Future Pharmacol., Volume 4, Issue 3 (September 2024) – 11 articles

Ovarian cancer (OC) ranks as the fifth most common cancer among women in the United States and globally, posing a significant health threat. Reactive oxygen species (ROS) have emerged as critical factors in the pathophysiology of this malignancy. ROS, characterized by their instability due to an unpaired electron, are involved in essential cellular functions and play a crucial role in the immune response under normal physiological conditions. However, an imbalance in ROS homeostasis, leading to excessive ROS production, results in oxidative stress (OS), which can cause indiscriminate damage to cellular structures and contribute to the pathogenesis of specific diseases, including OC. OC is primarily classified based on the originating cell type into epithelial, stromal, and germinal tumors, with epithelial tumors being the most prevalent. Despite advancements in medical technology, early detection of OC remains challenging, often leading to delayed treatment initiation. Current therapeutic approaches include surgical excision of tumor tissue, radiotherapy, and chemotherapy. While these treatments are effective in early-stage OC, high mortality rates and frequent relapse underscore the urgent need for novel diagnostic and therapeutic strategies. This review aims to elucidate the role of ROS in OC, emphasizing the potential for developing innovative diagnostic tools and treatments that target ROS-mediated pathways. Given the critical impact of early detection and effective treatment, advancing our understanding of ROS in the context of OC could significantly enhance patient outcomes. Full article

Esophageal cancer (EC) is a very common form of cancer in developing countries, and its exponential progression is a cause for concern. Available treatments face the phenomenon of multi-drug resistance, as well as multiple disabling side effects. The number of deaths is expected to double by 2030 if nothing is done. Due to their high representativeness in plants, phenolic compounds are a potential alternative for halting the spread of this disease, which bereaves many thousands of families every year. This study aims to identify phenolic compounds with activity against esophageal cancer, assess their toxicological profiles, and explore future perspectives. To achieve this, the literature search was meticulously carried out in the Google Scholar, Scopus, Web of Sciences, and Pub-Med/Medline databases, in accordance with the PRISMA 2020 guidelines. The results show that proanthocyanidin and curcumin represent promising therapeutic options, given their significant in vitro and in vivo activity, and their safety in human subjects in clinical trials. Moscatilin, Genistein, and pristimerin have anticancer activities (≤10 µM) very close to those of doxorubicin and 5-FU, although their safety has not yet been fully established. The compounds identified in vivo exhibit highly significant activities compared with the results obtained in vitro, and are sometimes more effective than the molecules conventionally used to treat EC. Generally, with the exceptions of plumbagin, lapachol, and β-lapachone, all other molecules are relatively non-toxic to normal human cells and represent a therapeutic avenue to be explored by pharmaceutical companies in the fight against esophageal cancer. However, more detailed toxicological studies of certain molecules remain a priority. Full article

Cannabis sativa L. has garnered attention as a potential source for new antimicrobial agents, particularly due to the increased prevalence of microbial resistance to conventional antimicrobials and the emergence of multidrug-resistant pathogens. This review, conducted according to the PRISMA 2020 statement, systematically analyzed the antimicrobial properties of C. sativa extracts and cannabinoids against various bacteria, fungi, viruses, and parasites. Data were collected from the scientific literature (102 papers) and clinical trials (5 studies) from 2014 to June 2024. Findings revealed that cannabinoids, especially CBD, demonstrate significant antimicrobial activity against Gram-positive bacteria like MRSA, Gram-negative bacteria such as Pseudomonas aeruginosa, various Candida species, SARS-CoV-2, and HIV. Additionally, CBD showed efficacy against parasitic infections like Echinococcus granulosus and Leishmania species. These results suggest that cannabinoids may represent a new class of antimicrobial agents with unique and diverse mechanisms of action, potentially effective in broad-spectrum therapies. This study highlights the urgent need for further research and standardized clinical trials to validate these findings and to develop cannabinoid-based treatments. The antimicrobial properties of C. sativa align with WHO priorities and support global health initiatives, offering promising avenues for addressing antimicrobial resistance and improving public health outcomes. Full article

Genetic factors influence medication response (pharmacogenetics), affecting the pharmacodynamics and pharmacokinetics of many medicaments used in clinical care. The ability of medications to cross the blood–brain barrier (BBB) represents a critical putative factor in the effectiveness and tolerability of various medications relevant to central nervous system disorders (CNS), cancer, and broader medical conditions at a pharmacokinetic (dosing) level. Pharmacogenetics has the potential to personalise medicine to a greater extent than has been possible, with the potential to help reduce heuristic delays to effective tolerable pharmacotherapy. Here, we critically examine and summarise the evidence, particularly for ABCB1 polymorphisms associated with drug transportation and other clinical relevance. These transporters appear to have a role in BBB pharmacogenetics and may indicate new avenues of research that extend beyond the current paradigm of CYP450 polymorphisms. We identify some of the most promising variants for clinical translation while spotlighting the complexities of the involved systems and limitations of the current empirical literature. Full article

We have synthesized 22 symmetric and asymmetric 4-aryl-1,4-dihydropyridines (1,4-DHPs) by a “green” microwave-assisted one-pot multicomponent Hantzsch reaction and evaluated their cytotoxicity to three human cancer cell lines regarding U-251MG (human glioblastoma), HeLa 229 (human cervical adenocarcinoma), and MCF-7 (human breast carcinoma). None of the 1,4-DHPs were cytotoxic to U-251MG cells. Most of the 1,4-DHPs did not affect HeLa 229 or MCF-7 cell viability. On the other hand, symmetric 1,4-DHPs 18 (diethyl 4-(4-benzyloxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate), 19 (diethyl 4-(4-bromophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate), and 20 (diethyl 4-(3-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) reduced the HeLa (IC₅₀ = 3.6, 2.3, and 4.1 µM, respectively) and MCF-7 (IC₅₀ = 5.2, 5.7, and 11.9 µM, respectively) cell viability. These 1,4-DHPs were more cytotoxic to the HeLa and MCF-7 cells than to the GM07492 (normal human fibroblast) cells, as evidenced by their selectivity indexes. Therefore,1,4-DHPs 18, 19, and 20 may serve as novel lead compounds to discover other 1,4-DHP derivatives with improved anticancer potency and selectivity. Full article

Sex-related differences in psychopharmacology present unique challenges in both clinical and research settings. Recognition of sex differences in psychopharmacological treatment has increased in recent years, but a significant research gap regarding variations between men and women still exists. Biological factors, including hormonal fluctuations, genetic factors, and brain structure differences, contribute significantly to differential drug responses. Moreover, social determinants can influence the differential burden of psychiatric disorders between the sexes and may impact treatment plans. Incorporating sex as a key variable in personalized treatment programs and plans holds the potential to optimize efficacy and minimize adverse effects in psychopharmacology. Sex-related challenges in psychopharmacology necessitate a nuanced approach to treatment. Further research is needed to fully understand these differences and to develop guidelines for personalized medication management. By addressing these challenges, clinicians can improve treatment outcomes and enhance the quality of life of patients with psychiatric disorders. Full article

(1) Background: The SARS-CoV-2 papain-like protease (PLpro) remains an underexplored antiviral target so far. The reduced efficacy of approved treatments against novel variants highlights the importance of developing new agents. This review aims to provide a comprehensive understanding of phytochemicals as inhibitors of PLpro, identify gaps, and propose novel insights for future reference. (2) Methods: A thorough literature search was conducted using Google Scholar, ScienceDirect, and PubMed. Out of 150 articles reviewed, 57 met inclusion criteria, focusing on SARS-CoV-2 PLpro inhibitors, excluding studies on other coronaviruses or solely herbal extracts. Data were presented class-wise, and phytochemicals were grouped into virtual, weak, modest, and potential inhibitors. (3) Results: Approximately 100 phytochemicals are reported in the literature as PLpro inhibitors. We classified them as virtual inhibitors (70), weak inhibitors (13), modest inhibitors (11), and potential inhibitors (6). Flavonoids, terpenoids, and their glycosides predominated. Notably, six phytochemicals, including schaftoside, tanshinones, hypericin, and methyl 3,4-dihydroxybenzoate, emerged as potent PLpro inhibitors with favorable selectivity indices and disease-mitigation potential; (4) Conclusions: PLpro stands as a promising therapeutic target against SARS-CoV-2. The phytochemicals reported in the literature possess valuable drug potential; however, certain experimental and clinical gaps need to be filled to meet the therapeutic needs. Full article

Ampakines are a class of orally available positive allosteric modulators of the AMPA-glutamate receptor (AMPAR) and have therapeutic implications for neurological/neuropsychiatric disorders in which AMPAR signaling is compromised. Low-impact ampakines are a distinct subclass of drugs that only modestly offset receptor desensitization and do not alter agonist binding affinity and thus lack the neurotoxicity and epileptogenic effects associated with other AMPAR modulators. In these studies, we describe the pre-clinical pharmacology of ampakine 1-(benzofurazan-5-ylcarbonyl)morpholine (CX717). CX717 modestly offsets desensitization in hippocampal patches and augments synaptic transmission in vivo. CX717 also enhances long-term potentiation in rats, which is crucial for learning and memory. CX717 enhances performance in the eight-arm radial maze and abrogates amphetamine-induced locomotor activity while being devoid of cataleptic activity in rats. CX717 also ameliorates alfentanil-induced respiratory depression in rats and is not toxic to cultured rat neurons. CX717 is active at doses of 0.3–10 mg/kg and lacked serious adverse events in safety studies in mice up to 2000 mg/kg. CX717 was also previously shown to be safe in humans and effective in reversing opiate-induced respiratory depression and hyperactivity and inattentiveness in adults with ADHD. These findings support the continued clinical investigation of CX717 in the treatment of ADHD, dementia, and opiate-induced respiratory depression. Full article

The membrane impermeability of a drug poses a significant challenge in drug research and development, preventing effective drug delivery to the target site. Specifically, the blood-brain barrier (BBB) presents a formidable obstacle to the delivery of drugs targeting the central nervous system (CNS) into the brain, whereas the blood-retinal barrier (BRB) presents a tremendous obstacle to the delivery of drugs targeting the ocular diseases into the eyes. The development of drugs for Alzheimer’s or Parkinson’s disease targeting the CNS and for diabetic retinopathy and age-related macular degeneration targeting the eyes remains an unmet medical need for patients. Transporters play a crucial physiological role in maintaining homeostasis in metabolic organs. Various types of solute carrier (SLC) transporters are expressed in the capillary endothelial cells of the BBB, facilitating the delivery of nutrients from the blood flow to the brain. Therefore, carrier-mediated transport across the BBB can be achieved using SLC transporters present in capillary endothelial cells. It is well-known that CNS drugs typically incorporate N-containing groups, indicating that cation transporters facilitate their transport into the brain. In fact, carrier-mediated transport across the BBB can be accomplished using glucose transporter type 1 (Glut1) as a glucose transporter, L-type amino acid transporter 1 (LAT1) as a large neutral amino acid transporter, and H⁺/cation antiporter as a cation transporter. Surprisingly, although organic cation transporter novel type 2 (OCTN2) is expressed in the capillary endothelial cells, there has been limited investigation into OCTN2-mediated substance delivery into the brain across the BBB. Furthermore, it is suggested that OCTN2 is expressed at the BRB. In this prospective review, I present the advantages and possibilities of substance delivery into the brain across the BBB or into the eyes across the BRB, mediated by OCTN2 via carrier-mediated transport or receptor-mediated transcytosis. Full article

Breast cancer is the most common type of cancer globally and presents an escalating problem and a huge burden on societies. Several strategies are implemented in clinics to treat patients and prevent disease incidence. Efforts to understand the underlying causes of disease emergence are pivotal, and the latest examination of human transcriptomic studies showed the involvement of the noncoding RNA regulatory molecules in influencing both pathological and physiological conditions. Several molecular mechanisms are involved in the process and collaborate to develop tumor plasticity and drug resistance. In this review, we highlight for the first time the interplay between long noncoding RNAs and Aurora kinases in breast cancer and review the latest advances in the field in an attempt to pave the way for a better understanding of the course of the disease and to delineate the targets for treatment strategies in the clinic. Full article

Plants from the Myrtaceae family are known to contain considerable quantities of volatile compounds, ranging from oxygenated monoterpenes to hydrogenated sesquiterpenes, and others, which exhibit antimicrobial activity. One such plant includes Syzygium aromaticum, which has been extensively used to treat a number of disorders, including bacterial and fungal infections. Thus, the scientific validation of the essential oil (EO) of Syzygium aromaticum vis-à-vis Candida and Cryptococcus species is valuable. To this end, the present study sought to investigate the antifungal activity of EO from S. aromaticum (clove) leaves and flower buds against Candida and Cryptococcus species. The antioxidant activity of S. aromaticum’s essential oils was also elucidated. The EO was extracted from fresh leaves and floral buds of S. aromaticum using a Clevenger-type apparatus. The as-prepared essential oils were further evaluated for antifungal activity against Candida and Cryptococcus species using a microdilution method. The phytochemical analysis of the EOs was assessed by gas chromatography/mass spectrometry (GC-MS). Antioxidant activities of the EOs were evaluated using standard methods. As a result, the GC-MS analysis revealed the presence of volatile compounds, such as eugenol (87.08%), β-caryophyllene (6.40%) and acetyleugenol (4.45%) as the major constituents of EO from the flower buds, and eugenol (90.54%) and β-caryophyllene (8.42%) as the major components of the leaf’s EO. The eugenol-rich essential oils exhibited significant antifungal effects against Candida species (common MIC value: 200 ppm) and Cryptococcus neoformans (MIC value: 50 ppm), as well as antioxidant activity. Overall, essential oils of S. aromaticum demonstrated antioxidant and antifungal effects, thus validating the ethnopharmacological use of this plant in the treatment of fungal infections. However, antifungal mechanisms of action, in-depth toxicity and in vivo experiments, and pharmacokinetics are warranted to support the use of this plant in ethnomedicine. Full article