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Scientific Reports Jun 2024Relationship between depressive disorder and autonomic nervous system has been already discussed. Reduced emotional regulation is supposed to be associated with...
Relationship between depressive disorder and autonomic nervous system has been already discussed. Reduced emotional regulation is supposed to be associated with prefrontal hypofunction and subcortical hyperactivity. The aim of this study was to determine the effect of vortioxetine on heart rate variability (HRV), a parameter of cardiac autonomic regulation, in depressed hospitalized paediatric patients and assess the clinical effectiveness of the drug in this population. We performed repeated polysomnography analyses at admission and after a short treatment in hospital (15.2 days on average) and measured various HRV parameters (RRi, pNN50, RMSSD, LF-HRV, HF-HRV) during wakefulness, N3 and REM sleep stages. Out of 27 study subjects, 67% have improved depression symptoms as well as anxiety and subjective sleep quality after short vortioxetine treatment. We have found a significant decrease in parasympathetic parameters pNN50, RMSSD and HF-HRV during N3 sleep phase, though not exclusively among vortioxetine responders. The anticipated increase in cardiovagal regulation after vortioxetine treatment was not demonstrated in this pilot study, possibly due to the drug's multimodal mechanism and impact on the nucleus tractus solitarii, particularly its antagonism on 5HT-3 receptors. Application of selective drugs could further explain the effect of vortioxetine on HRV in depressed patients.
Topics: Humans; Vortioxetine; Heart Rate; Child; Adolescent; Male; Female; Autonomic Nervous System; Antidepressive Agents; Polysomnography; Depression; Pilot Projects
PubMed: 38910177
DOI: 10.1038/s41598-024-65278-9 -
Cell Death & Disease Jun 2024The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell...
The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell surface Fas expression desensitizes cancer cells to Fas-induced apoptosis. Here, we show that the increase in Fas microaggregate formation on the plasma membrane in response to the inhibition of endocytosis sensitizes cancer cells to Fas-induced apoptosis. We used a clinically accessible Rho-kinase inhibitor, fasudil, that reduces endocytosis dynamics by increasing plasma membrane tension. In combination with exogenous soluble FasL (sFasL), fasudil promoted cancer cell apoptosis, but this collaborative effect was substantially weaker in nonmalignant cells. The combination of sFasL and fasudil prevented glioblastoma cell growth in embryonic stem cell-derived brain organoids and induced tumor regression in a xenograft mouse model. Our results demonstrate that sFasL has strong potential for apoptosis-directed cancer therapy when Fas microaggregate formation is augmented by mechano-inhibition of endocytosis.
Topics: Humans; Endocytosis; Apoptosis; Animals; Fas Ligand Protein; fas Receptor; Mice; Cell Line, Tumor; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Xenograft Model Antitumor Assays; Glioblastoma
PubMed: 38909035
DOI: 10.1038/s41419-024-06822-3 -
Annals of Clinical Microbiology and... Jun 2024Chromoblastomycosis (CBM), a chronic fungal infection affecting the skin and subcutaneous tissues, is predominantly caused by dematiaceous fungi in tropical and...
Chromoblastomycosis (CBM), a chronic fungal infection affecting the skin and subcutaneous tissues, is predominantly caused by dematiaceous fungi in tropical and subtropical areas. Characteristically, CBM presents as plaques and nodules, often leading to scarring post-healing. Besides traditional diagnostic methods such as fungal microscopy, culture, and histopathology, dermatoscopy and reflectance confocal microscopy can aid in diagnosis. The treatment of CBM is an extended and protracted process. Imiquimod, acting as an immune response modifier, boosts the host's immune response against CBM, and controls scar hyperplasia, thereby reducing the treatment duration. We present a case of CBM in Guangdong with characteristic reflectance confocal microscopy manifestations, effectively managed through a combination of itraconazole, terbinafine, and imiquimod, shedding light on novel strategies for managing this challenging condition.
Topics: Chromoblastomycosis; Imiquimod; Humans; Antifungal Agents; Itraconazole; Terbinafine; Male; Treatment Outcome; Microscopy, Confocal; Skin; Middle Aged
PubMed: 38902740
DOI: 10.1186/s12941-024-00718-y -
Oncology (Williston Park, N.Y.) Jun 2024Spiradenocarcinomas are rare malignant skin adnexal tumors. We describe a novel case of a patient with an aggressive CDKN2A-mutated spiradenocarcinoma who responded to a...
Spiradenocarcinomas are rare malignant skin adnexal tumors. We describe a novel case of a patient with an aggressive CDKN2A-mutated spiradenocarcinoma who responded to a CDK4/6 inhibitor. This case highlights the unique nature of spiradenocarcinomas as well as the potential benefit of targeted therapy.
Topics: Humans; Mutation; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase 4; Female; Skin Neoplasms; Middle Aged; Adenocarcinoma; Protein Kinase Inhibitors; Cyclin-Dependent Kinase 6; Male; Pyridines; Sweat Gland Neoplasms; Piperazines
PubMed: 38899982
DOI: 10.46883/2024.25921022 -
International Journal of Molecular... May 2024Until the late 1800s, drug development was a chance finding based on observations and repeated trials and errors. Today, drug development must go through many iterations... (Review)
Review
Until the late 1800s, drug development was a chance finding based on observations and repeated trials and errors. Today, drug development must go through many iterations and tests to ensure it is safe, potent, and effective. This process is a long and costly endeavor, with many pitfalls and hurdles. The aim of the present review article is to explore what is needed for a molecule to move from the researcher bench to the patients' bedside, presented from an industry perspective through the development program of cariprazine. Cariprazine is a relatively novel antipsychotic medication, approved for the treatment of schizophrenia, bipolar mania, bipolar depression, and major depression as an add-on. It is a D3-preferring D3-D2 partial agonist with the highest binding to the D3 receptors compared to all other antipsychotics. Based on the example of cariprazine, there are several key factors that are needed for a molecule to move from the researcher bench to the patients' bedside, such as targeting an unmet medical need, having a novel mechanism of action, and a smart implementation of development plans.
Topics: Humans; Antipsychotic Agents; Piperazines; Receptors, Dopamine D3; Schizophrenia; Animals; Bipolar Disorder; Drug Development
PubMed: 38891871
DOI: 10.3390/ijms25115682 -
AIDS Research and Therapy Jun 2024Scholars recommend providing migrants living with HIV (MLWH) with free treatment, rapidly, once linked to care to optimize their HIV-related experiences and health...
BACKGROUND
Scholars recommend providing migrants living with HIV (MLWH) with free treatment, rapidly, once linked to care to optimize their HIV-related experiences and health outcomes. Quantitative evaluations of patient-reported measures for MLWH in such models are necessary to explore the viability of these recommendations.
METHODS
Within a 96-week prospective cohort study at a multidisciplinary HIV clinic, participants received bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) for free and rapidly following care linkage. Eight patient-reported measures were administered at weeks 4, 24, and 48: (1) mMOS-SS to measure perceived social support; (2) IA-RSS to measure internalized stigma; (3) K6 to measure psychological distress; (4) PROMIS to measure self-efficacy with treatment taking; (5) G-MISS to measure perceived compliance with clinicians' treatment plans; (6) HIVTSQ to measure treatment satisfaction; (7) CARE to measure perceived provider empathy; and (8) PRPCC to measure perceived clinician cultural competence. Linear mixed modelling with bootstrapping was conducted to identify significant differences by sociodemographics and time.
RESULTS
Across weeks 4, 24, and 48, results suggest that MLWH enrolled in this study experienced moderate levels of social support; elevated levels of HIV-related stigma; moderate levels of distress; high self-efficacy with daily medication self-management; great compliance with clinicians' treatment plans; high treatment satisfaction; high perceived empathy; and high perceived cultural competence. Experience of social support (i.e., mMOS-SS scores) differed significantly by birth region. Experience of HIV-related stigma (i.e., IA-RSS scores) differed significantly by birth region, age, and language. Experience of distress (i.e., K6 scores) differed significantly by sexual orientation. Experience of treatment satisfaction (i.e., HIVTSQ scores) differed significantly by birth region and age. No significant differences were identified by time for any measure.
CONCLUSION
Overall, participants expressed positive experiences around treatment and care, alongside comparably lower perceptions of social support, internalized stigma, and distress, potentially underscoring a need to embed targeted, well-funded, and accessible mental health support within HIV care models.
Topics: Humans; HIV Infections; Male; Patient Reported Outcome Measures; Female; Adult; Prospective Studies; Anti-HIV Agents; Social Stigma; Middle Aged; Transients and Migrants; Social Support; Heterocyclic Compounds, 4 or More Rings; Tenofovir; Emtricitabine; Piperazines; Medication Adherence; Pyridones; Drug Combinations; Patient Satisfaction; Young Adult; Self Efficacy; Amides; Heterocyclic Compounds, 3-Ring
PubMed: 38890671
DOI: 10.1186/s12981-024-00632-5 -
Nature Communications Jun 2024Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly...
Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly understood. In this study, we uncover a critical role for SmD2, a core component of the spliceosome machinery, in modulating DNA damage in HCC through its impact on BRCA1/FANC cassette exons and expression. Our findings reveal that SmD2 depletion sensitizes HCC cells to PARP inhibitors, expanding the potential therapeutic targets. We also demonstrate that SmD2 acetylation by p300 leads to its degradation, while HDAC2-mediated deacetylation stabilizes SmD2. Importantly, we show that the combination of Romidepsin and Olaparib exhibits significant therapeutic potential in multiple HCC models, highlighting the promise of targeting SmD2 acetylation and HDAC2 inhibition alongside PARP inhibitors for HCC treatment.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Acetylation; Poly(ADP-ribose) Polymerase Inhibitors; Spliceosomes; Cell Line, Tumor; Phthalazines; Exons; Piperazines; Animals; BRCA1 Protein; Depsipeptides; Mice; DNA Damage; Gene Expression Regulation, Neoplastic
PubMed: 38890388
DOI: 10.1038/s41467-024-49573-7 -
PeerJ 2024Keloid is a chronic proliferative fibrotic disease caused by abnormal fibroblasts proliferation and excessive extracellular matrix (ECM) production. Numerous fibrotic...
BACKGROUND
Keloid is a chronic proliferative fibrotic disease caused by abnormal fibroblasts proliferation and excessive extracellular matrix (ECM) production. Numerous fibrotic disorders are significantly influenced by ferroptosis, and targeting ferroptosis can effectively mitigate fibrosis development. This study aimed to investigate the role and mechanism of ferroptosis in keloid development.
METHODS
Keloid tissues from keloid patients and normal skin tissues from healthy controls were collected. Iron content, lipid peroxidation (LPO) level, and the mRNA and protein expression of ferroptosis-related genes including solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), transferrin receptor (TFRC), and nuclear factor erythroid 2-related factor 2 (Nrf2) were determined. Mitochondrial morphology was observed using transmission electron microscopy (TEM). Keloid fibroblasts (KFs) were isolated from keloid tissues, and treated with ferroptosis inhibitor ferrostatin-1 (fer-1) or ferroptosis activator erastin. Iron content, ferroptosis-related marker levels, LPO level, mitochondrial membrane potential, ATP content, and mitochondrial morphology in KFs were detected. Furthermore, the protein levels of α-smooth muscle actin (α-SMA), collagen I, and collagen III were measured to investigate whether ferroptosis affect fibrosis in KFs.
RESULTS
We found that iron content and LPO level were substantially elevated in keloid tissues and KFs. SLC7A11, GPX4, and Nrf2 were downregulated and TFRC was upregulated in keloid tissues and KFs. Mitochondria in keloid tissues and KFs exhibited ferroptosis-related pathology. Fer-1 treatment reduced iron content, restrained ferroptosis and mitochondrial dysfunction in KFs, Moreover, ferrostatin-1 restrained the protein expression of α-SMA, collagen I, and collagen III in KFs. Whereas erastin treatment showed the opposite results.
CONCLUSION
Ferroptosis exists in keloid. Ferrostatin-1 restrained ECM deposition and fibrosis in keloid through inhibiting ferroptosis, and erastin induced ECM deposition and fibrosis through intensifying ferroptosis.
Topics: Humans; Ferroptosis; Keloid; Fibroblasts; Cyclohexylamines; Fibrosis; Phenylenediamines; NF-E2-Related Factor 2; Phospholipid Hydroperoxide Glutathione Peroxidase; Male; Lipid Peroxidation; Female; Adult; Iron; Amino Acid Transport System y+; Receptors, Transferrin; Piperazines; Actins; Mitochondria; Membrane Potential, Mitochondrial
PubMed: 38887622
DOI: 10.7717/peerj.17551 -
Journal of Experimental & Clinical... Jun 2024The cyclin D1-cyclin dependent kinases (CDK)4/6 inhibitor palbociclib in combination with endocrine therapy shows remarkable efficacy in the management of estrogen...
BACKGROUND
The cyclin D1-cyclin dependent kinases (CDK)4/6 inhibitor palbociclib in combination with endocrine therapy shows remarkable efficacy in the management of estrogen receptor (ER)-positive and HER2-negative advanced breast cancer (BC). Nevertheless, resistance to palbociclib frequently arises, highlighting the need to identify new targets toward more comprehensive therapeutic strategies in BC patients.
METHODS
BC cell lines resistant to palbociclib were generated and used as a model system. Gene silencing techniques and overexpression experiments, real-time PCR, immunoblotting and chromatin immunoprecipitation studies as well as cell viability, colony and 3D spheroid formation assays served to evaluate the involvement of the G protein-coupled estrogen receptor (GPER) in the resistance to palbociclib in BC cells. Molecular docking simulations were also performed to investigate the potential interaction of palbociclib with GPER. Furthermore, BC cells co-cultured with cancer-associated fibroblasts (CAFs) isolated from mammary carcinoma, were used to investigate whether GPER signaling may contribute to functional cell interactions within the tumor microenvironment toward palbociclib resistance. Finally, by bioinformatics analyses and k-means clustering on clinical and expression data of large cohorts of BC patients, the clinical significance of novel mediators of palbociclib resistance was explored.
RESULTS
Dissecting the molecular events that characterize ER-positive BC cells resistant to palbociclib, the down-regulation of ERα along with the up-regulation of GPER were found. To evaluate the molecular events involved in the up-regulation of GPER, we determined that the epidermal growth factor receptor (EGFR) interacts with the promoter region of GPER and stimulates its expression toward BC cells resistance to palbociclib treatment. Adding further cues to these data, we ascertained that palbociclib does induce pro-inflammatory transcriptional events via GPER signaling in CAFs. Of note, by performing co-culture assays we demonstrated that GPER contributes to the reduced sensitivity to palbociclib also facilitating the functional interaction between BC cells and main components of the tumor microenvironment named CAFs.
CONCLUSIONS
Overall, our results provide novel insights on the molecular events through which GPER may contribute to palbociclib resistance in BC cells. Additional investigations are warranted in order to assess whether targeting the GPER-mediated interactions between BC cells and CAFs may be useful in more comprehensive therapeutic approaches of BC resistant to palbociclib.
Topics: Humans; Pyridines; Breast Neoplasms; Piperazines; Female; Receptors, Estrogen; Drug Resistance, Neoplasm; Cyclin-Dependent Kinase 4; Cell Line, Tumor; Receptors, G-Protein-Coupled; Cyclin-Dependent Kinase 6; Protein Kinase Inhibitors; Tumor Microenvironment
PubMed: 38886784
DOI: 10.1186/s13046-024-03096-7 -
ChemistryOpen Jun 2024Quinolone antibiotics are extensively used clinically for human treatment and in agriculture. However, improper and excessive use can lead to the persistence of...
RATIONALE
Quinolone antibiotics are extensively used clinically for human treatment and in agriculture. However, improper and excessive use can lead to the persistence of quinolone residues in animal tissues, potentially accumulating in the human body and posing health risks. Investigating the correlation between mass spectrometry cleavage patterns and molecular structural features enhances the analytical framework for detecting trace or unknown impurities in quinolones.
METHODS
To collect data, we employed triple quadrupole linear ion trap mass spectrometry in electrospray positive ion mode. Primary mass spectrometry scanning was utilized to confirm parent ions, while secondary mass spectrometry scanning enabled the observation of fragment ions. The cleavage characteristics and pathways of the compounds were inferred from accurate mass-to-charge ratios obtained from both primary and secondary mass spectrometry.
RESULTS
Under soft ionization conditions, the compounds generally exhibited characteristic fragment ions of [M+H-HO], [M+H-CO], and [M+H-HO-CO]. Additionally, subtle variations were observed in each compound due to differences in modifying groups. For instance, upon deacidification, the piperazine ring structure underwent breakage and rearrangement, yielding fragment ion peaks devoid of neutral molecules such as CHN, CHN, or CHN. Notably, compounds featuring a cyclopropyl substituent group at the N-1 position typically exhibited characteristic fragments resulting from the loss of the cyclopropyl radical (⋅CH). Moreover, substituents at the N-1 and C-8 positions, when linked to form a six-membered carbocyclic ring, were prone to cleavage, releasing the neutral CH molecule.
CONCLUSION
Quinolone antibiotics share structural similarities in their parent nuclei, leading to partially similar cleavage pathways. Nevertheless, distinct cleavage patterns emerge due to variations in functional groups. According to the difference of mass spectrometry cleavage patterns, it can provide an identification basis for the measured detection of antibiotics.
PubMed: 38884376
DOI: 10.1002/open.202400061