Target For Treatment Research Articles

Development and validation of a prognostic risk score model for hepatocellular carcinoma in the Asian population based on immunogenic cell death-related genes

BackgroundHepatocellular carcinoma (HCC), the predominant form of liver cancer, is marked by limited therapeutic success and unfavorable prognoses. Its etiology varies regionally, with hepatitis B virus (HBV) being the predominant cause in most of Asia. Immunogenic cell death (ICD), a specific type of cell death, has been extensively linked to HCC treatment in numerous studies. This research aims to explore the significance of ICD-related genes in the Asian HCC cohort, potentially offering novel approaches for HCC management.MethodsWe initially obtained transcriptomic and clinical data pertinent to Asian HCC from the TCGA database. Subsequently, we classified the samples into distinct subgroups according to ICD gene expression levels and conducted analyses of the tumor microenvironment and enrichment. Furthermore, we randomly allocated the samples into training and testing cohorts, thereafter developing and validating an ICD gene-based prognostic model tailored for the Asian HCC population.ResultsThe Asian HCC samples were categorized into two subgroups: high and low ICD expression. In the low ICD expression group, we observed diminished infiltration of immune and stromal cells, increased tumor purity, and improved prognosis. Moreover, we devised a 5-gene risk-score prognostic model comprising BAX, CASP8, HMGB1, HSP90AA1, and IL6, demonstrating efficacy in prognostic predictions for the Asian HCC cohort.ConclusionOur investigation unveils new perspectives on the influence of ICDs within Asian HCC populations. The derived 5-gene risk-score prognostic model, based on ICDs, not only serves as a tool for assessing prognosis in Asian HCC cases but also suggests potential therapeutic targets for HCC treatment.

Optimization and Biological Evaluation of Novel 1H-Pyrrolo[2,3-c]pyridin Derivatives as Potent and Reversible Lysine Specific Demethylase 1 Inhibitors for the Treatment of Acute Myelogenous Leukemia.

Lysine-specific demethylase 1 (LSD1) plays a vital role in the epigenetic regulation of various cancers, making it a promising therapeutic target for anticancer treatments. Herein, we designed and synthesized a novel series of 1H-pyrrolo[2,3-c]pyridin derivatives as potent LSD1 inhibitors. A detailed structure-activity relationship exploration was carried out to discover multiple derivatives with nanomolar enzymatic IC50 values. Further biological evaluation demonstrated that these compounds acted as selective and reversible LSD1 inhibitors. The representative compounds exhibited highly potent antiproliferative activity against both AML (MV4-11 and Kasumi-1) and SCLC (NCI-H526) cell lines. Additionally, they effectively activated CD86 mRNA expression in MV4-11 cells and induced differentiation of AML cell lines. Notably, the most promising compound 23e showed a favorable oral PK profile and effectively suppressed the tumor growth in an AML xenograft model. Overall, our medicinal chemistry efforts provide compound 23e as a lead compound for developing LSD1 inhibitors for the treatment of AML and other advanced malignancies.

Dynamic assessment, more than a diagnostic tool? Uses for goals, teaching moments, and procedural issues during intervention of speech sound disorder

ABSTRACT Dynamic assessment is typically used for diagnostic and baseline purposes; however, the current study explored expanding the use of dynamic assessment as a curriculum-based measure to additionally capture teaching moments and observe intervention elements during treatment of speech sound disorder (NCT06075303). Teaching moments occur when an SLT presents an antecedent, the child produces a behaviour, and the SLT responds with a consequence related to accuracy; yet, little is known about the characteristics of these elements that are the most essential for improving treatment outcomes. To address this gap, we used the Glaspey Dynamic Assessment of Phonology’s scoring system to establish the goal, code teaching moments, describe procedural issues, and evaluate children’s skill development. The participants included two English-speaking boys, ages three and six, with speech sound disorder. A modified cycles approach was administered by an SLT and a student clinician with two blocks of targets (minimally and moderately adaptable). Results indicated that coding with dynamic assessment was successfully used for tracking changes within the teaching moments and provided a more complete perspective of treatment efficacy when combined with outcome measures, yet more research is needed to establish goals with dynamic assessment. Both children demonstrated progress in a short period of time, though Participant 1 made more significant gains, which may be attributed to many elements including treatment intensity, target selection, clinician variables, or client variables. Overall, this preliminary research supports that dynamic assessment may lead to dynamic intervention, thus bridging assessment and treatment practices.

Protective effect of Apelin-13 on oxygen and glucose deprivation induced-damage in retinal ganglion cells cultured in vitro.

Ischemic-anoxic injury plays an important role in the pathophysiology of diabetes retinopathy, optic neuropathy, even glaucoma and other ocular diseases. It may ultimately cause damage to neuronal death like retinal ganglion cells (RGCs) and subsequent visual loss. RGCs are essential elements of the retina and optic nerve that are crucial to visual formation. Ischemic-anoxic injury, inflammation, and oxidative stress are vital causes of RGC death. Thus, neuroprotection is essential for the treatment of these ocular diseases. Recent studies have shown the neuroprotective property of apelin-13 in many disease models. In this study, we isolated RGCs and found that apelin-13 promoted the viability of RGCs and increased the phosphorylation of Protein kinase B (PKB, Akt) in an in vitro oxygen-glucose deprivation model. Moreover, apelin-13 increased the expressions of glucose-6-phosphate dehydrogenase (G6PD) and nicotinamide adenine dinucleotide phosphate (NADPH) and reduced the level of reactive oxygen species (ROS). And, we also found that apelin-13 could promote the expressions of glucose transporter-1 (GLUT1) and adenosine triphosphate (ATP). These results indicated that apelin-13 could delay or stop RGC death, which might be as potential therapeutic targets for treatment of diseases mediated by ischemic-anoxic damage like diabetes retinopathy, optic neuropathy, even glaucoma.

A psychometric examination of the cognitive flexibility scale and its association with Orthorexia Nervosa

BackgroundThe Cognitive Flexibility Scale (CFS) is a 12-item self-report questionnaire designed to assess cognitive flexibility. Despite its widespread use, its psychometric properties have yet to be evaluated in the Italian context. Furthermore, while cognitive flexibility has emerged as a central correlate in Feeding and Eating Disorders, only a limited number of studies have investigated its association with Orthorexia Nervosa (ON), a clinical condition characterized by a pathological fixation with healthy eating. The present study aimed to fill these two knowledge gaps.MethodsA total of 803 participants (Mage = 33.89, SD = 9.44; 68.6% females) were enrolled in the investigation. The sample was randomly split into two subsamples: the first one for examining the psychometric properties of the CFS, and the second one for evaluating its association with ON symptoms. Participants completed self-report questionnaires assessing the constructs under investigation.ResultsConfirmatory factor analysis revealed a global dimension of cognitive flexibility, alongside a method factor accounting for covariance arising by reverse-worded items. The CFS, which was factorially invariant across genders, yielded a reliable total score (ω = 0.834) and provided evidence of convergent and criterion-related validity. Importantly, structural equation modelling showed that cognitive flexibility was negatively associated with emotional distress resulting from violations of orthorexic dietary rules (β = -0.279, p < .001).ConclusionsThe CFS demonstrated to be a psychometrically robust instrument in the Italian context. Moreover, cognitive flexibility may be an important treatment target for mitigating the distress derived from ON symptoms, informing the development of future therapeutic approaches.

A new perspective on macrophage-targeted drug research: the potential of KDELR2 in bladder cancer immunotherapy

IntroductionBladder cancer was recognized as one of the most common malignant tumors in the urinary system, and treatment options remained largely limited to conventional surgery, radiotherapy, and chemotherapy, which limited patient benefits.MethodsResearchers constructed an RNA transcriptome map of bladder cancer by integrating single-cell RNA sequencing and clinical data, identifying potential molecular targets for diagnosis and treatment. We also verified the antitumor activity of the target through in vitro experiment.ResultsA distinct tumor cell subpopulation characterized by elevated S100A8 expression exhibited high copy number variation, high stemness, and low differentiation. It interacted with myeloid cells via the MIF-(CD74+CD44) and MIF-(CD74+CXCR4) signaling pathways. This study underscored KDELR2’s role in promoting cell proliferation, invasion, and migration, providing new therapeutic insights. Prognostic analysis revealed that KDELR2 correlated with poor survival, higher immune scores, and increased macrophage infiltration.DiscussionThe findings suggested that patients with high KDELR2 expression might benefit from immune checkpoint therapy. KDELR2 was also shown to enhance bladder cancer cell proliferation, invasion, and migration, highlighting it as a promising target for macrophage-focused drug development.

Type 2 Diabetes Health Care Outcomes for Patients with Alcohol Use Disorder Starting Addiction Treatment.

Alcohol use disorder (AUD) is common and may complicate type 2 diabetes (T2DM) management. Little research has examined diabetes outcomes for people with T2DM and AUD, including during the window when patients start specialty addiction treatment. To examine diabetes-related health monitoring, clinical outcomes, and acute health care use among patients with T2DM and AUD newly accessing specialty addiction treatment. This retrospective cohort study included electronic health record data from a large, integrated health care delivery system. Adults with T2DM and an index outpatient health care visit during 2016-2021 were included. Patients whose index visit was an initial AUD-related visit in specialty addiction treatment were in the AUD group. The comparison group had no AUD or addiction medicine visits. Outcomes were diabetes-related health monitoring, achievement of treatment targets, complications, and acute health care use during the 12months post-index visit. The study included 222,334 adults with T2DM, 1,998 with AUD. Relative to the comparison group, participants with AUD had elevated risk for hypoglycemia (adjusted risk ratio [aRR] = 2.14; 95% confidence interval [CI] = 1.49, 3.08), cardiovascular complications (aRR = 1.43; 95% CI = 1.34, 1.53), and neuropathy (aRR = 1.26; 95% CI = 1.14, 1.41), and were less likely to be non-smokers (aRR = 0.88; 95% CI = 0.86, 0.90), after adjusting for confounding factors. In adjusted models, the AUD versus comparison group had similar or higher rates of diabetes monitoring (e.g., any glycemic test, aRR = 1.19; 95% CI = 1.17, 1.22) and metabolic control (e.g., hemoglobin A1c < 8.0%, aRR = 1.14; 95% CI = 1.11, 1.18). Patients with co-occurring T2DM and AUD in an integrated health care delivery system are vulnerable to diabetes complications that could be addressed during the early phase of specialty addiction treatment.

Identification and Analysis of Autophagy-Related Genes as Diagnostic Markers and Potential Therapeutic Targets for Tuberculosis Through Bioinformatics.

According to the World Health Organization, Mycobacterium tuberculosis infections affect approximately 25% of the world's population. There is mounting evidence linking autophagy and immunological dysregulation to tuberculosis (TB). As a result, this research set out to discover TB-related autophagy-related biomarkers and prospective treatment targets. We used five autophagy databases to get genes linked to autophagy and Gene Expression Omnibus databases to get genes connected to TB. Then, functional modules associated with autophagy were obtained by analyzing them using weighted gene co-expression network analysis. Both Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used to examine the autophagy-related genes (ATGs) of important modules. Limma was used to identify differentially expressed ATGs (DE-ATGs), and the external datasets were used to further confirm their identification. We used DE-ATGs and a protein-protein interaction network to search the hub genes. CIBERSORT was used to estimate the kinds and amounts of immune cells. After that, we built a drug-gene interaction network and a network that included messenger RNA, small RNA, and DNA. At last, the differential expression of hub ATGs was confirmed by RT-qPCR, immunohistochemistry, and western blotting. The diagnostic usefulness of hub ATGs was evaluated using receiver operating characteristic curve analysis. Including 508 ATGs, four of the nine modules strongly linked with TB were deemed essential. Interleukin 1B (IL1B), CAPS1, and signal transducer and activator of transcription 1 (STAT1) were identified by intersection out of 22 DE-ATGs discovered by differential expression analysis. Research into immune cell infiltration found that patients with TB had an increased proportion of plasma cells, CD8 T cells, and M0 macrophages. A competitive endogenous RNA network utilized 10 long non-coding RNAs and 2 miRNAs. Then, the IL1B-targeted drug Cankinumad was assessed using this network. During bioinformatics analysis, three hub genes were validated in mouse and macrophage infection models. We found that IL1B, CASP1, and STAT1 are important biomarkers for TB. As a result, these crucial hub genes may hold promise as TB treatment targets.

FOXA1 knockdown alleviates inflammation and enhances osteogenic differentiation of periodontal ligament stem cells via STAT3 pathway

BackgroundEvidence has confirmed that forkhead box protein A1 (FOXA1) inhibits the osteogenic differentiation of bone marrow mesenchymal stem cells. However, whether FOXA1 regulates the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) to participate in periodontitis process is unclear.MethodsLipopolysaccharide (LPS) was used to treat hPDLSCs to mimic inflammation environments. FOXA1 expression was examined by quantitative real-time PCR and western blot. The levels of IL-6 and TNF-α were evaluated by quantitative real-time PCR, ELISA and immunohistochemistry staining. hPDLSCs osteogenic differentiation was assessed by measuring alkaline phosphatase activity, alizarin red S intensity and the levels of osteogenic differentiation-related markers. Besides, the expression of signal transducer and activator of transcription 3 (STAT3) pathway-related markers were examined by western blot and immunofluorescence staining.ResultsFOXA1 was upregulated in the periodontal ligament tissues of periodontitis patients, and its knockdown enhanced osteogenic differentiation of hPDLSCs. Besides, downregulation of FOXA1 suppressed inflammation levels in LPS-induced hPDLSCs. Also, FOXA1 silencing promoted the osteogenic differentiation of LPS-induced hPDLSCs by the inactivation of STAT3 pathway.ConclusionOur data confirmed that knockdown of FOXA1 attenuated inflammation and enhanced osteogenic differentiation of LPS-induced hPDLSCs by regulating STAT3 pathway, indicating that FOXA1 might be a target for periodontitis treatment.

Deficits in spontaneous versus instructed emotion regulation in problematic pornographyuse.

Deficits in emotion regulation (ER) are considered a key factor in the development of addiction, highlighting ER as a potential target for treatment. However, ER in problematic pornography use (PPU) remains poorly understood. The current study investigated both spontaneous and instructed ER in male individuals at-risk for PPU (n = 35, average age = 20.40 ± 1.29) and in a control group (n = 33, average age = 20.06 ± 1.44). Initially, participants were evaluated with the Emotion Regulation Profile-Revised (ERP-R) to measure their spontaneous use of eight ER strategies across various negative emotion-eliciting scenarios. Subsequently, they completed an emotion reappraisal task, in which they were instructed to either observe or reappraise their reactions to negative images. Subjective emotional ratings (valence and arousal) and event-related potentials (ERPs) were recorded to examine the effects of deliberate ER on emotional processing. The results indicated that individuals at-risk for PPU reported less frequent spontaneous use of reappraisal compared to those in the control group. Furthermore, in both groups, reappraisal led to a decrease in the late positive potential (LPP) and the self-reported intensity of emotions elicited by negative images. This indicates that both groups were able to effectively downregulate negative emotions through reappraisal when instructed. Our findings underscore the importance of incorporating ER skills, particularly reappraisal-based strategies, into the prevention and psychotherapy of PPU.

Glucocorticoids and HPA axis regulation in the stress-obesity connection: A comprehensive overview of biological, physiological and behavioural dimensions.

Chronic stress, characterized by increased long-term exposure to the glucocorticoid hormone cortisol, is increasingly linked to obesity development. Still, various knowledge gaps persist, including on underlying pathophysiological mechanisms. The aim of the current review is to provide the latest insights on the connection between stress and obesity. We discuss three biological stress systems-the autonomic nervous system, the hypothalamus-pituitary-adrenal (HPA) axis and the immune system-and their link with obesity, with a particular focus on the HPA axis. The role of cortisol and its regulatory variations (including glucocorticoid rhythmicity and altered sensitivity) in adipose tissue biology and obesity development is discussed. Moreover, we highlight the physiological, affective, cognitive and behavioural dimensions of the stress response offering a deeper understanding of how stress contributes to obesity development and vice versa. Finally, stress as a treatment target for obesity is discussed. We conclude that the link between stress and obesity is complex and multifaceted, influenced by physiological, affective, cognitive and behavioural stress response mechanisms, which especially when chronically present, play a key role in the development of obesity and associated cardiometabolic diseases. This necessitates integrated approaches tailored to individual needs, including lifestyle modifications, behavioural interventions, psychosocial support and possible additional pharmacological interventions.

Knowledge and perspectives towards the use of histology in inflammatory bowel disease by gastroenterologists across the Asia-Pacific region.

Recently, histological mucosal assessment has gained momentum as a potential new treatment target for patients with inflammatory bowel disease (IBD) in the Asia-Pacific region. This study aimed to evaluate and compare the knowledge and acceptability of histological assessment among gastroenterologists across the region. A cross-sectional survey among gastroenterologists in the Asia-Pacific region was conducted and compared against a previous Australian survey. The questionnaire assessed knowledge and attitude towards the role and application of histology in IBD practice. Statistical analyses were employed to compare scores and identify predictors. A total of 221 gastroenterologists from 12 countries, including 77 (34.8%) from Australia, responded to questionnaire, with 185 (83.7%) completing the survey. The mean knowledge score was 9.8 ± 3.3 (51.6%). There was no significant difference in the average score among countries (P= 0.53). IBD specialist (P< 0.01), doctoral degree (P= 0.02), and regular participation in IBD multidisciplinary meetings (P= 0.01) were associated with higher scores. Most respondents (90.7%) agreed on the importance of histology in IBD. While 54.6% of Australians perceived the role of histology as established, only 37.0% of Asians respondents considered this similarly (P= 0.02). Histological activity alone minimally influences treatment escalation in patients with endoscopic remission, but achieving combined histo-endoscopic remission often leads to therapy de-escalation. Although gastroenterologists in the Asia-Pacific region are aware of the role of histology in IBD, their knowledge remains limited, and its clinical utility is not widely adopted. There is a need to promote the routine use of standardized histological assessment in IBD practice.

Study on miR-29a inhibiting papillary thyroid carcinoma by downregulating TAGLN2

ObjectiveThis study aims to explore the possible mechanism of miR-29a inhibiting papillary thyroid carcinoma (PTC) through the downregulation of TAGLN2. The paper expects to find novel targets for PTC treatment and prognosis improvement, and is also of great significance in enhancing the overall therapeutic level of PTC and improving life quality of patients. MethodsChanges in PTC cell growth, migration, and invasive ability were respectively detected using MTS assays, wound healing experiments, and Matrigel matrix invasion assays. Expressions of E-cadherin, N-cadherin, vimentin, and MMP2 were determined by Western blotting. Differences in protein expressions between groups were compared. Overexpression and knockdown of TAGLN2 were performed in K1 cells, and the expression levels of PI3K/AKT pathway protein in K1 cells were detected by Western blotting. ResultmiR-29a significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of K1 cells. Overexpression of miR-29a played an important role in improving the malignant phenotype of PTC by regulating the expression of actin-binding protein TAGLN2. Overexpression of TAGLN2 can counteract the inhibitory effect of miR-29a on K1 cells. TAGLN2 can activate the PI3K/AKT signaling pathway, indicating that it may promote the progress of EMT by activating PI3K/AKT. ConclusionThe miR-29a/TAGLN2 axis may affect the malignant phenotype of K1 cells by regulating downstream PI3K/AKT signaling pathways, thus providing a new target for the treatment of PTC.

Current Concepts in the Molecular Mechanisms and Management of Diabetic Neuropathy by Pharmacotherapeutics and Natural Compounds.

One of the most crippling effects of diabetes mellitus is diabetic neuropathy, which can cause discomfort, loss of movement, and even amputation. Diabetic neuropathy manifests in a variety of ways, ranging from pain to death. Diagnosing diabetic neuropathy can be challenging since it often goes unnoticed for many years following the onset of diabetes. In addition to oxidative stress in neurons, hyperglycemia activates a number of metabolic pathways that are important sources of damage and possible targets for treatment in diabetic neuropathy. Downstream metabolic cascades caused by prolonged hyperglycemia include activation of protein kinase C, increased production of advanced glycation end products, excessive release of cytokines, increased oxidative stress, and injury to peripheral nerves. Despite the fact that these metabolic anomalies are considered the main cause of diabetes-related microvascular issues, the diverse mechanistic processes of neuropathy are characterized by organ-specific histological and biochemical features. Although the symptoms of diabetic neuropathy can be treated, there are few options to correct the underlying problem. Diabetic neuropathy exerts a tremendous financial, psychological, and physical burden on society, emphasizing the need for efficient and focused treatment. The major goal of this review is to shed light on the multiple mechanisms and pathways that contribute to the onset of diabetic neuropathy and to provide readers with a comprehensive understanding of emerging therapeutic strategies to postpone or reverse various forms of diabetic neuropathy. The article discusses available medications and provides the latest guidelines for the treatment of pain and distal symmetric polyneuropathy, including diabetic autonomic neuropathy, which may help the patients control pain well and assess alternatives for treatment that might be more successful in preventing or delaying the course of a disease.

How to personalise cognitive–behavioural therapy for chronic primary pain using network analysis: study protocol for a single-case experimental design with multiple baselines

IntroductionCognitive–behavioural therapy (CBT) is an effective treatment for chronic primary pain (CPP), but effect sizes are small to moderate. Process orientation, personalisation, and data-driven clinical decision-making might address the heterogeneity...

Clinical outcomes with immune checkpoint inhibitors in patients with FGFR2/3, MTAP or ERBB2 genomic alterations in advanced urothelial carcinoma

BackgroundFGFR2/3, MTAP and ERBB2 genomic alterations have treatment targets in advanced urothelial carcinoma (aUC). These alterations may affect tumor microenvironment and outcomes with immune checkpoint inhibitors (ICIs) in aUC. Patients and MethodsWe identified patients with available genomic data in our multi-institution cohort of patients with aUC treated with ICI. Outcomes (observed response rate [ORR], progression-free and overall survival [PFS, OS]) with ICI were compared between patients with and without FGFR 2/3, MTAP, ERBB2 alterations. We compared ORR using logistic regression and PFS/OS using Cox proportional hazards. ResultsOut of 1,514 patients, 276 (18%), 174 (11%) and 208 (14%) patients had known FGFR2/3, MTAP and ERBB2 alteration status, respectively and were treated with ICI in 1L or 2+L. In patients with (vs without) FGFR2/3 alteration, ORR with ICI was 21% (95%CI 14-30%) vs 32% (95%CI 27-38%) (OR 0.54 [95%CI 0.32-0.91]), PFS was significantly shorter in patients with FGFR2/3 alterations (HR=1.36 [95%CI 1.03-1.80], p=0.03); OS was not significantly different between groups (HR=1.22 [95%CI 0.86-1.47]). In patients with (vs without) MTAP alteration, ORR with ICI was 25% (95%CI 10-48%) vs 40% (95%CI 33-47%) (OR 0.52 [95%CI 0.20-1.38]); PFS and OS were non-significantly different. In patients with (vs without) ERBB2 alteration, ORR with ICI was similar (37% vs 35%; OR 1.06, 95%CI 0.57-1.97); PFS and OS were significantly longer in patients with ERBB2 alteration [HR 0.63 (95%CI 0.41-0.95), p=0.03; HR 0.66, [95% CI 0.44-0.97]), respectively. ConclusionOur results support further evaluation of FGFR2/3, MTAP and ERBB2 alterations as putative biomarkers in patients with aUC treated with ICI. MicroabstractImmune checkpoint inhibitors (ICI) improve overall survival in advanced urothelial carcinoma (aUC), but response rates as monotherapy remain modest. We performed a multi-institutional retrospective cohort study comparing outcomes (observed response rate, progression-free and overall survival) between patients with and without tumor genomic alterations (FGFR2/3, MTAP, ERBB2 genes) that may impact the immune tumor microenvironment and affect treatment selection. Our hypothesis-generating results suggest that specific genomic alterations may have association with response and survival with ICI in patients with aUC and support further validation in other retrospective studies and clinical trials.

Inhibition of CDGSH iron‑sulfur domain 2 exhibits tumor-suppressing effects on diffuse large B-cell lymphoma (DLBCL) by inducing ferroptosis through the regulation of the NRF2/SLC7A11/GPX4 pathway

CDGSH iron‑sulfur domain 2 (CISD2) is recognized as a ferroptosis-related gene that has potential as a target for cancer treatment. However, it is still uncertain whether targeting CISD2 can modulate ferroptosis in diffuse large B-cell lymphoma (DLBCL) cells and exhibit cancer-suppressing effects. The present study thoroughly investigated the role of CISD2 in DLBCL. CISD2 was found to be overexpressed in DLBCL, and its inhibition resulted in substantial growth inhibition in DLBCL cells. The growth inhibition effect resulting from CISD2 silencing could be reversed by a ferroptosis inhibitor, whereas inhibitors of apoptosis and necrosis did not yield the same reversal. CISD2-silenced DLBCL cells exhibited increased sensitivity to growth inhibition induced by ferroptosis suppressors. The inhibition of CISD2 induced ferroptotic cell death in DLBCL cells, which was supported by the overproduction of lipid peroxides, depletion of glutathione, accumulation of iron, and increased presence of shrunken mitochondria. Further investigation revealed reduced levels of NRF2, GPX4, and SLC7A11 in CISD2-silenced DLBCL cells. The overexpression of NRF2 significantly reduced the occurrence of ferroptotic cell death in DLBCL cells in which CISD2 was silenced. Furthermore, CISD2 inhibition exhibited tumor-suppressing effects in vivo associated with the induction of ferroptotic cell death in xenografts. These findings suggest that CISD2inhibition has tumor-suppressing effects on DLBCL by promoting ferroptotic cell death via the NRF2/SLC7A11/GPX4 pathway. Therefore, CISD2 holds promise as a viable candidate target for treating DLBCL.

The Multifaceted Roles of Hippo-YAP in Cardiovascular Diseases.

The Hippo-yes-associated protein (YAP) signaling pathway plays a crucial role in cell proliferation, differentiation, and death. It is known to have impact on the progression and development of cardiovascular diseases (CVDs) as well as in the regeneration of cardiomyocytes (CMs). However, further research is needed to understand the molecular mechanisms by which the Hippo-YAP pathway affects the pathological processes of CVDs in order to evaluate its potential clinical applications. In this review, we have summarized the recent findings on the role of the Hippo-YAP pathway in CVDs such as myocardial infarction, heart failure, and cardiomyopathy, as well as its in CM development. This review calls attention to the potential roles of the Hippo-YAP pathway as a relevant target for the future treatment of CVDs.

Discovery of KPT-6566 as STAG1/2 Inhibitor sensitizing PARP and NHEJ Inhibitors to suppress tumor cells growth in vitro

Stromal antigen 1 and 2 (STAG1 and STAG2) are two mutually exclusive components of the cohesin complex that is crucial for centromeric and telomeric cohesion. Beyond its structural role, STAG2 also plays a pivotal role in homologous recombination (HR) repair and has emerged as a promising therapeutic target in cancer treatment. Here, we employed a fluorescence polarization (FP)-based high-throughput screening and identified KPT-6566 as a dual inhibitor of STAG1 and STAG2. Biochemical and biophysical analyses demonstrated that KPT-6566 directly binds to STAG1 and STAG2, disrupting their interactions with SCC1 and double-stranded DNA. A metaphase chromosome spread assay showed that KPT-6566 causes premature chromosome separation and induces chromosome damages in HeLa cells. Furthermore, KPT-6566 also impairs DNA damage repair, leading to the accumulation of double-strand breaks and cell apoptosis. Finally, KPT-6566 can sensitize HeLa and HepG2 cells to PARP inhibitor Olaparib and the NHEJ inhibitor UMI-77, exhibiting a synergistic effect in suppressing cell proliferation. Our findings highlight the potential of STAG1/2 as promising therapeutic targets in cancer treatment, particularly when they are targeted in combination with other DNA damage response inhibitors.

Molecular Dynamics of a N-Cyclohexyl-1,2,4-Oxadiazole Derivative as a Reversible Cruzain Inhibitor in Trypanosoma cruzi.

Chagas disease kills around 10,000 people yearly, primarily in Latin America, where it is prevalent. Current treatment has limited chronic effectiveness, is unsafe, and has substantial side effects. As a result, the use of oxadiazole derivatives and similar heterocyclic compounds as bioisosteres are well known, and they are prospective candidates in the hunt for novel anti-Trypanosoma cruzi chemicals. Recent research has revealed that the cysteine protease cruzain from T. cruzi is a validated target for disease treatment. Thus, using a molecular dynamics simulation, the current study attempted to determine if a significant interaction occurred between the enzyme cruzain and its ligand. Interactions with the catalytic site and other critical locations were observed. Also, the RMSD values suggested that the molecule under research had stable interactions with its target. Finally, the findings indicate that the investigated molecule 2b can interfere enzymatic activity of cruzain, indicating that it might be a promising antichagasic drug.