Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood–brain barrier

Although the mechanisms of action of antipsychotics (APs) on neuronal function are well understood, very little is known about their effects on cells of the blood–brain barrier (BBB); one function of which is to limit the access of these amphiphilic compounds to the central nervous system. To address this question we have investigated the cytological and functional effects of four APs: chlorpromazine (CLP), haloperidol (HAL), risperidone (RIS) and clozapine (CLZ), at concentrations typical of high therapeutic dosage on a human brain microvascular endothelial cell (HBMEC) model of the BBB. At ~10 µM all four APs impaired the ability of HBMECs to reduce MTT which was followed by decreased Trypan blue exclusion and increased Lactate dehydrogenase release. These effects were associated with oxidative stress which was partly reversed by incubation in 10 mM glutathione. At their EC50 concentrations for MTT reduction, all four APs disrupted cellular ultrastructure and morphology. HAL, CPZ and CLZ increased Caspase -3, -8 and -9 activity, chromatin condensation and fragmentation, data indicative of apoptosis. These events were associated with decreased transcytosis of Evans blue and increased transendothelial potential difference and electrical resistance of this BBB model. These findings suggest that at high therapeutic concentrations, CPZ and CLZ are likely to incur cytoxic effects and apoptosis of BBB endothelia with an impairment of barrier functionality. Such events may underlie the aetiology of neuroleptic associated cerebral oedema and neuroleptic malignant syndrome

The role of oxidative stress in antipsychotics induced ovarian toxicity

This study tested the hypothesis that oxidative stress could be an underlying mechanism for APs-induced ovarian cytotoxicity and reproductive dysfunction. Rat ovarian theca interstitial cells (TICs) were isolated and treated with four APs [chlorpromazine (CPZ), haloperidol (HAL), risperidone (RIS) and clozapine (CLZ)]. MTT assay was used to test the effects of these antipsychotics on TICs viability and to estimate their 50% inhibitory concentrations (IC50s). The effects of APs (IC50s and 1 μM concentrations) on the activities of caspases-3, -8 and -9, reactive oxygen species (ROS) production, total intracellular glutathione and lipid peroxidation (LPO) in TICs were assessed. The effect of antioxidants (reduced glutathione (GSH) and quercetin) on the APs-induced cytotoxicity on TICs was investigated. MTT assay showed all APs to reduce TICs viability. CPZ, HAL and CLZ significantly increased the activity of caspases-3, -8 and -9 (P < 0.0001, < 0.0001 and < 0.01, respectively). All APs at IC50s significantly (P < 0.0001) increased ROS production, decreased total intracellular glutathione and increased LPO. MTT assay in the presence of antioxidants (reduced GSH (5 mM) or quercetin (50 mM)) showed each antioxidant to significantly inhibit the effects of APs at their IC50s on TICs viability. In conclusion, oxidative stress seems to be a possible mechanism for APs-induced ovarian and reproductive toxicity

Therapeutic concentrations of antidepressants inhibit pancreatic beta-cell function via mitochondrial complex inhibition

Diabetes mellitus risk is increased by prolonged usage of antidepressants (ADs). Although various mechanisms are suggested for their diabetogenic potential, whether a direct effect of ADs on pancreatic β-cells is involved is unclear. We examined this idea for 3 ADs: paroxetine, clomipramine and, with particular emphasis, fluoxetine, on insulin secretion, mitochondrial function, cellular bioenergetics, KATP channel activity, and caspase activity in murine and human cell-line models of pancreatic β-cells. Metabolic assays showed that these ADs decreased the redox, oxidative respiration, and energetic potential of β-cells in a time and concentration dependent manner, even at a concentration of 100 nM, well within the therapeutic window. These effects were related to inhibition of mitochondrial complex I and III. Consistent with impaired mitochondrial function, lactate output was increased and insulin secretion decreased. Neither fluoxetine, antimycin nor rotenone could reactivate KATP channel activity blocked by glucose unlike the mitochondrial uncoupler, FCCP. Chronic, but not acute, AD increased oxidative stress and activated caspases, 3, 8, and 9. A close agreement was found for the rates of oxidative respiration, lactate output and modulation of KATP channel activity in MIN6 cells with those of primary murine cells; data that supports MIN6 as a valid model to study beta-cell bioenergetics. To conclude, paroxetine, clomipramine and fluoxetine were all cytotoxic at therapeutic concentrations on pancreatic beta-cells; an action suggested to arise by inhibition of mitochondrial bioenergetics, oxidative stress and induction of apoptosis. These actions help explain the diabetogenic potential of these ADs in humans

Proximal femoral cortical thickness and medullary canal diameter in soft and hard water regions

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Deep Learning Algorithms for the Detection of Suspicious Pigmented Skin Lesions in Primary Care Settings: A Systematic Review and Meta- Analysis

Early detection of suspicious pigmented skin lesions is crucial for improving the outcomes and survival rates of skin cancers. However, the accuracy of clinical diagnosis by primary care physicians (PCPs) is suboptimal, leading to unnecessary referrals and biopsies. In recent years, deep learning (DL) algorithms have shown promising results in the automated detection and classification of skin lesions. This systematic review and meta-analysis aimed to evaluate the diagnostic performance of DL algorithms for the detection of suspicious pigmented skin lesions in primary care settings. A comprehensive literature search was conducted using electronic databases, including PubMed, Scopus, IEEE Xplore, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science. Data from eligible studies were extracted, including study characteristics, sample size, algorithm type, sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and receiver operating characteristic curve analysis. Three studies were included. The results showed that DL algorithms had a high sensitivity (90%, 95% CI: 90-91%) and specificity (85%, 95% CI: 84-86%) for detecting suspicious pigmented skin lesions in primary care settings. Significant heterogeneity was observed in both sensitivity (p = 0.0062, I² = 80.3%) and specificity (p < 0.001, I² = 98.8%). The analysis of DOR and PLR further demonstrated the strong diagnostic performance of DL algorithms. The DOR was 26.39, indicating a strong overall diagnostic performance of DL algorithms. The PLR was 4.30, highlighting the ability of these algorithms to influence diagnostic outcomes positively. The NLR was 0.16, indicating that a negative test result decreased the odds of misdiagnosis. The area under the curve of DL algorithms was 0.95, indicating excellent discriminative ability in distinguishing between benign and malignant pigmented skin lesions. DL algorithms have the potential to significantly improve the detection of suspicious pigmented skin lesions in primary care settings. Our analysis showed that DL exhibited promising performance in the early detection of suspicious pigmented skin lesions. However, further studies are needed

Orexins in apoptosis: a dual regulatory role

The orexins, also referred to as hypocretins, are neuropeptides that originate from the lateral hypothalamus (LH) region of the brain. They are composed of two small peptides, orexin-A, and orexin-B, which are broadly distributed throughout the central and peripheral nervous systems. Orexins are recognized to regulate diverse functions, involving energy homeostasis, the sleep-wake cycle, stress responses, and reward-seeking behaviors. Additionally, it is suggested that orexin-A deficiency is linked to sleepiness and narcolepsy. The orexins bind to their respective receptors, the orexin receptor type 1 (OX1R) and type 2 (OX2R), and activate different signaling pathways, which results in the mediation of various physiological functions. Orexin receptors are widely expressed in different parts of the body, including the skin, muscles, lungs, and bone marrow. The expression levels of orexins and their receptors play a crucial role in apoptosis, which makes them a potential target for clinical treatment of various disorders. This article delves into the significance of orexins and orexin receptors in the process of apoptosis, highlighting their expression levels and their potential contributions to different diseases. The article offers an overview of the existing understanding of the orexin/receptor system and how it influences the regulation of apoptosis

Adverse effects of anti-tuberculosis drugs on HepG2 cell bioenergetics

Tuberculosis (TB) is an intractable chronic infection. Disease treatment with anti-TB drugs remains challenging due to drug-induced hepatotoxicity. The toxicity of the anti-TB drugs rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) either alone or in combination was investigated in HepG2 cells. Assays of intracellular adenosine triphosphate (ATP) levels at 4-, 24- and 48-h post-exposure to gradient concentrations of RIF, INH and PZA were conducted. Drug-induced effects on mitochondrial membrane potential (MMP), mitochondrial complex I and complex III activity, nicotinamide adenine dinucleotide (NAD+) levels and cellular lactate production were assessed. Decreased ATP levels were dose-dependent and correlated with drug exposure duration. Approximate 24-h IC50s were 0.5 mM, 70 mM and 84 mM for RIF, INH and PZA, respectively. Twenty-four hours post-drug treatment, reductions of MMP (p = 0.0005), mitochondrial complex I and III activities (p = 0.0001 and p = 0.0003, respectively), NAD+ levels (p = 0.0057) and increased lactate production (p < 0.0001) were observed. Drug combinations used to mimic cumulative drug treatments induced a synergistic inhibition of mitochondrial complex I activity. An assessment of cellular ultrastructure using transmission electron microscopy indicated drug-induced mitophagy. Collectively, our study suggests that hepatotoxicity of commonly employed anti-TB drugs is mediated by their curtailment of mitochondrial function

The role of oxidative stress in ovarian toxicity induced by haloperidol and clozapine—a histological and biochemical study in albino rats

Oxidative stress has been implicated in reproductive toxicity induced by antipsychotics (APs). This study aims to further investigate the role of AP-induced oxidative stress in reproductive dysfunction. Thirty adult female albino rats were divided into three groups including a control group (n = 10) receiving distilled water, HAL group (n = 10) receiving haloperidol (HAL) (2 mg/kg/day), and CLZ group (n = 10) receiving clozapine (CLZ) (20 mg/kg/day). After 28 days, the rats were anesthetized, blood was withdrawn from their hearts, and ovaries were removed before they were sacrificed. Serum prolactin concentrations were measured. For each rat, one ovary was used for biochemical studies including mitochondrial complexes I and III activities and oxidative stress markers (lipid peroxidation, super oxide dismutase [SOD], catalase [CAT], and reduced glutathione [GSH]). The other ovary was used for histopathological examination and immunohistochemistry staining for p53 and Ki-67. HAL-treated rats showed significantly (p ≤0.001) higher serum prolactin concentrations compared with other groups. HAL significantly inhibited complexes I (p ≤ 0.001) and III activities (p ≤ 0.05), while CLZ inhibited only complex I (p ≤ 0.001). Lipid peroxidation was increased by HAL (p ≤ 0.001) and CLZ (p ≤ 0.01). HAL caused significant (p ≤ 0.001) reductions in SOD, CAT, and GSH. CLZ caused a significant decrease in SOD (p ≤ 0.001) and GSH (p ≤ 0.01) with no effect on CAT. Histopathological studies of CLZ- and HAL-treated ovaries showed features suggestive of hyperprolactinemia and oxidative stress. Ki-67- and P53-immunostained sections were suggestive of disruption of cellular proliferation. These findings support the hypothesis that HAL and CLZ induce reproductive dysfunction through mechanisms involving ovarian mitochondrial dysfunction and oxidative stress

Unveiling the therapeutic potential of exogenous β-hydroxybutyrate for chronic colitis in rats: novel insights on autophagy, apoptosis, and pyroptosis

Ulcerative colitis (UC) is a chronic relapsing inflammatory disease of the colorectal area that demonstrates a dramatically increasing incidence worldwide. This study provides novel insights into the capacity of the exogenous β-hydroxybutyrate and ketogenic diet (KD) consumption to alleviate dextran sodium sulfate (DSS)-induced UC in rats. Remarkably, both interventions attenuated disease activity and colon weight-to-length ratio, and improved macro and microstructures of the damaged colon. Importantly, both β-hydroxybutyrate and KD curbed the DSS-induced aberrant NLRP3 inflammasome activation as observed in mRNA and protein expression analysis. Additionally, inhibition of the NLRP3/NGSDMD-mediated pyroptosis was detected in response to both regimens. In parallel, these modalities attenuated caspase-1 and its associated consequences of IL-1β and IL-18 overproduction. They also mitigated apoptosis as indicated by the inactivation of caspase-3. The anti-inflammatory effects of BHB and KD were confirmed by the reported decline in the levels of inflammatory markers including MPO, NFκB, IL-6, and TNF-α. Moreover, these interventions exhibited antioxidative properties by reducing ROS production and improving antioxidative enzymes. Their effectiveness in mitigating UC was also evident in the renovation of normal intestinal epithelial barrier function, as shown by correcting the discrepancies in the levels of tight junction proteins ZO-1, OCLN, and CLDN5. Furthermore, their effects on the intestinal microbiota homeostasis were investigated. In terms of autophagy, exogenous β-hydroxybutyrate upregulated BECN-1 and downregulated p62, which may account for its superiority over KD in attenuating colonic damage. In conclusion, this study provides experimental evidence supporting the potential therapeutic use of β-hydroxybutyrate or β-hydroxybutyrate-boosting regimens in UC