Pharmacological Reports最新文献

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.

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.

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.

Background: Recently, the antinociceptive effect of LMH-2, a σ1 receptor antagonist, has been reported in diabetic mice with neuropathic pain. However, the mechanism by which this effect is produced is not completely clear. In this study, we explored the involvement of TRPV1 and the MOR-NMDAR complex in the antiallodynic effect of LMH-2 in hyperglycemic mice with neuropathic pain.

Methods: Hyperglycemia was induced in mice by administering streptozotocin-nicotinamide. Four weeks later, once neuropathic pain was established, the antiallodynic effect of LMH-2 (56.2 mg/kg) was evaluated using the up-down method with the von Frey filaments, both in the absence and the presence of capsazepine (8 mg/kg, ip), naloxone (NLX, 1 mg/kg, ip), NMDA (0.4 nM/10 µL, it), or their co-administration (NLX-NMDA). Gabapentin was used as positive control.

Results: Pretreatment with NLX did not alter the antiallodynic effect of LMH-2 in the up-down method with the von Frey filaments in hyperglycemic mice, whereas NMDA significantly reduced it. The addition of NLX to NMDA (NLX-NMDA) did not modify the effect of NMDA alone on the antiallodynic activity of LMH-2. Additionally, capsazepine completely blocked the antinociceptive effect of LMH-2 in hyperglycemic mice. Molecular docking analysis suggested a potential interaction between LMH-2 and TRPV1. Moreover, a higher dose of LMH-2 did not cause mortality or damage in healthy mice.

Conclusion: These results suggest the potential utility of LMH-2 in the treatment of diabetic neuropathy and highlight a key role for TRPV1 in LMH-2's antiallodynic mechanism, along with a possible, albeit limited, interaction with the MOR/NMDA complex.

Background: Bloodstream infection (BSI), defined as bacteraemia accompanied by sepsis or septic shock, is a frequent cause of hospitalization in departments of internal medicine (DIM). This study aimed to characterize the epidemiology, microbiological profile, and antibiotic treatment patterns of BSIs in a DIM setting in 2021-2023 in Polish hospital.

Methods: A three-year, single-centre retrospective analysis was conducted at a DIM in Southern Poland. Medical records from 2021 to 2023 were reviewed for patients diagnosed with sepsis (ICD-10 codes A40-A41) with microbiological confirmation. Antibiotic use was assessed using Days of Therapy (DOT) and Length of Therapy (LOT). Empiric and targeted therapies were classified according to the WHO AWaRe (Access, Watch, Reserve) framework.

Results: A total of 124 BSI cases were identified, with an incidence rate of 5.8%. Community-acquired BSIs accounted for 84.3% of cases, while 15.7% were hospital-acquired. The predominant pathogens were Escherichia coli and Staphylococcus aureus. The median LOT for empiric therapy was 3 days (IQR 2-4), with third-generation cephalosporins being the most frequently used agents (78 patients; 43.3%, 228 DOTs; 43.9%). Targeted therapy had a median LOT of 8 days (IQR 5-10), most commonly involving penicillins (33 patients; 28.4%, 291 DOTs; 34.5%). Access group antibiotics were significantly more prevalent in targeted therapy compared to empiric therapy (p < 0.001).

Conclusions: Microbiological confirmation of BSI facilitates a safe de-escalation from broad-spectrum empiric antibiotics to narrow-spectrum targeted therapy, supporting antimicrobial stewardship in internal medicine settings.