Pharmacological Reports最新文献

Gynecological tumors, such as ovarian, endometrial, and cervical cancers, alongside breast cancer, represent significant malignancies that pose serious threats to women's health worldwide. Standard treatments, including surgery, chemotherapy, radiotherapy, and targeted therapies, are commonly utilized in clinical practice. However, challenges such as high recurrence rates, drug resistance, and adverse side effects underscore the urgent need for more effective therapeutic options. Osthole, a natural coumarin compound derived from Chinese herbal medicine, has demonstrated remarkable antitumor activity against various cancers. Emerging evidence indicates that osthole can inhibit the proliferation, invasion, and metastasis of gynecological and breast cancer cells through various mechanisms, including inducing apoptosis and autophagy, regulating the tumor microenvironment, inhibiting tumor angiogenesis, and enhancing the sensitivity of cancer cells to chemotherapy and radiotherapy. This review highlights the recent advancements in osthole research within the context of gynecological and breast cancers, focusing on its molecular mechanisms, and offers a theoretical foundation for its potential development as an anticancer agent.

Melatonin, renowned for regulating sleep-wake cycles, also exhibits notable anti-aging properties for the skin. Synthesized in the pineal gland and various tissues including the skin, melatonin's efficacy arises from its capacity to combat oxidative stress and shield the skin from ultraviolet (UV)-induced damage. Moreover, it curbs melanin production, thereby potentially ameliorating hyperpigmentation. The presence of melatonin receptors in diverse skin cell types and its documented ability to enhance skin tone, hydration, and texture upon topical administration underscores its promise as an anti-aging agent. Melatonin's protective effects likely emanate from its multifaceted characteristics, encompassing antioxidant, anti-inflammatory, and immunomodulatory functions, as well as its influence on collagen synthesis and mitochondrial activity. Chronic inflammation and oxidative stress initiate a detrimental feedback loop. Reactive oxygen species (ROS), notorious for damaging cellular structures, provoke immune responses by oxidizing vital molecules and activating signaling proteins. This triggers heightened expression of inflammatory genes, perpetuating the cycle. Such dysregulation significantly compromises the body's resilience against infections and other health adversities. This study embarks on an exploration of the fundamental signaling pathways implicated in skin aging. Furthermore, it delves into the therapeutic potential of melatonin and its anti-aging attributes within the realm of skin health.

Background: Olaparib is a relatively new poly(ADP-ribose) polymerase inhibitor (PARPi) administered to ovarian cancer (OC) patients with a complete or partial response to first-line chemotherapy. One of the metabolic side effects of olaparib is the disruption of glucose homeostasis, often resulting in hyperglycemia The study was a retrospective analysis of olaparib-induced hyperglycemia in OC patients with initial normoglycemia following the first, second, and third month of olaparib treatment METHODS: The study involved 32 OC patients, classified into three groups according to their Body Mass Index (BMI): normal BMI (BMI 18.5-24.9 kg/m²; n = 13), overweight (BMI 25-29.9 kg/m²; n = 13), and obese (BMI ≥ 30 kg/m²; n = 6). The fasting glucose (FG) concentration was evaluated after the first, second, and third cycle of olaparib treatment (a cycle is the equivalent of 28 days of treatment). The severity of the observed hyperglycemia was assessed using the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Results: A significant increase in glycemia was observed after the first and second cycles of olaparib treatment in the group with normal BMI and after the third cycle in overweight and obese patients. There were no significant differences in glucose levels among the groups following the first, the second, and the third cycle. Grade 1 hyperglycemia with impaired fasting glucose levels (5.6-6.9 mmol/l) was found in 15 patients (normal BMI: n = 4, overweight: n = 9, and obesity: n = 2), while glycemia typical of diabetes (≥ 7.0 mmol/l) was observed in one obese patient.

Conclusions: Regardless of the weight of OC patients, it is essential to control glycemia during olaparib treatment.

Background: Epilepsy, a neurological disorder characterized by recurrent seizures, presents considerable difficulties in treatment, particularly when dealing with drug-resistant cases. Dapsone, recognized for its anti-inflammatory properties, holds promise as a potential therapeutic option. However, its effectiveness in epilepsy requires further investigation. The aim of this study is to explore the effects of dapsone on seizure activity and neuroinflammation, particularly through the nuclear factor erythroid-2-related factor (Nrf2)/ Heme Oxygenase 1 (HO-1) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) pathways, to better understand its therapeutic potential.

Methods: To evaluate the effects of dapsone, two seizure models were utilized in mice: pentylenetetrazole (PTZ)-induced clonic seizures and maximal electroshock (MES)-induced generalized tonic-clonic seizures (GTCS) in mice. The impact of dapsone on neuroinflammatory markers and oxidative stress pathways, specifically Nrf2/HO-1 and NLRP3, as well as interleukin-1β (IL-1β), IL-8, and IL-18, was assessed using Western blotting and ELISA techniques.

Results: In this study, dapsone (2, 5, 10, and 20 mg/kg, ip) showcased a significant increase in clonic seizure threshold following intravenous infusion of PTZ. Notably, doses of 5, 10, and 20 mg/kg exhibited increased latency and decreased the number of seizures. Additionally, dapsone at 10 and 20 mg/kg prevented the incidence of GTCS and subsequent mortality in the MES model. Furthermore, Dapsone demonstrated modulation of Nrf2/ HO-1 and NLRP3 IL-1 β/IL-18 pathways.

Conclusion: This study highlights the therapeutic potential of dapsone in epilepsy, emphasizing the involvement of Nrf2/HO-1 and NLRP3 pathways. These findings provide a foundation for future clinical research aimed at developing dapsone-based therapies for drug-resistant epilepsy.

Background: The current study investigated the effects of high-fat diet on acute response to 3,4-methylenedioxypyrovalerone (MDPV) in mice. MDPV is a beta-cathinone derivative endowed with psychostimulant activity. Similarly to recreational substances, consumption of palatable food stimulates the mesolimbic dopaminergic system, resulting in neuroadaptive changes.

Methods: Adolescent C57BL/6N mice were fed either control diet (CD), 10% of kcal from fat, or high-fat diet (HFD), 60% of kcal from fat. After eight weeks, one group of HFD-fed mice had their diet changed to CD for an additional two weeks. Fasting glucose levels and glucose tolerance were measured to detect impairment in glucose metabolism. Subsequently, the mice were treated with either MDPV (1 mg/kg) or saline, and their locomotor activity was measured. Using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), the expression of dopamine receptor D1 (Drd1), dopamine receptor D2 (Drd2), and FBJ osteosarcoma oncogene B (FosB) genes was measured in the striatum of mice.

Results: Feeding with HFD caused obesity and glucose intolerance in mice. Restriction of fat reduced body mass and reversed impairment of glucose metabolism. HFD-fed mice responded to MDPV with higher potency than CD-fed counterparts, with an increased incidence of stereotypies. A change of diet partially reversed this effect. Downregulation of Drd2 was observed in the mice that switched from HFD to CD, whereas treatment with MDPV caused upregulation of FosB only in the CD-fed mice.

Conclusions: Current results suggest that obesity may increase sensitivity to psychostimulant effects of MDPV and elevate the risk of addiction as mice fed with HFD responded to acute treatment with MDPV with higher potency and showed tolerance of FosB induction in response to the drug.

Background: Due to its availability and perceived safety, paracetamol is recommended even during pregnancy and for neonates. It is used frequently alone or in combination with other drugs required for the treatment of various chronic conditions. The aim of this study was to investigate potential effects of drug interactions on paracetamol metabolism and its placental transfer and entry into the developing brain.

Methods: Sprague Dawley rats at postnatal day P4, pregnant embryonic day E19 dams, and non-pregnant adult females were administered paracetamol (15 mg/kg) either as monotherapy or in combination with one of seven other drugs: cimetidine, digoxin, fluvoxamine, lamotrigine, lithium, olanzapine, valproate. Concentrations of parent paracetamol and its metabolites (paracetamol-glucuronide, paracetamol-glutathione, and paracetamol-sulfate) in plasma, cerebrospinal fluid (CSF) and brain were measured by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and their entry into the brain, CSF and transfer across the placenta were estimated.

Results: In monotherapy, concentration of parent paracetamol in plasma, CSF, and brain remained similar and at all ages brain entry was unrestricted. In combination therapies, CSF entry of paracetamol increased following co-treatment with olanzapine. Placental transfer of parent paracetamol remained unchanged, however, transfer of paracetamol-sulfate increased with lamotrigine co-administration. Acutely administered paracetamol was more extensively metabolized in adults compared to younger ages resulting in increased concentration of its metabolites with age.

Conclusions: Developmental changes in the apparent brain and CSF entry of paracetamol appear to be determined more by its metabolism, rather than by cellular control of its transfer across brain and placental barriers.

Type 1 diabetes (T1D) is an autoimmune disease that leads to the progressive destruction of insulin-producing β cells, resulting in lifelong insulin dependence and a range of severe complications. Beyond conventional glycemic control, innovative therapeutic strategies are needed to address the underlying disease mechanisms. Recent research has highlighted gamma-aminobutyric acid (GABA) as a promising therapeutic target for T1D due to its dual role in modulating both β cell survival and immune response within pancreatic islets. GABA signaling supports β cell regeneration, inhibits α cell hyperactivity, and promotes α-to-β cell transdifferentiation, contributing to improved islet function. Moreover, GABA's influence extends to mitigating T1D complications, including nephropathy, neuropathy, and retinopathy, as well as regulating central nervous system pathways involved in glucose metabolism. This review consolidates the latest advances in GABA-related T1D therapies, covering animal preclinical and human clinical studies and examining the therapeutic potential of GABA receptor modulation, combination therapies, and dietary interventions. Emphasis is placed on the translational potential of GABA-based approaches to enhance β cell viability and counteract autoimmune processes in T1D. Our findings underscore the therapeutic promise of GABA signaling modulation as a novel approach for T1D treatment and encourage further investigation into this pathway's role in comprehensive diabetes management.

Tacrolimus (TAC) is an immunosuppressant widely utilized in organ transplantation. One of its primary adverse effects is glucose metabolism disorder, which significantly increases the risk of diabetes. Investigating the molecular mechanisms underlying TAC-induced diabetes is essential for developing effective prevention and treatment strategies for these adverse effects. In addition, TAC can induce cost-effective, non-obese animal models of diabetes, where the metabolic parameter changes closely resemble those observed during the onset and progression of type 2 diabetes (T2DM), post-transplantation diabetes mellitus (PTDM), and associated complications. This review, based on articles indexed in PubMed up to August 19, 2024, identified 48 studies focusing on TAC-induced diabetic rodent models and 22 studies exploring the effects of TAC on diabetic or obese rodent models. These studies were systematically summarized based on TAC dosage, route of administration, duration of administration, and glucose metabolism indices used for evaluation. Additionally, the impact of TAC dose reduction or discontinuation on glucose metabolism was assessed, along with pharmacological agents that modulate TAC-induced diabetes, including anti-diabetic medications, anti-inflammatory and antioxidant compounds, biologics, and antibiotics. Key signaling pathways implicated in TAC-induced diabetes include CaN/NFAT, PI3K/AKT/mTOR, and TGF-β/Smad, all of which impair islet β-cell function, thereby contributing to diabetes development. This review provides a concise summary of the characteristics of relevant murine models, offering valuable guidance for selecting appropriate and economical animal models for future research.

Cardiovascular illnesses are multifactorial disorders and represent the primary reasons for death worldwide, according to the World Health Organization. As a signaling molecule, nitric oxide (NO) is extremely permeable across cellular membranes owing to its unique molecular features, like its small molecular size, lipophilicity, and free radical properties. Some of the biological effects of NO are vasodilation, inhibition in the growth of vascular smooth muscle cells, and functional regulation of cardiac cells. Several therapeutic approaches have been tested to increase the production of NO or some downstream NO signaling pathways. The health benefits of red wine are typically attributed to the polyphenolic phytoalexin, resveratrol (3,5,4'-trihydroxy-trans-stilbene), which is found in several plant species. Resveratrol has beneficial cardiovascular properties, some of which are mediated through endothelial nitric oxide synthase production (eNOS). Resveratrol promotes NO generation from eNOS through various methods, including upregulation of eNOS expression, activation in the enzymatic activity of eNOS, and reversal of eNOS uncoupling. Additionally, by reducing of oxidative stress, resveratrol inhibits the formation of superoxide and inactivation NO, increasing NO bioavailability. This review discusses the scientific literature on resveratrol's beneficial impact on NO signaling and how this effect improves the function of vascular endothelium.

Background: Cocaine Use Disorder (CUD) remains a significant problem in the United States, with high rates of relapse and no present FDA-approved treatment. The acetylcholine neurotransmitter system, specifically through modulation of muscarinic acetylcholine receptor (mAChR) function, has shown promise as a therapeutic target for multiple aspects of CUD. Enhancement of the M₄ mAChR subtype via positive allosteric modulation has been shown to inhibit the behavioral and neurochemical effects of cocaine across several rodent models of CUD. However, it is unclear how cocaine exposure affects M₄ mAChR expression or distribution.

Objectives: To evaluate the effects of cocaine self-administration on M₄ mAChR availability using [¹¹C]MK-6884 in vivo PET imaging in rats that self-administered cocaine (cocaine SA) or sucrose pellets (control).

Methods: Sprague-Dawley rats self-administered cocaine or sucrose pellets for 15 days under 2-h or 4-h sessions followed by PET imaging with [¹¹C]MK-6884, a radiolabeled M₄ selective positive allosteric modulator to determine the effects of cocaine on [¹¹C]MK-6884 standard uptake values with cerebellum as reference (SUVr).

Results: Cumulative cocaine intake ranged between 324 and 776 mg/kg. Cocaine self-administration was associated with significantly lower [¹¹C]MK-6884 SUVrs in the cortex, hippocampus, and striatum compared to cocaine-naive rats, with a negative correlation between radiotracer SUVrs and cocaine intake in the hippocampus.

Conclusions: These results suggest that cocaine self-administration decreases M₄ mAChR availability, providing further support for pursuing activation/enhancement of M₄ mAChR function as a viable pharmacotherapeutic approach for CUD.