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Biology Direct Aug 2023Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder...
Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder and major depressive disorder. However, they also induce debilitating extrapyramidal syndromes (EPS), such as Parkinsonism, in a significant minority of patients. The majority of antipsychotic drugs function as dopamine receptor antagonists in the brain while the most recent 'third'-generation, such as aripiprazole, act as partial agonists. Despite showing good clinical efficacy, these newer agents are still associated with EPS in ~ 5 to 15% of patients. However, it is not fully understood how these movement disorders develop. Here, we combine clinically-relevant drug concentrations with mutliscale model systems to show that aripiprazole and its primary active metabolite induce mitochondrial toxicity inducing robust declines in cellular ATP and viability. Aripiprazole, brexpiprazole and cariprazine were shown to directly inhibit respiratory complex I through its ubiquinone-binding channel. Importantly, all three drugs induced mitochondrial toxicity in primary embryonic mouse neurons, with greater bioenergetic inhibition in ventral midbrain neurons than forebrain neurons. Finally, chronic feeding with aripiprazole resulted in structural damage to mitochondria in the brain and thoracic muscle of adult Drosophila melanogaster consistent with locomotor dysfunction. Taken together, we show that antipsychotic drugs acting as partial dopamine receptor agonists exhibit off-target mitochondrial liabilities targeting complex I.
Topics: Animals; Mice; Aripiprazole; Antipsychotic Agents; Depressive Disorder, Major; Drosophila melanogaster; Electron Transport
PubMed: 37528429
DOI: 10.1186/s13062-023-00375-9 -
Molecules (Basel, Switzerland) Jul 2023A series of novel Mannich bases were designed, synthesized, and screened for their antimicrobial activity. The target compounds were synthesized from...
A series of novel Mannich bases were designed, synthesized, and screened for their antimicrobial activity. The target compounds were synthesized from 4-(3-chlorophenyl)-5-(3-fluorophenyl)-2,4-dihydro-3-1,2,4-triazole-3-thione and different piperazine derivatives. The structures of the products were confirmed by H and C NMR and elemental analysis. The activity of piperazine derivatives against bacteria (Gram-positive: , , , , and ; Gram-negative: , , , and ) and yeasts (, , and ) was determined by the minimum inhibitory concentration and minimum bactericidal concentration values. Significant activity was observed against Gram-positive bacteria, mainly staphylococci (-) and bacteria of the genes of and (), as well as selected strains of Gram-negative bacteria, including bacteria of the family (), while all tested compounds showed high fungistatic activity against spp. yeasts, especially , with MICs ranging from 0.49 µg/mL () to 0.98 µg/mL () and 62.5 µg/mL (). In conclusion, the results obtained confirm the multidirectional antimicrobial activity of the newly synthesized piperazine derivatives. Furthermore, in silico studies suggest that the tested compounds are likely to have good oral bioavailability. The results obtained will provide valuable data for further research into this interesting group of compounds. The library of compounds obtained is still the subject of pharmacological research aimed at finding new interesting biologically active compounds.
Topics: Piperazine; Mannich Bases; Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Gram-Negative Bacteria; Candida; Anti-Infective Agents; Anti-Bacterial Agents
PubMed: 37513434
DOI: 10.3390/molecules28145562 -
Canadian Journal of Microbiology Jun 2024have a uniquely complex developmental life cycle that involves the coordination of morphological differentiation with the production of numerous bioactive specialized... (Review)
Review
have a uniquely complex developmental life cycle that involves the coordination of morphological differentiation with the production of numerous bioactive specialized metabolites. The majority of spp. are soil-dwelling saprophytes, while plant pathogenicity is a rare attribute among members of this genus Phytopathogenic are responsible for economically important diseases such as common scab, which affects potato and other root crops. Following the acquisition of genes encoding virulence factors, pathogens are expected to have specifically adapted their regulatory pathways to enable transition from a primarily saprophytic to a pathogenic lifestyle. Investigations of the regulation of pathogenesis have primarily focused on and the principal pathogenicity determinant thaxtomin A. The coordination of growth and thaxtomin A production in this species is controlled in a hierarchical manner by cluster-situated regulators, pleiotropic regulators, signalling and plant-derived molecules, and nutrients. Although the majority of phytopathogenic produce thaxtomins, many also produce additional virulence factors, and there are scab-causing pathogens that do not produce thaxtomins. The development of effective control strategies for common scab and other plant diseases requires a more in-depth understanding of the genetic and environmental factors that modulate the plant pathogenic lifestyle of these organisms.
Topics: Streptomyces; Plant Diseases; Virulence; Virulence Factors; Gene Expression Regulation, Bacterial; Bacterial Proteins; Plants; Solanum tuberosum; Indoles; Piperazines
PubMed: 38190652
DOI: 10.1139/cjm-2023-0171 -
Nature May 2024PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer, who were germline BRCA1 and... (Randomized Controlled Trial)
Randomized Controlled Trial
PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer, who were germline BRCA1 and BRCA2 wild type. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR), and secondary end points included event-free survival (EFS) and overall survival (OS). pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .
Topics: Adult; Aged; Female; Humans; Middle Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Genes, BRCA1; Genes, BRCA2; Neoadjuvant Therapy; Paclitaxel; Pathologic Complete Response; Phthalazines; Piperazines; Progression-Free Survival; Prospective Studies; Survival Analysis; Time Factors; Triple Negative Breast Neoplasms; Adolescent; Young Adult
PubMed: 38588696
DOI: 10.1038/s41586-024-07384-2 -
BMC Pediatrics Jul 2023Sildenafil was first prescribed for angina pectoris and then for erectile dysfunction from its effects on vascular smooth muscle relaxation and vasodilatation. Recently,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Sildenafil was first prescribed for angina pectoris and then for erectile dysfunction from its effects on vascular smooth muscle relaxation and vasodilatation. Recently, sildenafil has been proposed for congenital heart diseases induced pulmonary hypertension, which constitutes a huge burden on children's health and can attribute to fatal complications due to presence of unoxygenated blood in the systemic circulation. Therefore, our meta-analysis aims to further investigate the safety and efficacy of sildenafil on children population.
METHODS
We searched the following electronic databases: PubMed, Cochrane CENTRAL, WOS, Embase, and Scopus from inception to April 20th, 2022. Randomized controlled trials that assess the efficacy of using sildenafil in comparison to a placebo or any other vasodilator drug were eligible for inclusion. The inverse variance method was used to pool study effect estimates using the random effect model. Effect sizes are provided in the form of mean difference (MD) with 95% confidence intervals (CI).
RESULTS
Our study included 14 studies with (n = 849 children) with a mean age of 7.9 months old. Sildenafil showed a statistically significant decrease over placebo in mean and systolic pulmonary artery pressure (PAP) with MD -7.42 (95%CI [-13.13, -1.71], P = 0.01) and -8.02 (95%CI [-11.16, -4.88], P < 0.0001), respectively. Sildenafil revealed a decrease in mean aortic pressure and pulmonary artery/aortic pressure ratio over placebo with MD -0.34 (95%CI [-2.42, 1.73], P = 0.75) and MD -0.10 (95%CI [-0.11, -0.09], P < 0.00001), respectively. Regarding post corrective operations parameters, sildenafil had a statistically significant lower mechanical ventilation time, intensive care unit stay, and hospital stay over placebo with MD -19.43 (95%CI [-31.04, -7.81], s = 0.001), MD -34.85 (95%CI [-50.84, -18.87], P < 0.00001), and MD -41.87 (95%CI [-79.41, -4.33], P = 0.03), respectively. Nevertheless, no difference in mortality rates between sildenafil and placebo with OR 0.25 (95%CI 0.05, 1.30], P = 0.10) or tadalafil with OR 1 (95%CI 0.06, 17.12], P = 1).
CONCLUSION
Sildenafil is a well-tolerated treatment in congenital heart diseases induced pulmonary hypertension, as it has proven its efficacy not only in lowering both PAP mean and systolic but also in reducing the ventilation time, intensive care unit and hospital stay with no difference observed regarding mortality rates.
Topics: Male; Child; Humans; Infant; Sildenafil Citrate; Hypertension, Pulmonary; Randomized Controlled Trials as Topic; Vasodilator Agents; Heart Defects, Congenital
PubMed: 37474896
DOI: 10.1186/s12887-023-04180-1 -
Molecular Psychiatry Aug 2023Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology... (Review)
Review
Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression-mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine's potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine's demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.
Topics: Humans; Trimetazidine; Vasodilator Agents; Bipolar Disorder; Angina Pectoris; Antioxidants
PubMed: 37386057
DOI: 10.1038/s41380-023-02134-8 -
Breast (Edinburgh, Scotland) Aug 2023The optimal treatment following endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has not been established. We aimed to investigate treatment... (Observational Study)
Observational Study
PURPOSE
The optimal treatment following endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has not been established. We aimed to investigate treatment patterns and time to treatment failure (TTF) of subsequent therapy after palbociclib in a Japanese real-world setting.
METHDS
This retrospective observational study used de-identified data of patients with advanced breast cancer treated with palbociclib, using a nationwide claims database (April 2008 to June 2021). Measures included the type of subsequent therapies after palbociclib (endocrine-based therapy: ET alone, ET + CDK4/6i, and ET + mammalian target of rapamycin inhibitor [mTORi]; chemotherapy; chemotherapy + ET; and others) and their TTFs. The median TTF and 95% confidence interval (CI) were estimated using the Kaplan-Meier method.
RESULTS
Of 1170 patients treated with palbociclib, 224 and 235 received subsequent therapies after first- and second-line palbociclib treatment, respectively. Among them, 60.7% and 52.8% were treated with endocrine-based therapies as first subsequent therapy, including ET + CDK4/6i (31.2% and 29.8%, respectively). The median TTF (95% CI) of ET alone, ET + CDK4/6i, and ET + mTORi as first subsequent therapy after first-line palbociclib were 4.4 (2.8-13.7), 10.9 (6.5-15.6), and 6.1 (5.1-7.2) months, respectively. No apparent relationship between the treatment duration of prior ET + palbociclib and subsequent abemaciclib was observed.
CONCLUSION
This real-world study revealed that one-third of the patients received sequential CDK4/6i after ET + palbociclib, and treatment duration of ET + CDK4/6i following ET + palbociclib was the longest among the treatment options. Further data are awaited to determine whether ET + targeted therapy with CDK4/6i and mTORi provides acceptable treatment options following ET + palbociclib.
Topics: Humans; Female; Breast Neoplasms; Japan; Pyridines; Piperazines; Antineoplastic Combined Chemotherapy Protocols; Cyclin-Dependent Kinase 4; Protein Kinase Inhibitors; Receptor, ErbB-2
PubMed: 37267715
DOI: 10.1016/j.breast.2023.05.006 -
Developmental Cell Oct 2023Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a...
Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a promising therapeutic approach for this devastating disease. Here, we show that the CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal differentiation of adrenergic neuroblastoma cells. Palbociclib-mediated differentiation is manifested by extensive phenotypic and transcriptional changes accompanied by the establishment of an epigenetic program driving expression of mature neuronal features. In vivo palbociclib significantly inhibits tumor growth in mouse neuroblastoma models. Furthermore, dual treatment with retinoic acid resets the oncogenic adrenergic core regulatory circuit of neuroblastoma cells, further suppresses proliferation, and can enhance differentiation, altering gene expression in ways that significantly correlate with improved patient survival. We therefore identify palbociclib as a therapeutic approach to dramatically enhance neuroblastoma differentiation efficacy that could be used in combination with retinoic acid to improve patient outcomes.
Topics: Animals; Mice; Humans; Cell Line, Tumor; Cell Differentiation; Tretinoin; Neuroblastoma; Adrenergic Agents; Piperazines; Pyridines
PubMed: 37734383
DOI: 10.1016/j.devcel.2023.08.028 -
Journal of Clinical Microbiology Aug 2023Dermatophytes are common causes of skin, hair, and nail infections in humans. The most common species causing infections in humans are Trichophyton rubrum, Trichophyton...
Dermatophytes are common causes of skin, hair, and nail infections in humans. The most common species causing infections in humans are Trichophyton rubrum, Trichophyton mentagrophytes, and Trichophyton interdigitale. Outbreaks of recalcitrant dermatophytosis have been reported in parts of South Asia, including those caused by a hypervirulent and resistant species, Trichophyton indotineae. We evaluated the antifungal susceptibility profiles of dermatophytes received by our laboratory from institutions across North America between 2021 and 2022 and performed species identification for isolates deemed to demonstrate resistance. Susceptibility testing was performed by CLSI broth microdilution methods, and species identification was performed by DNA sequence analysis. During this 2-year period, 271 dermatophyte isolates were included, the majority of which demonstrated low MIC values for terbinafine (geometric mean [GM] and modal MIC, 0.031 μg/mL and 0.008 μg/mL, respectively) and the azoles itraconazole, posaconazole, and voriconazole (0.035 to 0.049 μg/mL and ≤0.03 μg/mL). However, 18.6% of the isolates tested were resistant to terbinafine (MIC ≥ 0.5 μg/mL), including 21 T. rubrum and 21 T. indotineae isolates. These isolates were received from several different states in the United States and two provinces in Canada. In contrast, resistance to itraconazole was relatively rare. We also searched our laboratory database for earlier isolates that were resistant to terbinafine and identified 3 additional T. indotineae isolates, the earliest of which was from 2017. These results demonstrate that terbinafine resistance in dermatophytes was relatively common over this 2-year period and that T. indotineae is present in multiple areas in North America. Continued surveillance is warranted.
Topics: Humans; Terbinafine; Trichophyton; Itraconazole; Arthrodermataceae; Microbial Sensitivity Tests; Antifungal Agents; North America; Drug Resistance, Fungal
PubMed: 37432126
DOI: 10.1128/jcm.00562-23 -
Pharmacological Research Feb 2024Sepsis is a dysregulated response to infection that can result in life-threatening organ failure, and septic cardiomyopathy is a serious complication involving...
Sepsis is a dysregulated response to infection that can result in life-threatening organ failure, and septic cardiomyopathy is a serious complication involving ferroptosis. Olaparib, a classic targeted drug used in oncology, has demonstrated potential protective effects against sepsis. However, the exact mechanisms underlying its action remain to be elucidated. In our study, we meticulously screened ferroptosis genes associated with sepsis, and conducted comprehensive functional enrichment analyses to delineate the relationship between ferroptosis and mitochondrial damage. Eight sepsis-characterized ferroptosis genes were identified in sepsis patients, including DPP4, LPIN1, PGD, HP, MAPK14, POR, GCLM, and SLC38A1, which were significantly correlated with mitochondrial quality imbalance. Utilizing DrugBank and molecular docking, we demonstrated a robust interaction of Olaparib with these genes. Lipopolysaccharide (LPS)-stimulated HL-1 cells and monocytes were used to establish an in vitro sepsis model. Additionally, an in vivo model was developed using mice subjected to cecal ligation and perforation (CLP). Intriguingly, low-dose Olaparib (5 mg/kg) effectively targeted and mitigated markers associated with ferroptosis, concurrently improving mitochondrial quality. This led to a marked enhancement in cardiac function and a significant increase in survival rates in septic mice (p < 0.05). The mechanism through which Olaparib ameliorates ferroptosis in cardiac and leukocyte cells post-sepsis is attributed to its facilitation of mitophagy, thus favoring mitochondrial integrity. In conclusion, our findings suggest that low-dose Olaparib can improve mitochondrial quality by accelerating mitophagy flux, consequently inhibiting ferroptosis and preserving cardiac function after sepsis.
Topics: Humans; Mice; Animals; Mitophagy; Ferroptosis; Molecular Docking Simulation; Sepsis; Phosphatidate Phosphatase; Phthalazines; Piperazines
PubMed: 38228256
DOI: 10.1016/j.phrs.2023.107056