Pharmacological Reports最新文献

Methylphenidate (MPH) is a central nervous system stimulant that is approved and widely used for the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy. It acts primarily by inhibiting the reuptake of dopamine and norepinephrine, thereby enhancing synaptic concentrations of these neurotransmitters and improving attention, impulse control, and wakefulness. Despite its well-established therapeutic efficacy, MPH is associated with a complex safety profile that necessitates careful consideration, particularly in long-term use and in populations with preexisting health conditions. Cardiovascular risks, including increased heart rate, elevated blood pressure, and, in rare cases, serious adverse events such as myocardial infarction, arrhythmias, and sudden cardiac death, have been reported. Psychiatric adverse effects, including anxiety, agitation, psychotic symptoms, and exacerbation of preexisting mood disorders, also warrant close monitoring. Additionally, MPH has the potential for misuse, abuse, and dependence, particularly due to its dopaminergic effects, which can contribute to reinforcement and addiction-related behaviors. This review synthesizes current evidence on the safety of MPH, with a focus on its impact on cardiovascular and psychiatric health, and addiction potential. Special attention is given to vulnerable populations, including children, adolescents, individuals with comorbid psychiatric or cardiovascular conditions, and those with a history of substance use disorders. Furthermore, sex and gender influence health outcomes, for MPH healthcare strategies have been addressed. Given these concerns, the necessity for rigorous patient monitoring, individualized risk assessment, and adherence to prescribing guidelines is emphasized to optimize therapeutic outcomes while minimizing risks. Clinical trial number: Not applicable.

Background: C57BL/6 and DBA/2 mouse strains differ markedly in behavioral responses to acute and chronic morphine administration. Some of these disparities might be underlain by and/or correlated with different expression of the opioid propeptide genes Pdyn and Penk. The objective of our study was to characterize the influence of morphine on Pdyn and Penk expression in substance abuse-related forebrain regions of C57BL/6 and DBA/2 mice.

Methods: Pdyn and Penk mRNA levels were measured using in situ hybridization after acute or chronic morphine administration, and during 24-48-h withdrawal.

Results: Pdyn and Penk gene expression was increased after chronic morphine and throughout withdrawal in all investigated brain regions. The changes were strain-specific in the central amygdaloid nucleus (CeA), where both genes were upregulated exclusively in C57BL/6 mice. The effect of morphine on Penk and Pdyn mRNA levels in the NAc core and shell did not significantly differ between the strains. However, trends within the data suggest greater upregulation of Pdyn in DBA/2 mice and of Penk in C57BL/6 mice. No such trends were observed in the dorsal striatum.

Conclusions: Our results suggest that Penk-expressing neurons of the CeA, which are critical for some withdrawal symptoms, adapt differently to chronic morphine in C57BL/6 vs. DBA/2 mice. We discuss how this may correspond to the inter-strain disparity in the opioid withdrawal syndrome intensity. We also analyze possible causes and consequences of the presumed inter-strain differences in morphine effects within the NAc.

Background: The skin is a pivotal organ that serves as a physical barrier, protecting the body from harmful substances such as pathogens, allergens, and other environmental irritants. Chronic inflammation in the skin, along with the anthropogenic effects, can cause reactive oxygen species (ROS) overproduction. Prolonged exposure to elevated ROS levels and inadequate antioxidant defenses in the skin can contribute to the onset of various skin disorders. The nuclear factor erythroid 2-related factor-2 (Nrf-2) signaling pathway plays a key role in enhancing antioxidant capacity by promoting the production of antioxidant and detoxifying molecules. Consequently, pharmacological activation of the Nrf-2 pathway may help restore the oxidant-antioxidant balance, thereby improving therapeutic outcomes for chronic skin disorders. This study aimed to investigate the potential effect of novel agent: (5-((4-(4-(methoxycarbonyl)-2-oxopyrrolidin-1-yl)phenyl)carbamoyl)benzene-1,2,3-triyl triacetate (LN-53), synthesized based on the structure of previously developed by our team lead compound SK-119, on Nrf-2 signaling pathway in human epidermal keratinocytes (HEKs) at mRNA and protein level.

Methods: The cytotoxicity of LN-53 was evaluated by MTT, LDH, live/dead cell staining, and caspase-3,-8,-9 multiplex activity assays. Intracellular ROS production was assessed by DCFH-DA staining. The Nrf-2 gene was silenced by transient transfection using human Nrf-2 siRNA. Nrf-2 and related factors (heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase: quinone-1 (NQO1)) were evaluated at the mRNA level by qPCR and protein level in nuclear and cytosolic fractions by Nrf-2 activation assay and Western blot. The levels of inflammatory cytokines (IL-6 and IL-8) in supernatants were determined by ELISA.

Results: Our results indicate that LN-53 effectively reduces intracellular ROS production triggered by tert-butyl hydroperoxide (TBHP), without leading to any noticeable cell damage. It promoted the nuclear translocation of Nrf-2 and induced the production of Nrf-2, HO-1, and NQO1 at both the mRNA and protein levels. LN-53-mediated alterations in antioxidant gene expressions were blocked by Nrf-2 knockdown. LN-53 treatment also suppressed the release of IL-6 and IL-8 cytokines mediated by TBHP exposure. Additionally, novel compound LN-53 was found to be more stable than the parent compound SK-119.

Conclusion: LN-53 can effectively induce antioxidant mechanisms by promoting Nrf-2 nuclear translocation and suppressing ROS production in human epidermal keratinocytes. These data may suggest that LN-53 can contribute to maintaining redox balance and homeostasis in the skin.

Out of several types of tumors of the central nervous system (CNS), glioblastoma (GBM) represents one of the most frequent and malignant forms of brain neoplasms. To date, GBM holds very limited therapeutic options leaving patients with poor prognosis of survival. As such, novel treatment approaches are constantly quested. One of these strategies is based on the utilization of proteasome inhibitors (PIs). However, although several PIs have been approved as therapy for patients with hematological malignancies, these treatment benefits cannot not be easily extrapolated to brain tumors. This is mostly due to the blood-brain barrier (BBB) impermeability of the majority of PIs, which is then followed by their low brain bioavailability. Marizomib (MZB) is a unique, irreversible, second-generation proteasome inhibitor, which unlike other PIs can penetrate through the BBB, making it a promising therapeutic tool in brain tumors. Despite an indisputable therapeutic potential of MZB, it has yet failed to be successfully introduced to the clinics as a ready-to-use chemotherapy for GBM-suffering patients. Therefore, in this work we describe the potential of PIs as candidates for neuro-oncological drugs, present results of preclinical and clinical investigations concerning MZB in brain tumors, discuss possible reasons of failure of MZB-based therapies and delineate future directions of MZB-related studies.

Neurological disorders represent a leading cause of mortality and disability worldwide, encompassing a broad spectrum of prevalent conditions such as Alzheimer's disease, epilepsy, and stroke. In recent years, natural compounds have garnered increasing attention as potential therapeutic and preventive agents for neurological disorders. Galangin, a naturally occurring flavonoid primarily derived from Alpinia officinarum Hance, exhibits diverse biological properties, including notable neuroprotective, anti-tumor, and anti-inflammatory effects. Emerging evidence indicates that galangin exerts significant neuroprotective effects through multiple mechanisms. This review systematically summarizes the in vivo metabolism and pharmacokinetics of galangin, elucidates its mechanism of action, and highlights recent advances in its application for neurological disorders. Furthermore, the prospect of nanodrug carriers for enhancing the therapeutic efficacy of galangin is explored. Additionally, this review addresses the current research limitations and outlines future research directions to provide a theoretical foundation for its clinical application in neurological disorders. Collectively, the findings underscore the extensive pharmacological properties and therapeutic potential of galangin, highlighting its promise as a novel candidate for the treatment and prevention of neurological disorders and warranting further in-depth investigation and development.

Metabolic changes in cancer cells are crucial for maintaining their high growth and proliferation rate. As a result, many tumors are characterized by high glucose consumption and intensified aerobic glycolysis, a phenomenon known as the Warburg effect. Through the Warburg effect, cancer cells can rapidly acquire energy, obtain intermediates for biosynthesis, and ensure a source of NAD⁺ for oxidized biomass synthesis. Altered metabolism and the Warburg effect are characteristic features not only of most transformed proliferating cells but also of normal, rapidly dividing cells, thus posing a challenge for potential anticancer strategies disrupting cellular metabolism. Therefore, targeting the Warburg effect requires a carefully considered strategy so as not to affect the basal metabolism of normal cells and prevent the various side effects in the patient commonly observed with classical chemotherapies targeting DNA replication. On the other hand, strategies/agents that slow metabolic rate are likely to be less toxic to normal cells than to highly metabolically deregulated cancer cells. The aim of this work is to discuss the most optimal approach for inhibiting these favorable metabolic changes in cancer cells while ensuring specificity. The work discusses proteins, enzymes and pathways that, according to the current state of knowledge, can be optimal candidates for cancer specific targeting such as: HK2, PKM2, PFKFB3, PFKFB4, NAD⁺ de novo metabolism, NADH oxidation, MCT4, MCT1, LDHA and LDHB. In the era of rapid progress in diagnostic tools providing more and more data on molecular changes, the therapeutic strategy should take into account not only the specificity of the cancer, but also a personalized, optimal approach for each individual patient. This article presents an overview, including available databases, showing the heterogeneity of expression of genes involved in metabolic reprogramming among various cancer patients, which clearly suggests the need to develop a specific theranostic approach for targeting the Warburg effect in a personalized manner. Clinical trial number Not applicable.

Background: The pharmacological maintenance treatment for bipolar disorder patients depends on mood stabilizers such as lithium and valproate. An association between GRIN2B and NTRK2 gene polymorphisms and treatment response to lithium and valproate has been reported. Therefore, we examined the relationship between polymorphisms of GRIN2B and NTRK2 and the long-term treatment response to valproate and lithium in bipolar disorder patients.

Methods: We performed a genetic association study involving bipolar disorder patients treated with valproate and lithium, along with a control group. The long-term treatment response was retrospectively assessed using Alda's scale. Genotyping of GRIN2B (rs1806201, rs890) and NTRK2 (rs2289656) was conducted with allele discrimination TaqMan assays.

Results: We analyzed 251 bipolar disorder patients, 130 treated with valproate and 121 with lithium, and 300 controls. The analysis, which controlled for sex and age as covariates, observed an association between rs1806201 and BD (p = 0.003). The analysis of treatment response showed an effect of the NTRK2/rs2289656 and treatment response to valproate, with the number of depressive, hypomanic, psychotic, and mixed episodes as covariates (p = 0.043). No association was found between the two genes analyzed and the response to lithium treatment.

Conclusions: Our findings suggest that GRIN2B and NTRK2 may play a crucial role in the cause of bipolar disorder. The analysis of treatment response revealed a link between the NTRK2 gene and valproate response in BD patients. However, our results did not reproduce the association of these two genes with lithium response in Mexican patients.

Background: The neuropeptide B/W receptor 1 (NPBWR1) system, including its two endogenous ligands, Neuropeptides B and W (NPB and NPW), has garnered interest as a potential target to develop novel analgesics. Behavioral studies were typically conducted with exogenously administered endogenous ligands. In this study, we examined truncated NPB-23 and its peptidomimetic RTIBW-16 in a panel of antinociceptive assays, including the hot plate, carrageenan-induced inflammatory, and paclitaxel chemotherapy-induced peripheral neuropathy (CIPN) pain assays.

Methods: Male and female C57BL/6 mice underwent testing in the hot plate acute nociception assay. After a minimum one-week washout, mice were enrolled in the carrageenan inflammatory pain model, receiving intraplanar carrageenan (0.3% carrageenan in a 20 µL volume). Separate mouse cohorts received a cycle of intraperitoneal paclitaxel injections (cumulative dose 32 mg/kg). The von Frey assay was utilized to assess CIPN and carrageenan-induced allodynia. NPB-23 and RTIBW-16 (0.56-100 µg) were administered via acute intrathecal (it) injections.

Results: Single it doses of NPB-23 and RTIBW-16 evoked dose-dependent antinociception (hotplate) and evoked dose-dependent anti-allodynia in mouse models of CIPN and carrageenan-induced unilateral hind paw inflammation. In the hot plate assay, RTIBW-16 showed an earlier onset but shorter duration of action than NPB-23 with similar maximum peak effects. Both compounds were statistically equipotent in the reversal of mechanical allodynia induced by either paclitaxel or carrageenan. RTIBW-16 maintained a longer duration of action than NPB-23 in the CIPN assay.

Conclusions: Single it doses of both NPBWR1 agonists alleviated acute pain in the hotplate test and mechanical allodynia in the hind paws of a mouse model of inflammatory pain. NPBWRI agonists also evoked anti-allodynia in a mouse model of CIPN. Our findings suggest that NPBWR1 is a promising target for developing analgesics with novel mechanisms.

Breast cancer (BC) is one of the most common malignant tumors in women worldwide, and its treatment faces numerous challenges. Despite the effectiveness of modern treatment methods such as surgery, radiotherapy, chemotherapy, and targeted therapy, issues like recurrence, metastasis, and drug resistance still significantly affect patient prognosis and survival rates. This is particularly true for triple-negative breast cancer (TNBC) and HER2-positive BC, for which treatment outcomes are relatively poor. Withaferin A (WA), a natural plant-derived compound, has shown significant anti-cancer effects in the treatment of BC. WA inhibits the progression of BC through multiple mechanisms, including suppressing cell migration and invasion, inducing tumor cell apoptosis, regulating autophagy and metabolic pathways, and modulating miRNA expression. In combination therapy, WA exhibits a good synergistic effect when used with other anti-cancer drugs such as phenethyl isothiocyanate (PEITC), cisplatin, and sulforaphane, significantly enhancing therapeutic efficacy and reducing drug resistance. This review summarizes the research progress on the mechanisms of WA in combating BC, aiming to provide a foundation for the scientific development and clinical application of WA in BC treatment.

Telmisartan, a well-established antihypertensive drug, has shown promising therapeutic potential for a variety of central nervous system (CNS) disorders. This review outlines the fundamental characteristics of telmisartan, focusing on its dual pharmacological effects as an angiotensin II type 1 receptor (AT1R) antagonist and a peroxisome proliferator-activated receptor (PPAR) γ activator. These mechanisms underpin its neuroprotective and anti-inflammatory effects, which are essential to its therapeutic benefits in CNS diseases. Telmisartan modulates key cellular components of the CNS, including microglia, astrocytes, oligodendrocytes, vascular endothelial cells, and neurons, thereby offering protection against neuroinflammation, oxidative stress, and neuronal damage. We summarize telmisartan's efficacy in addressing a range of neurological conditions, such as stroke, traumatic brain injury, dementia, Parkinson's disease, demyelinating diseases, psychiatric disorders, and gliomas. By targeting multiple pathways involved in these disorders, telmisartan demonstrates potential as both an adjunctive and standalone therapy. Its ability to attenuate neuroinflammation and promote cellular repair highlights its versatility in CNS disease management. This review underscores the potential of telmisartan as a valuable therapeutic option for CNS disorders, warranting continued exploration to optimize its clinical application.