BMC Pharmacology & Toxicology最新文献

Background: Methamphetamine is widely abused in all parts of the world. It has been reported that short-term and long-term methamphetamine exposure could damage the dopaminergic system and induce cardiomyopathy and cardiotoxicity via mitochondrial dysfunction and oxidative stress. Vanillic acid (VA), a phenolic acid compound derived from plants, is known for its antioxidant and mitochondrial protection properties.

Methods: In the current study we used VA for attenuating of Methamphetamine-induced mitochondrial toxicity in cardiac mitochondria. Isolated mitochondria obtained from rat heart were grouped as: control, methamphetamine (250 µM), VA (10, 50 and 100 µM) was cotreated with methamphetamine (250 µM) and VA (100 µM) alone. After 60 min, mitochondrial fraction including: succinate dehydrogenases (SDH) activity, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial glutathione (GSH), reactive oxygen species (ROS) and lipid peroxidation (LPO) were evaluated.

Results: Methamphetamine exposure significantly disrupted mitochondrial function and induced ROS formation, lipid peroxidation, GSH depletion, MMP collapse and mitochondrial swelling, while VA significantly increased SDH activity as indicator of mitochondrial toxicity and dysfunction. VA also significantly decreased ROS formation, lipid peroxidation, mitochondrial swelling, MMP collapse and depletion of GSH in cardiac mitochondria in the presence of methamphetamine.

Conclusion: These findings suggested that VA is able to reduce methamphetamine-induced mitochondrial dysfunction and oxidative stress. Our results demonstrate that VA could potentially serve as a promising and accessible cardioprotective agent against methamphetamine-induced cardiotoxicity, via antioxidant and mitochondrial protection properties.

Background: Many trials supported pembrolizumab as a first-line monotherapy to significantly improve overall survival (OS) in selected patients with previously untreated metastatic Non-Small Cell Lung Cancer (mNSCLC) and a PD-L1 TPS of ≥50% without EGFR/ALK mutations. The aim of this study was to reveal the correlation between OS and adverse events in real-world settings after 42 months.

Methods: This retrospective observational study involved 98 patients with mNSCLC, TPS ≥ 50%, and no EGFR/ALK aberrations. Patients were treated with pembrolizumab (200 mg q3w) as a first-line treatment. Clinical data, including PD-L1 expression, Performance Status (ECOG-PS), treatment duration, toxicity, and outcomes were retrieved from local electronic medical records and from the Italian Regulatory Agency Registry.

Results: The cohort's main characteristics were as follows: median age 73 [44-89] years, 64.3% were male and 35.7% were female, an ECOG-PS score of 0 (n = 73) and 1 or 2 (n = 25), and a PD-L1 > 90% in 29.6% of patients. The entire cohort had stage IV NSCLC at diagnosis. The median number of cycles was 8.5 at a median follow-up of 13 months. The median OS of 13.6 months (95% CI: 11.7-NA) was not influenced by sex and PD-L1, but was significantly associated with ECOG-PS (p = 0.02). Immune-Related Adverse Events (irAEs) occurred in 77.5% of patients (30.1% cutaneous, 27.5% gastrointestinal, and 20.4% endocrinological), but no grade 4 or 5 irAEs were identified. Patients experiencing any type of toxicity had a significantly longer median OS (20.39 months, 95% CI: 13.08-NA) than those with no toxicities (6.46 months, 95% CI: 1.41-NA, p = 0.006).

Conclusion: The percentage of irAEs detected was comparable to that reported in KEYNOTE-024 and KEYNOTE-042. These real-world findings demonstrated the significant correlation between OS and cutaneous toxicities.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disorder. The naturally occurring phytosterol; β-sitosterol has antiobesogenic and anti-diabetic properties. The purpose of this study was to explore the role of β-sitosterol in preventing hepatic steatosis induced by a high-fat diet (HFD) in rats. In the current study, to induce NAFLD in the female Wister rats, an HFD was administered to them for 8 weeks. The pathogenic severity of steatosis in rats receiving an HFD diet was dramatically decreased by oral administration of β-sitosterol. After administering β-sitosterol to HFD-induced steatosis for three weeks, several oxidative stress-related markers were then assessed. We showed that β-sitosterol reduced steatosis and the serum levels of triglycerides, transaminases (ALT and AST) and inflammatory markers (IL-1β and iNOS) compared to HFD-fed rats. Additionally, β-sitosterol reduced endoplasmic reticulum stress by preventing the overexpression of inositol-requiring enzyme-1 (IRE-1α), X-box binding protein 1(sXBP1) and C/EBP homologous protein (CHOP) genes which, showing a function in the homeostatic regulation of protein folding. Also, it was found that the expression of the lipogenic factors; peroxisome proliferator-activated receptor (PPAR-α), sterol regulatory element binding protein (SREBP-1c) and carnitine palmitoyltransferase-1(CPT-1), which are involved in the regulation of the fatty acid oxidation process, may be regulated by β-sitosterol. It can be concluded that β-sitosterol may prevent NAFLD by reducing oxidative stress, endoplasmic reticulum stress and inflammatory responses, which supports the possibility of using β-sitosterol as an alternative therapy for NAFLD. Together, β-sitosterol may be an option for NAFLD prevention.

Background: First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, have been shown to target tumors with L858R (exon 21) and exon 19 deletions, resulting in significant clinical benefits. However, acquired resistance often occurs due to EGFR mutations. Therefore, novel therapeutic strategies for treatment of patients with EGFR-positive tumors are needed. Berberine (BBR) is an active alkaloid extracted from pharmaceutical plants such as Coptis chinensis. Berberine has been shown to significantly inhibit EGFR activity and mediate anticancer effects in multiple preclinical studies. We investigated whether combining BBR with erlotinib could augment erlotinib-induced cell growth inhibition of EGFR-positive cells in a mouse xenograft model.

Methods: We examined the antitumor activities and potential mechanisms of erlotinib in combination with berberine in vitro and in vivo using the MTT assay, immunoblotting, flow cytometry, and tumor xenograft models.

Results: In vitro studies with A431 cells showed that synergistic cell growth inhibition by the combination of BBR and erlotinib was associated with significantly greater inhibition of pEGFR and pAKT, and inhibition of cyclin D and Bcl-2 expression compared to that observed in response to BBR or erlotinib alone. The efficacy of the combination treatment was also investigated in nude mice. Consistent with the in vitro results, BBR plus erlotinib significantly reduced tumor growth.

Conclusion: Our data supported use of BBR in combination with erlotinib as a novel strategy for treatment of patients with EGFR positive tumors.

Background: The plants Aloe weloensis, Lepidium sativum, and Lobelia gibberoa have been used in Ethiopian folklore medicine to treat various diseases including malaria.

Method: The in vitro anti-plasmodial activity of the three crude extracts was evaluated using parasite lactate dehydrogenase assay against the chloroquine (CQ)-sensitive D10 and the chloroquine (CQ)-resistant W2 strains.

Result: The methanolic extract of L. gibberoa roots showed the highest in vitro anti-plasmodial effect against both D10 and W2 Plasmodium falciparum strains with IC₅₀ value of 103.83 ± 26.17 µg/mL and 47.11 ± 12.46 µg/mL, respectively. However, the methanolic extract of L. sativum seeds and the leaf latex of A. weloensis were not active with an IC₅₀ value > 200 µg/mL against both D10 and W2 strains.

Conclusion: The methanolic extract of L. gibberoa roots showed a promising in vitro anti-plasmodial activity against the CQ-sensitive (D10) and CQ-resistant (W2) strains of P. falciparum. Thus, the anti-plasmodial activity of this plant partly justifies and may also support the traditional use against malaria. However, the methanolic extract of L. sativum seeds and the leaf latex of A. weloensis did not exert suppressive activity on the growth of P. falciparum strains.

Background: Stroke is one of the most common noncommunicable diseases, with significant public health implications both globally and in Malaysia. The aim of this study was to evaluate post-stroke survivability as well as the major drug classes prescribed for hospitalized stroke patients.

Methods: A 5-year retrospective study was carried out on the survival of stroke patients admitted to Hospital Seberang Jaya, a main stroke center in the state of Penang, Malaysia. Patients admitted for stroke were first identified using the local stroke registry database, and their medical records were then accessed for data collection, which included demographic information, comorbid conditions, and medications prescribed during admission.

Results: The Kaplan-Meier overall survivability analysis performed indicated 50.5% survival for the duration of 10 days (p < 0.001) post-stroke. Ten-day survivability differences (p < 0.05) were observed for the categories of type of stroke (ischemic stroke (60.9%) and hemorrhagic stroke (14.1%)); stroke episodes (first (61.1%) and recurrent (39.6%)); anti-platelets (prescribed (46.2%) and not prescribed (41.5%)); statins (prescribed (68.7%) and not prescribed (28.1%)); anti-hypertensive (prescribed (65.4%) and not prescribed (45.9%)); and anti-infectives (prescribed (42.5%) and not prescribed (59.6%)) respectively. Higher risks of mortality were observed among patients with hemorrhagic stroke (HR: 10.61, p = 0.004); with 3 or more comorbidities (HR:6.60, p = 0.020); and not prescribed with statins and anti-diabetic. Patients prescribed anti-infectives, on the other hand, had a higher risk of mortality when compared to patients who did not receive anti-infectives (HR: 13.10, p = 0.019). The major drug classes prescribed for stroke patients were antiplatelet drugs (86.7%), statins (84.4%), and protein pump inhibitors (75.6%).

Conclusion: The findings of the study are intended to encourage more non-stroke hospitals in Malaysia to increase their efforts in treating stroke patients, as early treatment can help reduce the severity of the stroke. With the incorporation of evidence-based data, this study also contributes to local data for comparison and improves the implementation of regularly prescribed stroke medication.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects from children to adults widely, presenting symptoms such as pruritus, erythema, scaling, and dryness. Lupeol, a pentacyclic triterpenoid, has anti-inflammatory and antimicrobial activities. Based on these properties, the therapeutic effects of lupeol on skin disorders have been actively studied. In the present study, we aimed to determine the effectiveness of lupeol on AD.

Methods: We utilized tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated keratinocytes and 2, 4-dinitrochlorobenzene/Dermatophagoides farinae extract (DFE)-induced AD mice to confirm the action.

Results: Lupeol inhibited TNF-α/IFN-γ-stimulated keratinocytes activation by reducing the expressions of pro-inflammatory cytokines and chemokines which are mediated by the activation of signaling molecules such as signal transducer and activator of transcription 1, mitogen-activated protein kinases (p38 and ERK), and nuclear factor-κB. Oral administration of lupeol suppressed epidermal and dermal thickening and immune cell infiltration in ear tissue. Immunoglobulin (Ig) E (total and DFE-specific) and IgG2a levels in serum were also reduced by lupeol. The gene expression and protein secretion of T helper (Th) 2 cytokines, Th1 cytokines, and pro-inflammatory cytokine in ear tissue were decreased by lupeol.

Conclusions: These results suggest that lupeol has inhibitory effects on AD-related responses. Therefore, lupeol could be a promising therapeutic agent for AD.

Background: Medical therapies can cause cardiotoxicity. Chloroquine (QC) and hydroxychloroquine (HQC) are drugs used in the treatment of malaria and skin and rheumatic disorders. These drugs were considered to help treatment of coronavirus disease (COVID-19) in 2019. Despite the low cost and availability of QC and HQC, reports indicate that this class of drugs can cause cardiotoxicity. The mechanism of this event is not well known, but evidence shows that QC and HQC can cause cardiotoxicity by affecting mitochondria and lysosomes.

Methods: Therefore, our study was designed to investigate the effects of QC and HQC on heart mitochondria. In order to achieve this aim, mitochondrial function, reactive oxygen species (ROS) level, mitochondrial membrane disruption, and cytochrome c release in heart mitochondria were evaluated. Statistical significance was determined using the one-way and two-way analysis of variance (ANOVA) followed by post hoc Tukey to evaluate mitochondrial succinate dehydrogenase (SDH) activity and cytochrome c release, and Bonferroni test to evaluate the ROS level, mitochondrial membrane potential (MMP) collapse, and mitochondrial swelling.

Results: Based on ANOVA analysis (one-way), the results of mitochondrial SDH activity showed that the IC₅₀ concentration for CQ is 20 µM and for HCQ is 50 µM. Based on two-way ANOVA analysis, the highest effect of CQ and HCQ on the generation of ROS, collapse in the MMP, and mitochondrial swelling were observed at 40 µM and 100 µM concentrations, respectively (p < 0.05). Also, the highest effect of these two drugs has been observed in 60 min (p < 0.05). The statistical results showed that compared to CQ, HCQ is able to cause the release of cytochrome c from mitochondria in all applied concentrations (p < 0.05).

Conclusions: The results suggest that QC and HQC can cause cardiotoxicity which can lead to heart disorders through oxidative stress and disfunction of heart mitochondria.

Background: Previous studies on animal models have suggested that δ-opioid receptor (OR) signaling is the primary pathway responsible for opioids' cardioprotective effect. We hypothesize that the μ-OR's activation protects the human heart muscle.

Methods: We performed the experiments on muscular trabeculae obtained from the right atrial appendages of 104 consecutive patients subjected to coronary artery bypass surgery. Two trabeculae from each patient were studied simultaneously and exposed to 60 min of hypoxia with subsequent 60 min of reoxygenation. Remifentanil (5 μM or 50 μM) or sufentanil (40 μM or 400 μM) was used from the time of reoxygenation. Trabeculae contractility was assessed as the maximal amplitude of the contraction at baseline, after 60 min of hypoxia, during reoxygenation, and after norepinephrine application.

Results: During reperfusion, the application of remifentanil improved cardiomyocytes' function as compared to the control group (time from reperfusion: 15 min: 39.8% vs. 21.7%, p = 0.01; 30 min: 41.4% vs. 21.8%, p = 0.01; 60 min: 42.7% vs. 26.9%, p = 0.04; after norepinephrine: 64.7% vs. 43.2%, p = 0.03). The application of sufentanil did not influence cardiomyocyte function as can be seen when comparing the results of the experimental and control group.

Conclusions: Remifentanil, but not sufentanil, induces a cardioprotective effect on human right atria muscle in in vitro conditions, manifested as the increased amplitude of their contraction during reperfusion after 60 min of ischemia.

Background: Renin-angiotensin-aldosterone system (RAAS) is hypothesized to be in the center of COVID pathophysiology as the angiotensin converting enzyme 2 (ACE2) represents the main entrance of the virus, thus there is a need to address the effect of chronic use of RAAS blockers, as in case of treatment of cardiovascular diseases, on the expression of ACE2. Accordingly, this study aimed to clarify the effect of ACE inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) on ACE2 and to assess the correlation between ACE2 and several anthropometric and clinic-pathological factors.

Methods: A total of 40 healthy controls and 60 Egyptian patients suffering from chronic cardiovascular diseases were enrolled in this study. Patients were divided into 40 patients treated with ACEIs and 20 patients treated with ARBs. Serum ACE2 levels were assessed by ELISA.

Results: Assessment of serum ACE2 level in different groups showed a significant difference between ACEIs and healthy groups and ACEIs and ARBs group, while there was no difference between ARBs and healthy. Multivariate analysis using ACE2 level as constant and age, female sex, ACEIs use and myocardial infarction (MI) showed that there was a significant effect of female sex and ACEIs use on ACE2 level with no effect of age, MI and diabetes.

Conclusion: ACE2 levels varied between ACEIs and ARBs. It tends to be lower in ACEIs group and there is a strong positive association between ACE2 level and the female sex. This needs to be considered in Future studies to further understand the relationship between gender, sex hormones and ACE2 level.

Trial registration: Retrospectively registered ClinicalTrials.gov ID: NCT05418361 (June 2022).