Therapeutic Intervention Research Articles

Comparison of Post PCI TIMI Flow Between Diabetic and Non-Diabetic Individuals

Background: Cardiovascular diseases remain the leading cause of morbidity and mortality globally, with diabetes significantly exacerbating the incidence and severity of coronary artery disease. Diabetic patients experience altered coronary blood flow dynamics, which can impact the efficacy of therapeutic interventions like percutaneous coronary intervention (PCI). Objective: This study aims to compare the post-PCI Thrombolysis in Myocardial Infarction (TIMI) flow grades between diabetic and non-diabetic patients to assess the impact of diabetes on the short-term outcomes of coronary revascularization. Methods: A retrospective observational study was conducted at the National Institute of Cardiovascular Diseases in Karachi, involving 3,000 patients who underwent primary PCI between January 2018 and December 2020. Patients were categorized into diabetic (1,500) and non-diabetic (1,500) groups. Data collected included demographics, coronary artery risk factors, TIMI flow grades before and after PCI, and the use of GPIIb/IIIa inhibitors. Statistical analysis was performed using SPSS version 25, employing chi-square tests, t-tests, and Mann-Whitney U tests for comparative analysis, with a p-value of <0.05 considered statistically significant. Results: The study found significant differences in postoperative TIMI3 flow rates, with non-diabetic patients achieving a higher rate of TIMI3 (59.4%) compared to diabetic patients (58.1%). The use of GPIIb/IIIa inhibitors was higher in diabetic patients (34.7%) than in non-diabetic patients (1.8%). Additionally, diabetic patients showed a higher incidence of multi-vessel disease and more severe lesion profiles, including higher rates of triple branch lesions (45.9% vs. 39.9%) and left main lesions (53% vs. 43.9%). Conclusion: Diabetic patients exhibit worse post-PCI TIMI flow grades and more complex coronary lesions compared to non-diabetic patients, suggesting that diabetes adversely affects the outcomes of coronary revascularization. These findings underscore the need for tailored therapeutic approaches to improve PCI outcomes in diabetic patients.

Frilufts-therapy can improve adolescents’ mental health. A systematic review and meta-analysis of intervention studies

ABSTRACT This study aims to investigate the impact of frilufts-therapy (Nordic inspired therapeutic interventions in nature) on adolescents’ mental health through a systematic literature review following PRISMA 2020 guidelines. Inclusion criteria encompassed peer-reviewed intervention studies in English, Danish, or Norwegian, quantitatively evaluated with pre- and post-measurements on outcomes pertaining to salutogenesis. Papers published between 2010–2021 were selected from PubMed and PsycInfo in November 2021. Risk of bias was assessed using Cochrane RoB 2, ROBINS-I, and NIH tools synthesized into a six-domain assessment. Ten papers evaluating 12 studies (1711 adolescents) were selected. Meta-analysis of effect estimates on controlled studies (7) revealed a medium to large effect (ES = 0.70; CI = 0.41–0.98) favouring frilufts-therapy. Meta-analysis without control (11 studies) showed a medium effect (ES = 0.52; CI = 0.34–0.70) favouring post-test measurements. This support evidence that frilufts-therapy can improve the mental health of adolescents, but caution is advised due to potential study limitations, necessitating further research.

The TNFSF12/TWEAK Modulates Colonic Inflammatory Fibroblast Differentiation and Promotes Fibroblast-Monocyte Interactions.

Fibroblasts acquire a proinflammatory phenotype in inflammatory bowel disease, but the factors driving this process and how fibroblasts contribute to mucosal immune responses are incompletely understood. TNF superfamily member 12 (TNFSF12, or TNF-like weak inducer of apoptosis [TWEAK]) has gained interest as a mediator of chronic inflammation. In this study, we explore its role as a driver of inflammatory responses in fibroblasts and its contribution to fibroblast-monocyte interaction using human primary colonic fibroblasts, THP-1 and primary monocytes. Recombinant human TWEAK induced the expression of cytokines, chemokines, and immune receptors in primary colonic fibroblasts. The TWEAK upregulated transcriptome shared 29% homology with a previously published transcriptional profile of inflammatory fibroblasts from ulcerative colitis. TWEAK elevated surface expression of activated fibroblast markers and adhesion molecules (podoplanin [PDPN], ICAM-1, and VCAM-1) and secretion of IL-6, CCL2, and CXCL10. In coculture, fibroblasts induced monocyte adhesion and secretion of CXCL1 and IL-8, and they promoted a CD14high/ICAM-1high phenotype in THP-1 cells, which was enhanced when fibroblasts were prestimulated with TWEAK. Primary monocytes in coculture with TWEAK-treated fibroblasts had altered surface expression of CD16 and triggering receptor expressed on myeloid cells-1 (TREM-1) as well as increased CXCL1 and CXCL10 secretion. Conversely, inhibition of the noncanonical NF-κB pathway on colonic fibroblasts with a NF-κB-inducing kinase small molecule inhibitor impaired their ability to induce a CD14high phenotype on monocytes. Our results indicate that TWEAK promotes an inflammatory fibroblast-monocyte crosstalk that may be amenable for therapeutic intervention.

Skeletal Muscle Injury in Chronic Kidney Disease—From Histologic Changes to Molecular Mechanisms and to Novel Therapies

Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes fatigue and contributes to high mortality rates. In CKD, the cellular protein turnover is imbalanced, with protein degradation outweighing protein synthesis, leading to a loss of protein and cell mass, which impairs tissue function. As CKD itself, skeletal muscle wasting, or sarcopenia, can have various origins and causes, and both CKD and sarcopenia share common risk factors, such as diabetes, obesity, and age. While these pathologies together with reduced physical performance and malnutrition contribute to muscle loss, they cannot explain all features of CKD-associated sarcopenia. Metabolic acidosis, systemic inflammation, insulin resistance and the accumulation of uremic toxins have been identified as additional factors that occur in CKD and that can contribute to sarcopenia. Here, we discuss the elevation of systemic phosphate levels, also called hyperphosphatemia, and the imbalance in the endocrine regulators of phosphate metabolism as another CKD-associated pathology that can directly and indirectly harm skeletal muscle tissue. To identify causes, affected cell types, and the mechanisms of sarcopenia and thereby novel targets for therapeutic interventions, it is important to first characterize the precise pathologic changes on molecular, cellular, and histologic levels, and to do so in CKD patients as well as in animal models of CKD, which we describe here in detail. We also discuss the currently known pathomechanisms and therapeutic approaches of CKD-associated sarcopenia, as well as the effects of hyperphosphatemia and the novel drug targets it could provide to protect skeletal muscle in CKD.

In-vitro studies of relative intracellular alterations caused by three variants of Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2)

BACKGROUND: The comparative understanding between cellular basis of transmission and clinical severities caused by Wuhan, Delta and Omicron strains of SARS-CoV-2 is important. OBJECTIVE: To conduct In-Vitro studies on cellular infection caused by different variants by performing cytotoxic assays and studying the live microscopic observations. METHODS: The swab samples positive for Wuhan, Delta and Omicron strains were inoculated in the Vero cell lines and their rate of infectivity and nature of cytopathy was observed. RESULTS: The study showed maximum inter cellular connectivity among cells infected by Delta variant, followed by Wuhan and least inter cellular connections in the cells infected by Omicron variant. The Delta strain causing highest mortality as per reported epidemiological trends, showed highest inter cellular connections and maximum cell damage supporting the fastest cell to cell spread of infection and causing most mortality among patients. CONCLUSIONS: The paper reports that numerous inter cellular connections is the cause of spread of infection among cells and maximum cell damage as the cause of clinical severities. The paper sensitizes the issue that 52 subunit of viral Spike Protein could act as fusion enzyme causing the numerous inter cellular connections. Study suggests that the S2 subunit of the viral Spike Protein could be the drug target for therapeutic intervention.

Retinal morphological differences in atypical Parkinsonism: A cross-sectional analysis of the AlzEye cohort

ObjectiveAtypical Parkinsonian syndrome (APS) describes a heterogeneous group of disorders mimicking the clinical presentation of Parkinson disease (PD) but with disparate natural history and pathophysiology. While retinal markers of PD are increasingly described, APS has been afforded less attention possibly owing to its lower prevalence. Here, we investigate retinal morphological differences in individuals with APS in a large real world cohort. MethodsWe conducted a cross-sectional analysis of the AlzEye study, a retrospective cohort where ophthalmic data of individuals attending Moorfields Eye Hospital between January 2008 and March 31st 2018 (inclusive) has been linked with systemic disease data through national hospital admissions. Retinal features were extracted from macula-centered color fundus photography (CFP) and optical coherence tomography (OCT) and compared between individuals with APS and those unaffected. Individuals with idiopathic PD were excluded. Retinal neural and vascular features were measured using automated segmentation and analyzed with multivariable-adjusted regression models. ResultsAmong a cohort of 91,170 patients, there were 51 patients with APS and 91,119 controls. Individuals with APS were older and more likely to have hypertension and diabetes mellitus. After adjusting for age, sex, hypertension and diabetes melitus, individuals with APS had a thinner ganglion cell-inner plexiform layer (-3.95 microns, 95% CI: −7.53, −0.37, p = 0.031) but no difference in other retinoneural or retinovascular indices. Optic nerve cup-to-disc ratio was similar between groups. ConclusionOur cross-sectional analysis of the AlzEye cohort reveals distinct retinal morphological characteristics in APS compared to healthy controls. The study notably identifies a thinner ganglion cell-inner plexiform layer in APS patients, without accompanying changes in the inner nuclear layer or significant alterations in retinovascular indices and optic nerve cup-disc ratio. These changes are distinct from those observed in PD, where thinning of the inner nuclear layer (INL) is a characteristic feature. SignificanceThese findings demonstrate a retinal phenotype in APS, markedly different from both healthy controls and idiopathic Parkinson's disease, highlighting the potential of retinal imaging in differentiating neurodegenerative disorders. By establishing a distinct retinal phenotype for APS, our findings underscore the potential of retinal imaging as a valuable, non-invasive diagnostic tool. This advancement is particularly significant for enhancing diagnostic accuracy, facilitating early detection, and offering a window into the underlying disease mechanisms in APS, thereby aiding in the development of targeted therapeutic interventions and personalized patient care strategies.

A prismatic view of the epigenetic-metabolic regulatory axis in breast cancer therapy resistance.

Epigenetic regulation established during development to maintain patterns of transcriptional expression and silencing for metabolism and other fundamental cell processes can be reprogrammed in cancer, providing a molecular mechanism for persistent alterations in phenotype. Metabolic deregulation and reprogramming are thus an emerging hallmark of cancer with opportunities for molecular classification as a critical preliminary step for precision therapeutic intervention. Yet, acquisition of therapy resistance against most conventional treatment regimens coupled with tumor relapse, continue to pose unsolved problems for precision healthcare, as exemplified in breast cancer where existing data informs both cancer genotype and phenotype. Furthermore, epigenetic reprograming of the metabolic milieu of cancer cells is among the most crucial determinants of therapeutic resistance and cancer relapse. Importantly, subtype-specific epigenetic-metabolic interplay profoundly affects malignant transformation, resistance to chemotherapy, and response to targeted therapies. In this review, we therefore prismatically dissect interconnected epigenetic and metabolic regulatory pathways and then integrate them into an observable cancer metabolism-therapy-resistance axis that may inform clinical intervention. Optimally coupling genome-wide analysis with an understanding of metabolic elements, epigenetic reprogramming, and their integration by metabolic profiling may decode missing molecular mechanisms at the level of individual tumors. The proposed approach of linking metabolic biochemistry back to genotype, epigenetics, and phenotype for specific tumors and their microenvironment may thus enable successful mechanistic targeting of epigenetic modifiers and oncometabolites despite tumor metabolic heterogeneity.

Antibody and siRNA Nanocarriers to Suppress Wnt Signaling, Tumor Growth, and Lung Metastasis in Triple‐Negative Breast Cancer

AbstractThe paucity of targeted therapies for triple‐negative breast cancer (TNBC) causes patients with this aggressive disease to suffer a poor clinical prognosis. A promising target for therapeutic intervention is the Wnt signaling pathway, which is activated in TNBC cells when extracellular Wnt ligands bind overexpressed Frizzled7 (FZD7) transmembrane receptors. This stabilizes intracellular β‐catenin proteins that in turn promote transcription of oncogenes that drive tumor growth and metastasis. To suppress Wnt signaling in TNBC cells, this work develops therapeutic nanoparticles (NPs) functionalized with FZD7 antibodies and β‐catenin small interfering RNAs (siRNAs). The antibodies enable TNBC cell specific binding and inhibit Wnt signaling by locking FZD7 receptors in a ligand unresponsive state, while the siRNAs suppress β‐catenin through RNA interference. Compared to NPs coated with antibodies or siRNAs individually, NPs coated with both agents more potently reduce the expression of several Wnt related genes in TNBC cells, leading to greater inhibition of cell proliferation, migration, and spheroid formation. In two murine models of metastatic TNBC, the dual antibody/siRNA nanocarriers outperformed controls in terms of inhibiting tumor growth, metastasis, and recurrence. These findings demonstrate suppressing Wnt signaling at both the receptor and mRNA levels via antibody/siRNA nanocarriers is a promising approach to combat TNBC.

Quality of Life in Patients with Chronic Low Back Pain and Differences by Sex: A Longitudinal Study

Background: The experience of chronic low back pain has a significant impact on the quality of life of affected people, resulting in difficulties in performing basic activities of daily living. Aim: To study the perceived quality of life of people affected by chronic low back pain and the associated factors by sex. Methods: A prospective, longitudinal and observational design was used. Results: A total of 129 people (58.1% women) with chronic low back pain were studied. The mean pain intensity scores were of moderate severity (6.42 points), with a modest improvement at follow-up (6.17 points). Epidural nerve blocks were the most effective therapeutic intervention in reducing the intensity of pain. Participants described a negative perception of their health with regard to quality of life, with low scores for the two constructs both at baseline (health index, 0.444; perception of health, 38.76 points) and at follow-up (health index, 0.447; perception of health, 40.43 points). Participants had severe functional limitation scores (50.79 points). The results were significantly better among men. There was an inverse relationship between the average pain intensity (β = −0.304; p < 0.001), functional limitation (β = −0.466; p < 0.001) and mental health (β = −0.565; p < 0.001) and quality of life. Conclusions: The chronification of low back pain complicates people’s biopsychosocial adaptation to life. There is a longitudinal inverse association between pain and functional limitation and health-related quality of life.

Icariside II modulates pulmonary fibrosis via PI3K/Akt/β-catenin pathway inhibition of M2 macrophage program

BackgroundIdiopathic pulmonary fibrosis (IPF) is a debilitating interstitial lung disorder characterized by its limited therapeutic interventions. Macrophages, particularly the alternatively activated macrophages (M2 subtype), have been acknowledged for their substantial involvement in the development of pulmonary fibrosis. Hence, targeting macrophages emerges as a plausible therapeutic avenue for IPF. Icariside II (ISE II) is a natural flavonoid glycoside molecule known for its excellent anti-tumor and anti-fibrotic activities. Nevertheless, the impact of ISE II on pulmonary fibrosis and the intricate mechanisms through which it operates have yet to be elucidated. ObjectiveTo scrutinize the impact of ISE II on the regulation of M2 macrophage polarization and its inhibitory effect on pulmonary fibrosis, as well as to delve deeper into the underlying mechanisms of its actions. MethodsThe effect of ISE II on proliferation and apoptosis in RAW264.7 cells was assessed through the use of EdU-488 labeling and the Annexin V/PI assay. Flow cytometry, western blot, and qPCR were employed to detect markers associated with the M2 polarization phenotype. The anti-fibrotic effects of ISE II in NIH-3T3 cells were investigated in a co-culture with M2 macrophages. Si-Ctnnb1 and pcDNA3.1(+)-Ctnnb1 plasmid were used to investigate the mechanism of targeted intervention. The murine model of pulmonary fibrosis was induced by intratracheal administration of bleomycin (BLM). Pulmonary function, histopathological manifestations, lung M2 macrophage infiltration, and markers associated with pulmonary fibrosis were evaluated. Furthermore, in vivo transcriptomics analysis was employed to elucidate differentially regulated genes in lung tissues. Immunofluorescence, western blot, and immunohistochemistry were conducted for corresponding validation. ResultsOur investigation demonstrated that ISE II effectively inhibited the proliferation of RAW264.7 cells and mitigated the pro-fibrotic characteristics of M2 macrophages, exemplified by the downregulation of CD206, Arg-1, and YM-1, Fizz1, through the inhibition of the PI3K/Akt/β-catenin signaling pathway. This impact led to the amelioration of myofibroblast activation and the suppression of nuclear translocation of β-catenin of NIH-3T3 cells in a co-culture. Consequently, it resulted in decreased collagen deposition, reduced infiltration of profibrotic macrophages, and a concurrent restoration of pulmonary function in mice IPF models. Furthermore, our RNA sequencing results showed that ISE II could suppress the expression of genes related to M2 polarization, primarily by inhibiting the PI3K/Akt and β-catenin signaling pathway. In essence, our findings suggest that ISE II holds potential as an anti-fibrotic agent by orchestrating macrophage polarization. This may have significant implications in clinical practice. ConclusionThis study has provided evidence that ISE II exerts a significant anti-fibrotic effect by inhibiting macrophage M2 polarization through the suppression of the PI3K/Akt/β-catenin signaling pathway. These findings underscore the potential of ISE II as a promising candidate for the development of anti-fibrotic pharmaceuticals in the future.

FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms.

Rare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD). Distinct genetic variants in FLT4 are also an established cause of Milroy disease, the most prevalent form of primary hereditary lymphoedema. Phenotypic features of these two conditions are non-overlapping, implying pleiotropic cellular mechanisms during development. Here, we show that FLT4 variants identified in TOF patients, when expressed in primary human endothelial cells, cause aggregation of FLT4 protein in the perinuclear endoplasmic reticulum, activating proteostatic and metabolic signalling, whereas lymphoedema-associated FLT4 variants and wildtype FLT4 do not. FLT4 TOF variants display characteristic gene expression profiles in key developmental signalling pathways, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of proteostatic signalling abrogates these effects, identifying potential avenues for therapeutic intervention. Depletion of flt4 in zebrafish caused cardiac phenotypes of reduced heart size and altered heart looping. These phenotypes were rescued with coinjection of wildtype human FLT4 mRNA, but incompletely or not at all by mRNA harbouring FLT4 TOF variants. Taken together, we identify a pathogenic mechanism for FLT4 variants predisposing to TOF that is distinct from the known dominant negative mechanism of Milroy-causative variants. FLT4 variants give rise to conditions of the two circulatory subdivisions of the vascular system via distinct developmental pleiotropic molecular mechanisms. Proteostatic dysfunction, if confirmed as a mechanism of CHD pathogenesis for other predisposing genes, may identify pathways to therapeutic interventions. Distinguishing mechanistically how variants in FLT4 give rise to CHD may have potential to individualise genetic counselling in affected families.

Protective Effect of Boric Acid Against Ochratoxin A-Induced Toxic Effects in Human Embryonal Kidney Cells (HEK293): A Study on Cytotoxic, Genotoxic, Oxidative, and Apoptotic Effects.

The present study evaluates the protective properties of boric acid (BA) against the toxic effects induced by ochratoxin A (OTA) in human embryonic kidney cells (HEK293). The focus is on various parameters such as cytotoxicity, genotoxicity, oxidative stress, and apoptosis. OTA is a known mycotoxin that has harmful effects on the liver, kidneys, brain, and nervous system. BA, on the other hand, a boron-based compound, is known for its potential as a vital micronutrient with important cellular functions. The results show that BA administration not only increases cell viability but also mitigates the cytotoxic effects of OTA. This is evidenced by a reduction in the release of lactate dehydrogenase (LDH), indicating less damage to cell membranes. In addition, BA shows efficacy in reducing genotoxic effects, as the frequency of micronucleus (MN) and chromosomal aberrations (CA) decreases significantly, suggesting a protective role against DNA damage. In addition, the study shows that treatment with BA leads to a decrease in oxidative stress markers, highlighting its potential as a therapeutic intervention against the deleterious effects of OTA. These results emphasize the need for further research into the protective mechanisms of boron, particularly BA, in combating cell damage caused by OTA.

Current and novel approaches in yeast cell death research.

The study of cell death mechanisms in fungi, particularly yeasts, has gained substantial interest in recent decades driven by the potential for biotechnological advancements and therapeutic interventions. Examples include the development of robust yeast strains for industrial fermentations and high-value compound production, novel food preservation strategies against spoilage yeasts, and the identification of targets for treating fungal infections in the clinic. In this review, we discuss a wide range of methods to characterize cellular alterations associated with yeast cell death, noting the advantages and limitations. We describe assays to monitor reversible events versus those that mark a commitment to cell death (point-of-no-return), as these distinctions are important to decipher the underlying regulatory mechanisms. Several well-known challenges remain, including the varied susceptibilities to death within a cell population and the delineation of detailed cell death mechanisms. The identification and characterization of morphologically distinct subsets of dying yeast cells within dynamic yeast populations provides opportunities to reveal novel vulnerabilities and survival mechanisms. Elucidating the intricacies of yeast regulated cell death (yRCD) will contribute to the advancement of scientific knowledge and foster breakthrough discoveries with broad-ranging implications.

Psychedelics, the Bible, and the Divine

The current psychedelic renaissance intersects with Christian practices in two key ways. First, as psychedelic-assisted therapy (PAT) becomes more common, Christians undergoing therapeutic medical treatment may seek outside support for integrating into their religious lives mystical experiences that occur during psychedelic sessions. Second, with increasing legal access to psychedelics, more Christians may explore their spiritual potential outside of a medical context, either individually with spiritual guides or collectively in organized retreats. Many will have mystical encounters related to the Divine. Whether the experience involves the overwhelming presence or absence of the Divine, these Christians, too, will seek integration support. This essay argues that the Bible can serve as a rich source for such integration, because it contains significant material about mystical experiences marked by altered states of consciousness. First, I summarize the importance of the psychedelic renaissance, especially the scientific studies being conducted, as it relates to Christian practices of spiritual formation. Second, I explore new work being conducted by biblical scholars regarding embodied religious experiences with the Divine (and others), including mystical experiences. Third, I consider the Apostle Paul’s embodied mystical experience, with special attention to 2 Corinthians 12:1–10, as one example of biblical material that might intersect with or inform psychedelic mystical encounters that contemporary Christians might experience (whether in a medical therapeutic or non-medical spiritual formation setting). Finally, I indicate directions for further research and discussion.

Uncharacterized yeast gene YBR238C, an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging via HAP4- and RMD9-dependent mechanisms

Uncovering the regulators of cellular aging will unravel the complexity of aging biology and identify potential therapeutic interventions to delay the onset and progress of chronic, aging-related diseases. In this work, we systematically compared genesets involved in regulating the lifespan of Saccharomyces cerevisiae (a powerful model organism to study the cellular aging of humans) and those with expression changes under rapamycin treatment. Among the functionally uncharacterized genes in the overlap set, YBR238C stood out as the only one downregulated by rapamycin and with an increased chronological and replicative lifespan upon deletion. We show that YBR238C and its paralog RMD9 oppositely affect mitochondria and aging. YBR238C deletion increases the cellular lifespan by enhancing mitochondrial function. Its overexpression accelerates cellular aging via mitochondrial dysfunction. We find that the phenotypic effect of YBR238C is largely explained by HAP4- and RMD9-dependent mechanisms. Furthermore, we find that genetic- or chemical-based induction of mitochondrial dysfunction increases TORC1 (Target of Rapamycin Complex 1) activity that, subsequently, accelerates cellular aging. Notably, TORC1 inhibition by rapamycin (or deletion of YBR238C) improves the shortened lifespan under these mitochondrial dysfunction conditions in yeast and human cells. The growth of mutant cells (a proxy of TORC1 activity) with enhanced mitochondrial function is sensitive to rapamycin whereas the growth of defective mitochondrial mutants is largely resistant to rapamycin compared to wild type. Our findings demonstrate a feedback loop between TORC1 and mitochondria (the TORC1–MItochondria–TORC1 (TOMITO) signaling process) that regulates cellular aging processes. Hereby, YBR238C is an effector of TORC1 modulating mitochondrial function.

Regulating NCOA4-Mediated Ferritinophagy for Therapeutic Intervention in Cerebral Ischemia-Reperfusion Injury.

Ischemic stroke presents a global health challenge, necessitating an in-depth comprehension of its pathophysiology and therapeutic strategies. While reperfusion therapy salvages brain tissue, it also triggers detrimental cerebral ischemia-reperfusion injury (CIRI). In our investigation, we observed the activation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in an oxygen-glucose deprivation/reoxygenation (OGD/R) model using HT22 cells (P < 0.05). This activation contributed to oxidative stress (P < 0.05), enhanced autophagy (P < 0.05) and cell death (P < 0.05) during CIRI. Silencing NCOA4 effectively mitigated OGD/R-induced damage (P < 0.05). These findings suggested that targeting NCOA4-mediated ferritinophagy held promise for preventing and treating CIRI. Subsequently, we substantiated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway effectively regulated the NCOA4-mediated ferritinophagy, by applying the cGAS inhibitor RU.521 and performing NCOA4 overexpression (P < 0.05). Suppressing the cGAS-STING pathway efficiently curtailed ferritinophagy (P < 0.05), oxidative stress (P < 0.05), and cell damage (P < 0.05) of CIRI, while NCOA4 overexpression could alleviate this effect (P < 0.05). Finally, we elucidated the specific molecular mechanism underlying the protective effect of the iron chelator deferoxamine (DFO) on CIRI. Our findings revealed that DFO alleviated hypoxia-reoxygenation injury in HT22 cells through inhibiting NCOA4-mediated ferritinophagy and reducing ferrous ion levels (P < 0.05). However, the protective effects of DFO were counteracted by cGAS overexpression (P < 0.05). In summary, our results indicated that the activation of the cGAS-STING pathway intensified cerebral damage during CIRI by inducing NCOA4-mediated ferritinophagy. Administering the iron chelator DFO effectively attenuated NCOA4-induced ferritinophagy, thereby alleviating CIRI. Nevertheless, the role of the cGAS-STING pathway in CIRI regulation likely involves intricate mechanisms, necessitating further validation in subsequent investigations.

Epi-revolution in rheumatology: the potential of histone deacetylase inhibitors for targeted rheumatoid arthritis intervention.

Autoimmune diseases hold significant importance in the realm of medical research, prompting a thorough exploration of potential therapeutic interventions. One crucial aspect of this exploration involves understanding the intricate processes of histone acetylation and deacetylation. Histone acetylation, facilitated by histone acetyl transferases (HATs), is instrumental in rendering DNA transcriptionally active. Conversely, histone deacetylases (HDACs) are responsible for the removal of acetyl groups, influencing gene expression regulation. The upregulation of HDACs, observed in various cancers, has steered attention towards histone deacetylase inhibitors (HDACi) as promising anti-cancer agents. Beyond cancer, HDACi has demonstrated anti-inflammatory properties, prompting interest in their potential therapeutic applications for inflammatory diseases such as rheumatoid arthritis (RA). RA, characterized by the immune system erroneously attacking healthy cells, leads to joint inflammation. Recent studies suggest that HDACi could offer a viable therapeutic strategy for RA, with potential mechanisms including the inhibition of synovial tissue growth and suppression of pro-inflammatory cytokines. Furthermore, HDACi may exert protective effects on bone and cartilage, common targets in RA pathology. In-depth investigations through in vivo and histopathology studies contribute to the ongoing discourse on the therapeutic benefits of HDACis in the context of RA treatment.

Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex

GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation–inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal NKCC1/KCC2 ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABAA receptor subunits, GABRA1, and upregulation of GABRA2. Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.

The importance of utilizing CT images at early stages for COVID-19 diagnosis – a Scoping Review

Overcoming the challenges posed by the severe acute respiratory syndrome caused by COVID-19 (SARS-CoV-2) has been one of the most recurrent themes when it comes to public health in a global context. Since March 2020, when it reached the stage of a pandemic by the World Health Organization, the world has been unfolding itself to overcome the challenges posed by this disease. As time goes by, new variants are demanding an even greater effort from health services to overcome the impacts caused by the disease. Several diagnostic methods have been developed with the aim of detecting the main signs of the disease as early as possible. The accelerated deterioration of the health status of patients affected by this disease reinforces the need for a conscious and timely action, in order to allow a rapid therapeutic intervention to propitiate a more favorable clinical outcome for the patient. However, each of the different methods developed over the past two years has advantages and disadvantages. Thus, the objective of this article is to present a scoping review of the literature currently available based on the criteria established by Amog et all (2) and published in the “Journal of Clinical Epidemiology” – volume 147, aiming to systematically summarize the existing knowledge and, based on the literature, discuss the importance as well as the advantages and disadvantages of adopting computed tomography images in the diagnosis of patients infected by COVID-19.

Hopping the Hurdle: Strategies to Enhance the Molecular Delivery to the Brain through the Blood–Brain Barrier

Modern medicine has allowed for many advances in neurological and neurodegenerative disease (ND). However, the number of patients suffering from brain diseases is ever increasing and the treatment of brain diseases remains an issue, as drug efficacy is dramatically reduced due to the existence of the unique vascular structure, namely the blood–brain barrier (BBB). Several approaches to enhance drug delivery to the brain have been investigated but many have proven to be unsuccessful due to limited transport or damage induced in the BBB. Alternative approaches to enhance molecular delivery to the brain have been revealed in recent studies through the existence of molecular delivery pathways that regulate the passage of peripheral molecules. In this review, we present recent advancements of the basic research for these delivery pathways as well as examples of promising ventures to overcome the molecular hurdles that will enhance therapeutic interventions in the brain and potentially save the lives of millions of patients.