Selective Inhibitor Research Articles

Strategic Fluorination to Achieve a Potent, Selective, Metabolically Stable, and Orally Bioavailable Inhibitor of CSNK2.

The host kinase casein kinase 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug target in vivo, potent and selective CSNK2 inhibitors with good pharmacokinetic properties are required. Inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold possess outstanding potency and selectivity for CSNK2, but bioavailability and metabolic stability are often challenging. By strategically installing a fluorine atom on an electron-rich phenyl ring of a previously characterized inhibitor 1, we discovered compound 2 as a promising lead compound with improved in vivo metabolic stability. Compound 2 maintained excellent cellular potency against CSNK2, submicromolar antiviral potency, and favorable solubility, and was remarkably selective for CSNK2 when screened against 192 kinases across the human kinome. We additionally present a co-crystal structure to support its on-target binding mode. In vivo, compound 2 was orally bioavailable, and demonstrated modest and transient inhibition of CSNK2, although antiviral activity was not observed, possibly attributed to its lack of prolonged CSNK2 inhibition.

Rational design, synthesis and pharmacological characterization of novel aminopeptidase A inhibitors

Aminopeptidase A (APA) is a membrane-bound zinc metallopeptidase involved in the production of angiotensin III, one effector peptide of the brain renin-angiotensin system, making brain APA a relevant pharmacological target for the development of novel therapeutic treatments against hypertension and heart failure. The structure-based design of new APA inhibitors is described, based on previously developed thiol-containing inhibitors and APA crystal structure. Chemical synthesis, in vitro assessment against APA activity, pharmacological and pharmacokinetic profiling were performed, ultimately leading to a potent and selective APA inhibitor.

Paraventricular oxytocin neurons impact energy intake and expenditure: projections to the bed nucleus of the stria terminalis reduce sucrose consumption.

The part played by oxytocin and oxytocin neurons in the regulation of food intake is controversial. There is much pharmacological data to support a role for oxytocin notably in regulating sugar consumption, however, several recent experiments have questioned the importance of oxytocin neurons themselves. Here we use a combination of histological and chemogenetic techniques to investigate the selective activation or inhibition of oxytocin neurons in the hypothalamic paraventricular nucleus (OxtPVH). We then identify a pathway from OxtPVH neurons to the bed nucleus of the stria terminalis using the cell-selective expression of channel rhodopsin. OxtPVH neurons increase their expression of cFos after both physiological (fast-induced re-feeding or oral lipid) and pharmacological (systemic administration of cholecystokinin or lithium chloride) anorectic signals. Chemogenetic activation of OxtPVH neurons is sufficient to decrease free-feeding in Oxt Cre:hM3Dq mice, while inhibition in Oxt Cre:hM4Di mice attenuates the response to administration of cholecystokinin. Activation of OxtPVH neurons also increases energy expenditure and core-body temperature, without a significant effect on locomotor activity. Finally, the selective, optogenetic stimulation of a pathway from OxtPVH neurons to the bed nucleus of the stria terminalis reduces the consumption of sucrose. Our results support a role for oxytocin neurons in the regulation of whole-body metabolism, including a modulatory action on food intake and energy expenditure. Furthermore, we demonstrate that the pathway from OxtPVH neurons to the bed nucleus of the stria terminalis can regulate sugar consumption.

Targeting SRSF10 might inhibit M2 macrophage polarization and potentiate anti-PD-1 therapy in hepatocellular carcinoma.

The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma (HCC) remains poor. Although serine- and arginine-rich splicing factor (SRSF) family members play crucial roles in tumors, their impact on tumor immunology remains unclear. This study aimed to elucidate the role of SRSF10 in HCC immunotherapy. To identify the key genes associated with immunotherapy resistance, we conducted single-nuclear RNA sequencing, multiplex immunofluorescence, and The Cancer Genome Atlas and Gene Expression Omnibus database analyses. We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems, flow cytometry, various tumor-bearing mouse models, and patient-derived organotypic tumor spheroids. SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8+ T cell activity. Mechanistically, SRSF10 interacted with the 3'-untranslated region of MYB, enhancing MYB RNA stability, and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1 (GLUT1), hexokinase 1 (HK1), lactate dehydrogenase A (LDHA), resulting in elevated intracellular and extracellular lactate levels. Lactate accumulation induced histone lactylation, which further upregulated SRSF10 expression. Additionally, lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages, thereby activating transcription and enhancing pro-tumor macrophage activity. M2 macrophages, in turn, inhibited the enrichment of CD8+ T cells and the proportion of interferon-γ+CD8+ T cells in the tumor microenvironment (TME), thus creating an immunosuppressive TME. Clinically, SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) in both murine and human preclinical models. The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance. Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.

Novel Celecoxib Derivative, RF26, Blocks Colon Cancer Cell Growth by Inhibiting PDE5, Activating cGMP/PKG Signaling, and Suppressing β-catenin-dependent Transcription.

Previous studies have reported that the cGMP-specific PDE5 isozyme is overexpressed in colon adenomas and adenocarcinomas and essential for colon cancer cell proliferation, while PDE5 selective inhibitors (e.g., sildenafil) have been reported to have cancer chemopreventive activity. This study aimed to determine the anticancer activity of a novel PDE5 inhibitor, RF26, using colorectal cancer (CRC) cells and the role of PDE5 in CRC tumor growth in vivo. The objective of this study was to characterize the anticancer activity of a novel celecoxib derivative, RF26, in CRC cells previously reported to lack COX-2 inhibition but have potent PDE5 inhibitory activity. Anticancer activity of RF26 was studied using human CRC cell lines. Its effects on intracellular cGMP levels, cGMP-dependent protein kinase (PKG) activity, β-catenin levels, TCF/LEF transcriptional activity, cell cycle distribution, and apoptosis were measured. CRISPR/cas9 PDE5 knockout techniques were used to determine if PDE5 mediates the anticancer activity of RF26 and validate PDE5 as a cancer target. RF26 was appreciably more potent than celecoxib and sildenafil to suppress CRC cell growth and was effective at concentrations that increased intracellular cGMP levels and activated PKG signaling. RF26 suppressed β-catenin levels and TCF/LEF transcriptional activity and induced G1 cell cycle arrest and apoptosis within the same concentration range. CRISPR/cas9 PDE5 knockout CRC cells displayed reduced sensitivity to RF26, proliferated slower than parental cells, and failed to establish tumors in mice. Further evaluation of RF26 for the prevention or treatment of cancer and studying the role of PDE5 in tumorigenesis are warranted.

Novel Insights into the Biological Activity of Croton lechleri Twigs Extracts and Advancements in Their Sustainable Recovery.

Sangre de drago, the sap of Croton lechleri Müll. Arg. tree, has been used for centuries in traditional medicine owing to its diverse biological activities. Extracts derived from different parts of the species contain a multitude of phytochemicals with varied applications. Twigs, however, are among the least studied parts of the plant. This study unveils new biological activities of Croton lechleri twig extracts recovered by applying Soxhlet and advanced green techniques. For all extracts, total phenolic content and antioxidant activity were determined. Subsequently, four were selected, and their cytotoxic effects were assessed on both normal (HaCat) and malignant melanoma (A375) skin cell lines using the MTT assay and trypan blue exclusion assay. All showed dose-dependent cytotoxicity, with the Soxhlet ethanol extract demonstrating the highest selectivity towards A375 cells over HaCat cells. The extracts induced apoptosis and necrosis, as confirmed by Annexin V/PI dual-labeling and flow cytometry, highlighting their ability to trigger programmed cell death in cancer cells. The selective inhibition of cell cycle progression in A375 compared to HaCat observed both for Soxhlet ethanol and pressurized ethanol extracts induces cell cycle arrest at multiple points, primarily in the G1 and G2/M phases, and significantly reduces DNA synthesis as evidenced by the decrease in the S-phase population, confirmed by the EdU assay. Consequently, the Soxhlet extract composition was analyzed using LC-MS, which revealed their richness in polyphenolic compounds, particularly flavonoids from the flavonol subclass.

The Implication of Fragment-centric Mapping Strategy to Explore the First Selective Inhibitor Against Target Protein

Introduction: Identification of the first selective inhibitor, also called “hit molecules, " is crucial for developing drugs against a protein target. However, the crystal structures of protein-ligand complexes are usually not resolved in time due to the process's time-consuming and costly nature. However, it does not prevent scientists from understanding the binding modes’ urgent advantages and drawbacks of protein-ligand interaction to guide the optimization of hit molecules. Methods: Here, we have developed a pocket-centric computational strategy to facilitate a comprehensive understanding of the hit molecules against the protein target. Results: The results show that the pocket-centered mapping method not only allows for accurate prediction of the native docking pose and in-depth analysis of the binding mode but also has the potential of rapidly identifying partially unoccupied, unutilized, but targetable pockets to afford optimized hit molecules. We tested the strategy on the first selective inhibitor, epigallocatechin gallate (EGCG), against human arylacetamide deacetylase (AADAC). Molecular dynamics simulation and MM/PBSA binding energy calculation are used to verify the efficacy of the strategy. Conclusion: The results show that the pocket-centered mapping method not only allows for accurate prediction of the native docking pose and in-depth analysis of the binding mode but also has the potential of rapidly identifying partially unoccupied, unutilized, but targetable pockets to afford optimized hit molecules.

Effects of selective serotonin reuptake inhibitors on endocrine system (Review).

Selective serotonin reuptake inhibitors (SSRIs) are typically prescribed for treating major depressive disorder (MDD) due to their high efficacy. These drugs function by inhibiting the reuptake of serotonin [also termed 5-hydroxytryptamine (5-HT)], which raises the levels of 5-HT in the synaptic cleft, leading to prolonged activation of postsynaptic 5-HT receptors. Despite the therapeutic benefits of SSRIs, this mechanism of action also disturbs the neuroendocrine response. Hypothalamic-pituitary-adrenal (HPA) axis activity is strongly linked to both MDD and the response to antidepressants, owing to the intricate interplay within the serotonergic system, which regulates feeding, water intake, sexual drive, reproduction and circadian rhythms. The aim of the present review was to provide up-to-date evidence for the proposed effects of SSRIs, such as fluoxetine, citalopram, escitalopram, paroxetine, sertraline and fluvoxamine, on the endocrine system. For this purpose, the literature related to the effects of SSRIs on the endocrine system was searched using the PubMed database. According to the available literature, SSRIs may have an adverse effect on glucose metabolism, sexual function and fertility by dysregulating the function of the HPA axis, pancreas and gonads. Therefore, considering that SSRIs are often prescribed for extended periods, it is crucial to monitor the patient closely with particular attention to the function of the endocrine system.

In Vitro Ciclopirox Glucuronidation in Liver Microsomes from Humans and Various Experimental Animals.

Ciclopirox is a widely used antifungal drug, redisposition of which has drawn increasing attentions due to multiple promising activities. The drug undergoes extensive glucuronidation, which acts as a major obstacle in the ongoing novel application and still remains poorly understood. The current study aims to phenotype ciclopirox glucuronidation pathway and as well to decipher the related species differences. Ciclopirox glucuronidation was investigated in liver microsomes from humans (HLM) and various experimental animals. Assays with recombinant uridine diphosphate glucuronosyltransferases (UGTs), enzyme kinetic analyses and selective inhibitors were used to determine the role of individual UGTs in ciclopirox glucuronidation. HLM is highly active in ciclopirox glucuronidation withMichaelis-Menten constant (Km),maximum velocity (Vmax), and intrinsic clearance (CLint)values of 139 μM, 7.89 nmol/min/mg, and 56 μL/min/mg, respectively. UGT1A9 displays by far the highest activity, whereas several other isoforms (UGT1A6, UGT1A7, and UGT1A8) catalyze formation of traced glucuronides. Further kinetic analysis demonstrates that UGT1A9 has a closed Km value (167 μM) to HLM. UGT1A9 selective inhibitor (magnolol) can potently inhibit ciclopirox glucuronidation in HLM with the IC50 value of 0.12 μM. The reaction displays remarkable differences across liver microsomes from mice, rats, cynomolgus monkey, minipig, and beagle dog, with the CLint values in the range of 26-369 μL/min/mg. In addition, ciclopirox glucuronidation activities of experimental animals' liver microsomes were less sensitive to magnolol than that of HLM. Ciclopirox glucuronidation displays remarkable species differences with UGT1A9 as a dominant contributor in humans. It is suggested that the pharmacological or toxicological effects ofciclopirox may be UGT1A9 and species dependent.

Safety and efficacy of selective RIPK1 inhibitor SIR1-365 in hospitalized patients with severe COVID-19: A multicenter, randomized, double-blind, phase 1b trial

BackgroundReceptor-interacting protein kinase 1 (RIPK1), a serine/threonine protein kinase, is mainly activated by pro-inflammatory cytokines and pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its activation could result in apoptosis, necroptosis, or inflammation. This study was conducted to evaluate the safety and efficacy of a potent and selective inhibitor of RIPK1, SIR1-365, in hospitalized patients with severe coronavirus disease 2019 (COVID-19). MethodsThis multicenter, randomized, double-blind, phase 1b study screened patients from December 18, 2020 until November 27, 2021. Adults hospitalized with severe COVID-19 (diagnosed ≤2 weeks before screening) were randomized 1:1 to receive oral placebo or SIR1-365 100 mg three times daily for ≤14 consecutive days, with standard-of-care. The primary objective was to evaluate SIR1-365 safety and tolerability. Secondary objectives included an assessment of SIR1-365 efficacy. Descriptive statistics were used to summarize safety. The study was not powered for efficacy testing. Relevant inferential statistical tests were used to aid interpretation of differences in clinical efficacy. ResultsForty-five patients were randomized, 42 were treated. Eighteen patients experienced treatment-emergent adverse events (TEAEs) and 7 patients were >= grade 3. Fewer SIR1-365-treated vs. placebo-treated patients experienced TEAEs (30.4% vs. 57.9%) and serious TEAEs (13.0% vs. 26.3%) within 28 days of the first dose. There were no serious treatment-related TEAEs or deaths. SIR1-365 vs. placebo significantly increased arterial oxygenation from baseline to day 7 (least-squares mean change [standard error]: 109.4 [26.4] vs. -24.2 [23.6]; P=0.0095), significantly reduced hospitalization duration after treatment (mean±standard deviation: [4.7±3.7] days vs. [8.6±5.6] days; P=0.0145) and respiratory failure incidence (8.3% vs. 38.1%; two-sided P=0.0291) during the study, and numerically shortened the time to clinical improvement in World Health Organization ordinal scale (median: 5.0 days vs. 9.0 days, P=0.0766). ConclusionsSIR1-365 was well tolerated and demonstrated a trend toward quicker recovery than placebo in hospitalized patients with severe COVID-19.Trial Registration ClinicalTrials.gov number: NCT04622332

Discovery and preclinical profile of YK-2168, a differentiated selective CDK9 inhibitor in clinical development

Emerging clinical evidence indicates that selective CDK9 inhibition may provide clinical benefits in the management of certain cancers. Many CDK9 selective inhibitors have entered clinical developments, and are being investigated. No clear winner has emerged because of unforeseen toxicity often observed in clinic with these agents. Therefore, a novel agent with differentiated profiles is still desirable. Herein, we report our design, syntheses of a novel azaindole series of selective CDK9 inhibitors. SAR studies led to a preclinical candidate YK-2168. YK2168 exhibited improved CDK9 selectivity over AZD4573 and BAY1251152; also showed differentiated intravenous PK profile and remarkable solid tumor efficacy in a mouse gastric cancer SNU16 CDX model in preclinical studies. YK-2168 is currently in clinical development in China (CTR20212900).

Recent Development of CDK2 Inhibitors as Anticancer Drugs: An Update (2015–2023)

AbstractCyclin-dependent kinase 2 (CDK2) is a critical regulator of cell division and has emerged as a promising target for anticancer treatment. In this article, we summarize the structural features of CDK2 inhibitors and corresponding binding modes, in particular the noncompetitive binding modes that offer unique advantages for the development of highly selective inhibitors. In addition, we present an overview of the latest advancements in the development of CDK2 inhibitors and discuss the trend in the field. This review provides valuable insights into the structure–activity relationships of the reported CDK2 inhibitors, inspiring the development of potent and selective CDK2 inhibitors in the future.

Inhibition of transient receptor potential vanilloid 3 channels by antimalarial hydroxychloroquine alleviates TRPV3-dependent dermatitis

Transient receptor potential vanilloid 3 channel (TRPV3) is closely associated with skin inflammation, but there is a lack of effective and specific inhibitors for clinical use. In this study, we identified antimalarial HCQ as a selective TRPV3 inhibitor following the prediction by network pharmacology data analysis. In whole-cell patch-clamp recordings, HCQ inhibited the current of the TRPV3 channel, with an IC50 of 51.69 ± 4.78 μM. At the single-channel level, HCQ reduced the open probability of TRPV3 and decreased single-channel conductance. Molecular docking and site-directed mutagenesis confirmed that residues in the pore domain were critical for the activity of HCQ. In vivo, HCQ effectively reduced carvacrol-induced epidermal thickening, erythema, and desquamation. Additionally, the serum IgE and inflammatory factors such as TNF-α and IL-6 were markedly decreased in the dorsal skin tissues in the HCQ treatment group, as compared to the model group. Our results suggested the antimalarial HCQ may represent a potential alleviator for treating skin inflammation by inhibiting TRPV3 channels.

Investigating Neuroplasticity Changes Reflected by BDNF Levels in Astrocyte-Derived Extracellular Vesicles in Patients with Depression.

To investigate the neuroplasticity hypothesis of depression by measuring brain-derived neurotrophic factor (BDNF) levels in plasma astrocyte-derived extracellular vesicles (ADEVs) and to evaluate their potential as biomarkers for depression compared with plasma BDNF levels. Thirty-five patients with major depressive disorder (MDD) and 35 matched healthy controls (HCs) were enrolled. Plasma ADEVs were isolated using a combination of ultracentrifugation and immunoaffinity capture. Isolated ADEVs were validated using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. BDNF levels were quantified in both ADEVs and plasma. ALG-2-interacting protein X (Alix) and cluster of differentiation 81 (CD81) levels, two established extracellular vesicle markers, were measured in ADEVs. After false discovery rate correction, patients with MDD exhibited higher CD81 levels (P FDR = 0.040) and lower BDNF levels (P FDR = 0.043) in ADEVs than HCs at baseline. BDNF levels in ADEVs normalized to CD81 (P FDR = 0.002) and Alix (P FDR = 0.040) remained consistent with this finding. Following four weeks of selective serotonin reuptake inhibitor treatment (n=10), CD81 levels in ADEVs decreased (P FDR = 0.046), while BDNF levels normalized to CD81 increased (P FDR = 0.022). BDNF levels in ADEVs were more stable than in plasma. Exploratory analysis revealed no correlation between BDNF levels in ADEVs and plasma (ρ=0.117, P = 0.334). This study provides human in vivo evidence supporting the neuroplasticity hypothesis of depression by demonstrating altered BDNF levels in ADEVs. ADEVs may be more suitable for developing biomarkers of depression than plasma-derived biomarkers.

Design, synthesis, molecular docking, and evaluation of sulfonyl quinazoline analogues as promising liver cancer drugs

Inhibiting cyclin-dependent kinases (CDK) offers an important arsenal for cancer treatments by interfering with apoptotic proteins related to cancer. Novel selective cyclin-dependent kinases inhibitors using the Quinazoline as the cap with multiple electronic donating (EDG) and/or electron withdrawing group (EWG) substituted Aniline chain at the C-2 position were designed, synthesized, and evaluated for activity against liver cancer. Among the tested compounds, compounds B34 and B35 emerged as potent candidates in the series, with IC50 values of 0.102 ± 0.04 µM and 0.058 ± 0.003 µM, respectively. They also suppressed the enzymatic activity of CDK2/cyclinA2 selectively. Further biological studies revealed that compounds B34 and B35 arrested the cell cycle, and induced apoptosis in HepG-2 cancer cells through a Caspase-mediated mechanism, facilitating the release of Cyt-c through modulation of Caspase-3 expression. More importantly, compounds B34 and B35 suppressed the xenografted tumor growth in mice in a dose-dependent manner. Finally, through a molecular docking study, it was confirmed that compoundsB34 andB35 retained crucial hydrogen bonding and hydrophobic interactions with CDK receptor, rationalizing their higher efficacy compared to other compounds in the series. Taken together, the Quinazoline derivatives B34 and B35 may serve as novel chemotherapeutic agents through inhibition of CDK.

Mediterranean mussels (Mytilus galloprovincialis) exposure to fluoxetine: bioaccumulation and biotransformation products

The significant rise in antidepressant consumption in recent years was accentuated by COVID-19 pandemic. Among these antidepressant, fluoxetine, a selective serotonin re-uptake inhibitor (SSRI), is the most prescribed worldwide. The present study investigated its bioaccumulation and metabolization in the mussel Mytilus galloprovincialis, generally recognized as a reliable bioindicator for assessing environmental quality and the accumulation of various contaminants. Mussels were exposed to a nominal concentration of fluoxetine (3.1μg/L) for 28 days. Mussels were sacrificed at day 2, 7, 14 and 28 of exposure. The order of accumulation level was gills > digestive glands > soft tissues, and a regular increase in fluoxetine and norfluoxetine was observed across the various sampling days for both digestive glands and soft tissues. The calculated bioconcentration factor (BCF) ranged from 253 at D2 to 1734 at D28 for fluoxetine, and pseudo-BCF from 7 at D2 to 64 at D28 for norfluoxetine. Non-targeted approaches highlighted ten metabolites, which are reported for the first time in Mytilus, in addition to norfluoxetine. Notably, this study highlighted two phase I metabolites and one phase II metabolite previously unreported. These findings contribute to the understanding of fluoxetine accumulation and metabolism in Mytilus and enhance the knowledge of pharmaceuticals detoxification processes in non-target organisms.

Ameliorative effect of diclofenac in rotenone corneal kindling model of drug-resistant epilepsy: Edge of dual COX and KMO inhibition

Epilepsy affects millions of people worldwide, about one-third patients with epilepsy exhibits resistance to available antiseizures medications, known as drug-resistant epilepsy (DRE). Mitochondrial dysfunction has been implicated as a hallmark in drug-resistant epilepsy via activation of microglial kynurenine 3-monooxygenase (KMO) and cyclooxygenase (COX) enzymes, leading to neuroinflammation and oxidative stress. Diclofenac, an equipotent non selective cyclooxygenase inhibitor, has inhibitory action on KMO enzyme and has also shown anti-inflammatory and antioxidant properties in animal models of epilepsy. These properties make it a suitable candidate for amelioration of DRE. However, its potential in drug-resistant epilepsy remained unexplored till date. In this study, dose dependent effect of diclofenac (5 mg/kg, 10 mg/kg, 20 mg/kg) has been explored in rotenone corneal kindling model of mitochondrial DRE. The results of our study revealed the induction of drug resistance to antiseizure medications and induced kynurenine 3-monooxygenase activity in rotenone corneal kindled epileptic mice in comparison to naive mice. Treatment of rotenone corneal kindled epileptic mice with diclofenac resulted in a significant decrease in drug resistance to antiseizure medications as evident by a reduction in seizure score in the treatment groups as compared to control group, in post-treatment resistance validation. The kynurenine 3-monooxygenase inhibitory activity (as evidenced by decreased levels of neurotoxic quinolinic acid) and the antioxidant effect (as evident by significantly reduced oxidative stress) in the diclofenac treated groups, emerged as a major contributor for its ameliorative action. Findings of this study suggests, diclofenac can be used as an adjunct therapy in amelioration of drug-resistant epilepsy.

Mental health landscape in Kosova from 2017 to 2022: A retrospective study of antidepressant and anxiolytic market trends and the impact of COVID-19

ObjectivesThis study explores the mental health situation in Kosova and the impact of the COVID-19 pandemic. MethodsMarketed quantities of antidepressants (N06A) and anxiolytics (N05B) from 2017 to 2022 were analyzed using the Anatomical Therapeutic Chemical/Defined Daily Doses (ATC/DDD) methodology. Caution is advised as these quantities may not directly reflect patient usage and could include uses for conditions outside their primary indications. ResultsPrior to the pandemic, antidepressant quantities remained relatively stable, but rose from 6.8 DDD/1000 inhabitants/day in 2019 to 9.7 in 2020 and 12.4 in 2021, before returning to pre-pandemic levels of 6.8 DDD in 2022. Over 80 % of these were selective serotonin reuptake inhibitors. Meanwhile, anxiolytic quantities initially decreased from 17.4 DDD in 2017 to 9.9 in 2019, then rebounded to 17.9 DDD in 2020. Notably, alprazolam usage surged from 2.9 in 2017 to 6.9 in 2021, subsequently dropping to 2.0 in 2022. ConclusionsThe volatile trends in medication quantities during the pandemic suggest a fragile mental health landscape in Kosova—a developing, post-conflict country with a youthful population—underscoring the need for proactive interventions in similar contexts globally.

Effect of Selective Serotonin Reuptake Inhibitors on iron transport and metabolism in the placenta: Exploratory study using a choriocarcinoma cell line

Effect of Selective Serotonin Reuptake Inhibitors on iron transport and metabolism in the placenta: Exploratory study using a choriocarcinoma cell line

Targeted Inhibition of the PI3K/Akt/mTOR Signaling Axis: Potential for Sarcoma Therapy.

Sarcoma is a heterogeneous group of malignancies often resistant to conventional chemotherapy and radiation therapy. The phosphatidylinositol-3-kinase/ protein kinase B /mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway has emerged as a critical cancer target due to its central role in regulating key cellular processes such as cell growth, proliferation, survival, and metabolism. Dysregulation of this pathway has been implicated in the development and progression of bone sarcomas (BS) and soft tissue sarcomas (STS). PI3K/Akt/mTOR inhibitors have shown promising preclinical and clinical activity in various cancers. These agents can inhibit the activation of PI3K, Akt, and mTOR, thereby reducing the downstream signaling events that promote tumor growth and survival. In addition, PI3K/Akt/mTOR inhibitors have been shown to enhance the efficacy of other anticancer therapies, such as chemotherapy and radiation therapy. The different types of PI3K/Akt/mTOR inhibitors vary in their specificity, potency, and side effect profiles and may be effective depending on the specific sarcoma type and stage. The molecular targeting of PI3K/Akt/mToR pathway using drugs, phytochemicals, nanomaterials (NMs), and microbe-derived molecules as Pan-PI3K inhibitors, selective PI3K inhibitors, and dual PI3K/mTOR inhibitors have been delineated. While there are still challenges to be addressed, the preclinical and clinical evidence suggests that these inhibitors may significantly improve patient outcomes. Further research is needed to understand the potential of these inhibitors as sarcoma therapeutics and to continue developing more selective and effective agents to meet the clinical needs of sarcoma patients.