyse scientific literature on the changes in the functional characteristics of exosomes, depending on the method of manipulation, potentially contributing to the development of negative effects in the treatment of diseases of inflammatory genesis. Results: The choice of isolation method affects the expressed sets of protein markers, nucleic acids and receptors on microparticles. Various surface receptors present on the exosome membrane can be engineered to target lesions. Exosomes from healthy patients help to reduce inflammation, normalize intercellular communication and have anti-fibrotic, antioxidant, and cytoprotective effects. Exosomes can change the microenvironment, but the microenvironment can also change the composition of exosomes. Conclusion: Exosomes obtained from sick patients carry markers characteristic of the corresponding disease. Such exosomes can have pro-inflammatory, pro-fibrotic, cytotoxic, and oncogenic properties, and disrupt cellular cooperation. Until now, questions regarding the dose, reactions to repeated administration, and dosage regimes have not been completely resolved.

Aortic aneurism development is dependent on internal and external etiological factors that define the width of the therapeutic window available for the treatment of patients with such diagnosis. In this review, we provide a detailed overview of the most prominent of these factors. In particular, we discuss the input of elevated blood pressure to the remodeling of the aortic wall, describe the mechanisms of inflammatory remodeling of the aorta, and evaluate the cross-interaction of blood pressure, inflammation and immunity during the pathology development. Better understanding of this interaction will allow broadening the therapeutic options available for patients with aortic aneurism or preventive strategies for patients with known risk factors. To date, modulation of the immune signaling appears to be a promising point of the therapeutic intervention for the treatment of such patients. In this article, we also discuss the search for new diagnostic markers predicting changes in the width of the therapeutic window for the management of patients with aortic aneurysm.

Background: Normalization of the stromal microenvironment is a promising strategy for cancer control. Cancer-associated fibroblasts, tumor-associated macrophages, and mesenchymal stromal cells have a central role in stromal functions. Accordingly, understanding these stromal cells is indispensable for the development of next-generation cancer therapies. Growing evidence suggests that calpain-induced intracellular proteolysis is responsible for cancer growth and stromal regulation. Calpain is a family of stress-responsive intracellular proteases and is inducible in cancer and stromal cells during carcinogenesis. Objective: Here, we shed light on the recent advances that have been made in understanding how calpain contributes to stromal regulation in cancer. Conclusion: Calpains are activated in stromal cells, including pancreatic stellate cells and mesenchymal cells. They induce fibrogenic responses in cancer stroma. Moreover, these molecules contribute to epithelial-mesenchymal transition and endothelial-mesenchymal transition to provide mesenchymal stromal cells in the microenvironment and concomitantly participate in cancer angiogenesis. In addition to the conventional calpains, the unconventional calpain-9 is associated with epithelial-mesenchymal transition. Animal experiments showed that targeting calpain systems antagonizes cancer development; thus, this approach is promising for cancer control.

Tumor-associated macrophages (TAMs) are M2 phenotype dominant and promote tumor growth and metastasis. The new cancer treatment strategy includes TAM targeting and is aimed primarily at reprogramming TAMs toward the M1 phenotype or reducing the number and activity of M2 macrophages. Several marine invertebrate-derived drugs, combining efficacy and a low level of side effects, were approved for use in the cancer therapy. The mechanisms of action of some of them include TAM targeting. The review includes data showing immunomodulatory properties of these already approved anticancer drugs and drug candidates in clinical development which additionally incorporate data from screening studies of new substances from marine invertebrates. Based on screening data, the most promising marine compounds for cancer immunotherapy are supposed.

DNA damage usually happens in all cell types, which may originate from endogenous sources (i.e., DNA replication errors) or be emanated from radiations or chemicals. These damages range from changes in few nucleotides to significant structural abnormalities on chromosomes and, if not repaired, could disturb the cellular homeostasis or cause cell death. As the most significant response to DNA damage, DNA repair provides biological pathways by which DNA damages are corrected and returned into their natural circumstance. However, an aberration in the DNA repair mechanisms may result in genomic and chromosomal instability and the accumulation of mutations. The activation of oncogenes and/or inactivation of tumor suppressor genes is a serious consequence of genomic and chromosomal instability and may bring the cells into a cancerous phenotype. Therefore, genomic and chromosomal instability is usually considered a crucial factor in carcinogenesis and an important hallmark of various human malignancies. In the present study, we review our current understanding of the most updated mechanisms underlying genomic instability in cancer and discuss the potential promises of these mechanisms in finding new targets for the treatment of cancer.