Current Medicinal Chemistry - Volume 30, Issue 29, 2023

Background: The topical use of vitamin C has been explored for many decades due to its antioxidant potential, whitening action, and the essential role it plays in the synthesis and maintenance of collagen. As Ascorbic Acid (AA) is unstable, derivative molecules and stabilization strategies have been explored to facilitate its incorporation into dermatological products. Even though these molecules are already for sale, there is still a shortage of scientific data regarding efficacy studies of these assets, especially in vivo. Objective: The purpose of this review was to investigate and discuss issues regarding the topical application of vitamin C and its most common derivatives, including the difficulties, biases, and prospects for future clinical studies to better elucidate its effects. Methods: A literature review was carried out to select studies that evaluated the topical use of ascorbic acid and/or its derivatives. The studies which are “fully available”, “in vivo” and “in vitro”, were used as inclusion criteria. Results: Due to the instability of Ascorbic Acid, it is essential to study derivative molecules that maintain or even improve their effectiveness in dermatological products. Despite this, the studies of these derivatives presented in the scientific literature are mostly in vitro. In recent years, it has been possible to observe an increase in in vivo efficacy tests, and this trend is expected to continue in the future. However, they present very different approaches and issues. Conclusion: Studies of stability, safety, adverse reactions, and especially in vivo efficacy studies with a relevant number of subjects and standardized parameters are essential for better elucidating the effects of the topical application of vitamin C derivatives in comparison to ascorbic acid formulations for the skin.

Background: Breast cancer is considered to be 2nd most common cancer subtype investigated worldwide. It is mainly prevalent in postmenopausal women. Estrogen Receptor (ER) is a primary transcription factor for the survival and growth of tumors. Around 80% BCs of all classes are ER-positive (ER+). Powerful evidence for estrogen proved to be involved in BC pathogenesis both exogenously and endogenously. It brings the concept of ER inhibitors to treat BC with distinct mechanisms into focus and ER PROTACs (Proteolysis-Targeting Chimeras), AIs (Aromatase inhibitors), SERMs (Selective estrogen receptor modulators), and SERDs (Selective estrogen receptor degrader) were developed. For over 30 years, Tamoxifen, a triphenylethylene SERM, was the drug of choice solely to treat ER+BC patients. Although several SERMs got approval by US FDA after tamoxifen, complicacies remain because of dangerous adverse effects like endometrial carcinoma, hot flashes, and VTE (Venous thromboembolism). In addition to that, drug-resistant tumors put a surging need for novel, potent candidates with no or low adverse effects for ER+ BC prevention. Objectives: This article explores the possibilities of SERMs as effective BC agents. Methods: A detailed literature survey of the history and recent advancements of SERMs has been carried out, taking BC as the primary target. This review provides information about ER structure, signaling, pharmacological action, chemical classification with SAR analysis, and benefits and adverse effects of SERMs as potential BC agents. Results: Exhaustive literature studies suggested that SERMs having an agonistic, antagonistic or mixed activity to ER could efficiently inhibit BC cell proliferation. Conclusion: Each chemical class of SERMs comprises some salient features and potentials, which may be further investigated to obtain novel effective SERMs in BC therapy.

Drug delivery systems based on nanotechnology exhibit a number of advantages over traditional pharmacological formulations. Polymeric nanoparticles are commonly used as delivery systems and consist of synthetic or natural polymers that protect drugs from degradation in physiological environments. In this context, indolamine melatonin has been associated with several biological functions, including antioxidant, antitumor, immunoregulatory, neuroprotective, and cardioprotective effects. However, its availability, half-life, and absorption depend upon the route of administration, and this can limit its therapeutic potential. An alternative is the use of polymeric nanoparticle formulations associated with melatonin to increase its bioavailability and therapeutic dose at sites of interest. Thus, the objective of this review is to provide a general and concise approach to the therapeutic association between melatonin and polymeric nanoparticles applied to different biological disorders and to also highlight its advantages and potential applications compared to those of the typical drug formulations that are available.

Cancer remains a major worldwide health challenge. Current studies emphasize the tumor microenvironment that plays a vital role in tumor proliferation, invasion, metastasis, and drug resistance. The tumor microenvironment (TME) supports the cancer cell to evade conventional treatment such as surgery, radiotherapy, and chemotherapy. Moreover, the components of tumor microenvironments have a major contribution towards developing therapy resistance in solid tumors. Therefore, targeting the tumor microenvironment can be a novel approach for achieving advancement in cancer nanomedicine. The recent progress in understanding TME and developing TME-responsive nanoparticles offers a great advantage in treating cancer drug resistance. These nanoparticles are developed in response to TME stimuli such as low pH, redox, and hypoxia improve nanomedicine's pharmacokinetic and therapeutic efficacy. This review discusses the various components of the tumor microenvironment responsible for drug resistance and nanomedicine's role in overcoming it.

Background: The diagnostic value of apolipoprotein A-I (ApoA-I) as a marker of different malignancies has been reported in several investigations; however, the results have been contradictory. The current meta-analysis examined the association between ApoA-I levels and human malignancies. Methods: We reviewed the databases and retrieved papers for analysis until November 1st, 2021. Random-effects meta-analysis was performed to construct the pooled diagnostic parameters. To find the causes of heterogeneity, we utilized Spearman threshold effect analysis and subgroup analysis. The I² and Chi-square tests were used to examine the heterogeneity. Moreover, subgroup analyses were performed based on sample type (serum/urine) and geographical region of study. Finally, publication bias was explored using Begg's and Egger’s tests. Results: A total of 11 articles involving 4,121 participants (2,430 cases and 1,691 controls) were included. The overall pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.764 (95% CI: 0.746 - 0.781), 0.795 (95% CI: 0.775 - 0.814), 5.105 (95% CI: 3.313 - 7.865), 0.251 (95% CI: 0.174 - 0.364), 24.61 (95% CI: 12.22 - 49.54), and 0.93, respectively. In subgroup analyses, better diagnostic values were found for urine samples and East Asian Countries (China, Korea, and Taiwan). Conclusion: Urinary ApoA-I levels may serve as a favorable diagnostic marker for cancer.

Background: The role of WT1-associated protein (WTAP) in mediating the N6-methyladenosine (m6A) modification of pyruvate dehydrogenase kinase 4 (PDK4) in colorectal cancer (CRC) has been previously reported. Objective: This research manages to unveil the function and mechanism of WTAP mediating the m6A modification in CRC. Methods: Expressions of PDK4 and WTAP in CRC were assessed by bioinformatics analysis and verified by Western blot. After the transfection with short hairpin RNAs (shRNAs) for WTAP (shWTAP) and PDK4 (shPDK4) to manipulate the expressions of PDK4 and WTAP, the viability, proliferation, migration, invasion, and levels of m6A, PDK4 and WTAP in CRC cells were determined by cell counting kit-8 (CCK-8), colony formation, transwell, Western blot, or M6A-RNA immunoprecipitation (MeRIP)-qPCR assays. M6A binding sites in PDK4 were additionally predicted through bioinformatics analysis, and the interaction of PDK4 and WTAP was confirmed using an RNA pull-down assay. Tumor volume and weight in the constructed xenograft-tumor mouse model were recorded. Results: PDK4 expression was low, yet WTAP and m6A expressions were high in CRC cells. WTAP bound with the m6A binding sites in PDK4. PDK4 silencing facilitated the viability, proliferation, migration and invasion, inhibited the expression of PDK4 in CRC cells, and accelerated the growth of xenografts in vivo. However, the depletion of WTAP4 exerted the opposite effects and further offset the impact of PDK4 silencing. Conclusion: WTAP mediates the m6A modification of PDK4 to regulate the malignant behaviors of CRC cells in vitro and in vivo.