Small Extracellular Vesicle Signaling and Mitochondrial Transfer Reprograms T Helper Cell Function in Human Asthma.

RATIONALE: Asthma is a chronic inflammatory disease of the airways that involves crosstalk between myeloid-derived regulatory cells (MDRCs) and CD4+ T cells. Although small extracellular vesicles (sEVs) are known to mediate cell-cell communication, the role of sEV signaling via mitochondria in perpetuating asthmatic airway inflammation is unknown. OBJECTIVES: We investigated the effects of MDRC-derived exosomes on dysregulated T cell responses in asthmatics. METHODS: Small extracellular vesicles isolated from bronchoalveolar lavage fluid or airway MDRCs of mild to moderate asthmatics or healthy controls were co-cultured with autologous peripheral and airway CD4+ T lymphocytes. sEV internalization, sEV-mediated transfer of mitochondria targeted GFP to T cells, sEV mitochondrial signaling, and subsequent activation, proliferation and polarization of CD4+ T lymphocytes to Th1, Th2 and Th17 subsets were assessed. MEASUREMENTS AND MAIN RESULTS: Airway MDRC-derived sEVs from asthmatics mediated T cell receptor engagement and transfer of mitochondria that induced antigen-specific activation and polarization into Th17 and Th2 cells, drivers of chronic airway inflammation in asthma. CD4+ T cells internalized sEVs containing mitochondria predominantly by membrane fusion, and blocking mitochondrial oxidant signaling in MDRC-derived exosomes mitigated T cell activation. Reactive oxygen species-mediated signaling that elicited T cell activation in asthmatics was sEV-dependent. A Drp1-dependent mitochondrial fission in pro-inflammatory MDRCs promoted mitochondrial packaging within sEVs, which then co-localized with the polarized actin cytoskeleton and mitochondrial networks in the organized immune synapse of recipient T cells. CONCLUSIONS: Our studies indicate a previously unrecognized role for mitochondrial fission and exosomal mitochondrial transfer in dysregulated T cell activation and Th cell differentiation in asthma which could constitute a novel therapeutic target.

Construction of flake ball-shaped Bi2WO6 embedded on phenyl functionalized g-C3N4 nanosheet for efficient degradation insight of colorless pollutants and its biological application.

A facile solvent-free solid-state method was adapted to synthesize the spherical-shaped Bi2WO6 engraved on phenyl-doped g-C3N4 nanosheet, i.e., Bi2WO6/Ph-gC3N4 (or BPCN) composites with varying weights of Bi2WO6. Several spectral analyses were used to characterize all the synthesized nanomaterials. The synthesized photocatalyst showed good absorption under visible light as confirmed by UV-visible DRS analysis. Morphological analyses like SEM and TEM determine the successful fabrication of binary heterocomposite. Further, the elements available in the fabricated binary nanocomposite were confirmed by XPS. The photocatalyst was used for the aerobic photocatalytic degradation of a few colorless pollutants like bisphenol A (BPA, 30 mg L-1), a microplastic constituent, and tetracycline (TC, 40 mg L-1), an antibiotic derivative to achieve the impressive results. The less intense PL signal obtained for the 20BPCN heterocomposite reveals the remarkable enhancement in e--h+ pair separation and recombination rate. The quenching study, alkaline terephthalic acid photoluminescence test (TA-PL), and NBT phototransformation study explain the formation of reactive species involved in the decomposition process. An oral cancer cell line (A-254) was tested for the anticancer activity analysis of the 20BPCN photocatalyst. Based on the obtained results, a Z-scheme electron transfer mechanism has been proposed for the photodegradation of model compounds.

The global prevalence of depression, anxiety, and sleep disorder among patients coping with Post COVID-19 syndrome (long COVID): a systematic review and meta-analysis.

BACKGROUND: Post COVID-19 syndrome, also known as "Long COVID," is a complex and multifaceted condition that affects individuals who have recovered from SARS-CoV-2 infection. This systematic review and meta-analysis aim to comprehensively assess the global prevalence of depression, anxiety, and sleep disorder in individuals coping with Post COVID-19 syndrome. METHODS: A rigorous search of electronic databases was conducted to identify original studies until 24 January 2023. The inclusion criteria comprised studies employing previously validated assessment tools for depression, anxiety, and sleep disorders, reporting prevalence rates, and encompassing patients of all age groups and geographical regions for subgroup analysis Random effects model was utilized for the meta-analysis. Meta-regression analysis was done. RESULTS: The pooled prevalence of depression and anxiety among patients coping with Post COVID-19 syndrome was estimated to be 23% (95% CI: 20%-26%; I2 = 99.9%) based on data from 143 studies with 7,782,124 participants and 132 studies with 9,320,687 participants, respectively. The pooled prevalence of sleep disorder among these patients, derived from 27 studies with 15,362 participants, was estimated to be 45% (95% CI: 37%-53%; I2 = 98.7%). Subgroup analyses based on geographical regions and assessment scales revealed significant variations in prevalence rates. Meta-regression analysis showed significant correlations between the prevalence and total sample size of studies, the age of participants, and the percentage of male participants. Publication bias was assessed using Doi plot visualization and the Peters test, revealing a potential source of publication bias for depression (p = 0.0085) and sleep disorder (p = 0.02). However, no evidence of publication bias was found for anxiety (p = 0.11). CONCLUSION: This systematic review and meta-analysis demonstrate a considerable burden of mental health issues, including depression, anxiety, and sleep disorders, among individuals recovering from COVID-19. The findings emphasize the need for comprehensive mental health support and tailored interventions for patients experiencing persistent symptoms after COVID-19 recovery.

Cutaneous Arsenical Exposure Induces Distinct Metabolic Transcriptional Alterations of Kidney Cells.

Arsenicals are deadly chemical warfare agents that primarily cause death through systemic capillary fluid leakage and hypovolemic shock. Arsenical exposure is also known to cause acute kidney injury, a condition that contributes to arsenical-associated death due to the necessity of the kidney in maintaining whole-body fluid homeostasis. Because of the global health risk that arsenicals pose, a nuanced understanding of how arsenical exposure can lead to kidney injury is needed. We used a nontargeted transcriptional approach to evaluate the effects of cutaneous exposure to phenylarsine oxide, a common arsenical, in a murine model. Here we identified an upregulation of metabolic pathways such as fatty acid oxidation, fatty acid biosynthesis, and peroxisome proliferator-activated receptor (PPAR)-α signaling in proximal tubule epithelial cell and endothelial cell clusters. We also revealed highly upregulated genes such as Zbtb16, Cyp4a14, and Pdk4, which are involved in metabolism and metabolic switching and may serve as future therapeutic targets. The ability of arsenicals to inhibit enzymes such as pyruvate dehydrogenase has been previously described in vitro. This, along with our own data, led us to conclude that arsenical-induced acute kidney injury may be due to a metabolic impairment in proximal tubule and endothelial cells and that ameliorating these metabolic effects may lead to the development of life-saving therapies. SIGNIFICANCE STATEMENT: In this study, we demonstrate that cutaneous arsenical exposure leads to a transcriptional shift enhancing fatty acid metabolism in kidney cells, indicating that metabolic alterations might mechanistically link topical arsenical exposure to acute kidney injury. Targeting metabolic pathways may generate promising novel therapeutic approaches in combating arsenical-induced acute kidney injury.

HSP90, a Common Therapeutic Target for Suppressing Skin Injury Caused by Exposure to Chemically Diverse Classes of Blistering Agents.

Vesicants such as arsenicals and mustards produce highly painful cutaneous inflammatory and blistering responses, hence developed as chemical weapons during World War I/II. Here, using lewisite and sulfur mustard surrogates, namely phenylarsine oxide (PAO) and 2-chloroethyl ethyl sulfide (CEES), respectively, we defined a common underlying mechanism of toxic action by these two distinct classes of vesicants. Murine skin exposure to these chemicals causes tissue destruction characterized by increase in skin bifold thickness, Draize score, infiltration of inflammatory cells, and apoptosis of epidermal and dermal cells. RNA sequencing analysis identified ∼346 inflammatory genes that were commonly altered by both PAO and CEES, along with the identification of cytokine signaling activation as the top canonical pathway. Activation of several proinflammatory genes and pathways is associated with phosphorylation-dependent activation of heat shock protein 90α (p-HSP90α). Topical treatment with known HSP90 inhibitors SNX-5422 and IPI-504 post PAO or CEES skin challenge significantly attenuated skin damage including reduction in overall skin injury and clinical scores. In addition, highly upregulated inflammatory genes Saa3, Cxcl1, Ccl7, IL-6, Nlrp3, Csf3, Chil3, etc. by both PAO and CEES were significantly diminished by treatment with HSP90 inhibitors. These drugs not only reduced PAO- or CEES-induced p-HSP90α expression but also its client proteins NLRP3 and pP38 and the expression of their target inflammatory genes. Our data confirm a critical role of HSP90 as a shared underlying molecular target of toxicity by these two distinct vesicants and provide an effective and novel medical countermeasure to suppress vesicant-induced skin injury. SIGNIFICANCE STATEMENT: Development of effective and novel mechanism-based antidotes that can simultaneously block cutaneous toxic manifestations of distinct vesicants is important and urgently needed. Due to difficulties in determining the exact nature of onsite chemical exposure, a potent drug that can suppress widespread cutaneous damage may find great utility. Thus, this study identified HSP90 as a common molecular regulator of cutaneous inflammation and injury by two distinct warfare vesicants, arsenicals and mustards, and HSP90 inhibitors afford significant protection against skin damage.

The Involvement of Unfolded Protein Response in the Mechanism of Nitrogen Mustard-Induced Ocular Toxicity.

Nitrogen mustard (NM) is a known surrogate of sulfur mustard, a chemical-warfare agent that causes a wide range of ocular symptoms, from a permanent reduction in visual acuity to blindness upon exposure. Although it has been proposed that the two blistering agents have a similar mechanism of toxicity, the mode of NM-induced cell death in ocular tissue has not been fully explored. Therefore, we hypothesized that direct ocular exposure to NM in mice leads to retinal tissue injury through chronic activation of the unfolded protein response (UPR) PERK arm in corneal cells and VEGF secretion, eventually causing cell death. We topically applied NM directly to mice to analyze ocular and retinal tissues at 2 weeks postexposure. A dramatic decline in retinal function, measured by scotopic and photopic electroretinogram responses, was detected in the mice. This decline was associated with enhanced TUNEL staining in both corneal and retinal tissues. In addition, exposure of corneal cells to NM revealed 228 differentially and exclusively expressed proteins primarily associated with the UPR, ferroptosis, and necroptosis. Moreover, these cells exhibited activation of the UPR PERK arm and an increase in VEGF secretion. Enhancement of VEGF staining was later observed in the corneas of the exposed mice. Therefore, our data indicated that the mechanism of NM-induced ocular toxicity should be carefully examined and that future research should identify a signaling molecule transmitted via a prodeath pathway from the cornea to the retina. SIGNIFICANCE STATEMENT: This study demonstrated that NM topical exposure in mice results in dramatic decline in retinal function associated with enhanced TUNEL staining in both corneal and retinal tissues. We also found that the NM treatment of corneal cells resulted in 228 differentially and exclusively expressed proteins primarily associated with ferroptosis. Moreover, these cells manifest the UPR PERK activation and an increase in VEGF secretion. The latter was also found in the corneas of the cexposed mice.

A Murine Model of Vesicant-Induced Acute Lung Injury.

Burn injuries including those caused by chemicals can result in systemic effects and acute lung injury (ALI). Cutaneous exposure to Lewisite, a warfare and chemical burn agent, also causes ALI. To overcome the limitations in conducting direct research on Lewisite-induced ALI in a laboratory setting, an animal model was developed using phenylarsine oxide (PAO) as a surrogate for Lewisite. Due to lack of a reliable animal model mimicking the effects of such exposures, development of effective therapies to treat such injuries is challenging. We demonstrated that a single cutaneous exposure to PAO resulted in disruption of the alveolar-capillary barrier as evidenced by elevated protein levels in the bronchoalveolar lavage fluid (BALF). BALF supernatant of PAO-exposed animals had increased levels of high mobility group box 1, a damage associated molecular pattern molecule. Arterial blood-gas measurements showed decreased pH, increased PaCO2, and decreased partial pressure of arterial O2, indicative of respiratory acidosis, hypercapnia, and hypoxemia. Increased protein levels of interleukin (IL)-6, CXCL-1, CXCL-2, CXCL-5, granulocyte-macrophage colony-stimulating factor, CXCL-10, leukemia inhibitory factor, leptin, IL-18, CCL-2, CCL-3, and CCL-7 were observed in the lung of PAO-exposed mice. Further, vascular endothelial growth factor levels were reduced in the lung. Pulmonary function evaluated using a flexiVent showed a downward shift in the pressure-volume loop, decreases in static compliance and inspiratory capacity, increases in respiratory elastance and tissue elastance. These changes are consistent with an ALI phenotype. These results demonstrate that cutaneous PAO exposure leads to ALI and that the model can be used as an effective surrogate to investigate vesicant-induced ALI. SIGNIFICANCE STATEMENT: This study presents a robust model for studying ALI resulting from cutaneous exposure to PAO, a surrogate for the toxic vesicating agent Lewisite. The findings in this study mimic the effects of cutaneous Lewisite exposure, providing a reliable model for investigating mechanisms underlying toxicity. The model can also be used to develop medical countermeasures to mitigate ALI associated with cutaneous Lewisite exposure.

Cleaner Biofuel Production via Process Parametric Optimization of Nonedible Feedstock in a Membrane Reactor Using a Titania-Based Heterogeneous Nanocatalyst: An Aid to Sustainable Energy Development.

Membrane technology has been embraced as a feasible and suitable substitute for conventional time- and energy-intensive biodiesel synthesis processes. It is ecofriendly, easier to run and regulate, and requires less energy than conventional approaches, with excellent stability. Therefore, the present study involved the synthesis and application of a highly reactive and recyclable Titania-based heterogeneous nanocatalyst (TiO2) for biodiesel production from nonedible Azadhiracta indica seed oil via a membrane reactor, since Azadhiracta indica is easily and widely accessible and has a rich oil content (39% w/w). The high free fatty acids content (6.52 mg/g KOH) of the nonedible oil was decreased to less than 1% via two-step esterification. Following the esterification, transesterification was performed using a heterogeneous TiO2 nanocatalyst under optimum conditions, such as a 9:1 methanol-oil molar ratio, 90 °C reaction temperature, 2 wt.% catalyst loading, and an agitation rate of 600 rpm, and the biodiesel yield was optimized through response surface methodology (RSM). Azadhiracta indica seed oil contains 68.98% unsaturated (61.01% oleic acid, 8.97% linoleic acid) and 31.02% saturated fatty acids (15.91% palmitic acid, 15.11% stearic acid). These fatty acids transformed into respective methyl esters, with a total yield up to 95% achieved. The biodiesel was analyzed via advanced characterization techniques like gas chromatography-mass spectrometry (GC-MS), Fourier transform infrared spectroscopy (FT-IR), and nuclear magnetic resonance (NMR), whereas the catalyst was characterized via X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray (EDX), and Fourier transform infrared spectroscopy (FT-IR). Due to its physicochemical properties, Azadirachta indica seed oil is a highly recommended feedstock for biodiesel production. Moreover, it is concluded that the Titania-based heterogeneous nanocatalyst (TiO2) is effective for high-quality liquid fuel synthesis from nonedible Azadirachta indica seed oil in a membrane reactor, which could be an optional green route to cleaner production of bioenergy, eventually leading to sustenance, robustness, and resilience that will aid in developing a holistic framework for integrated waste management.

Multifunctional electrospun nanofibrous scaffold enriched with alendronate and hydroxyapatite for balancing osteogenic and osteoclast activity to promote bone regeneration.

Electrospun composite nanofiber scaffolds are well known for their bone and tissue regeneration applications. This research is focused on the development of PVP and PVA nanofiber composite scaffolds enriched with hydroxyapatite (HA) nanoparticles and alendronate (ALN) using the electrospinning technique. The developed nanofiber scaffolds were investigated for their physicochemical as well as bone regeneration potential. The results obtained from particle size, zeta potential, SEM and EDX analysis of HA nanoparticles confirmed their successful fabrication. Further, SEM analysis verified nanofiber's diameters within 200-250 nm, while EDX analysis confirmed the successful incorporation of HA and ALN into the scaffolds. XRD and TGA analysis revealed the amorphous and thermally stable nature of the nanofiber composite scaffolds. Contact angle, FTIR analysis, Swelling and biodegradability studies revealed the hydrophilicity, chemical compatibility, suitable water uptake capacity and increased in-vitro degradation making it appropriate for tissue regeneration. The addition of HA into nanofiber scaffolds enhanced the physiochemical properties. Additionally, hemolysis cell viability, cell adhesion and proliferation by SEM as well as confocal microscopy and live/dead assay results demonstrated the non-toxic and biocompatibility behavior of nanofiber scaffolds. Alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) assays demonstrated osteoblast promotion and osteoclast inhibition, respectively. These findings suggest that developed HA and ALN-loaded PVP/PVA-ALN-HA nanofiber composite scaffolds hold significant promise for bone regeneration applications.

NK and NKT cells in the pathogenesis of Hidradenitis suppurativa: Novel therapeutic strategy through targeting of CD2.

Hidradenitis suppurativa (HS) is a chronic debilitating inflammatory skin disease with poorly understood pathogenesis. Single-cell RNAseq analysis of HS lesional and healthy individual skins revealed that NKT and NK cell populations were greatly expanded in HS, and they expressed elevated CD2, an activation receptor. Immunohistochemistry analyses confirmed significantly expanded numbers of CD2+ cells distributed throughout HS lesional tissue, and many co-expressed the NK marker, CD56. While CD4+ T cells were expanded in HS, CD8 T cells were rare. CD20+ B cells in HS were localized within tertiary follicle like structures. Immunofluorescence microscopy showed that NK cells (CD2 + CD56 dim ) expressing perforin, granzymes A and B were enriched within the hyperplastic follicular epidermis and tunnels of HS and juxtaposed with apoptotic cells. In contrast, NKT cells (CD2 + CD3 + CD56 bright ) primarily expressed granzyme A and were associated with α-SMA expressing fibroblasts within the fibrotic regions of the hypodermis. Keratinocytes and fibroblasts expressed high levels of CD58 (CD2 ligand) and they interacted with CD2 expressing NKT and NK cells. The NKT/NK maturation and activating cytokines, IL-12, IL-15 and IL-18, were significantly elevated in HS. Inhibition of cognate CD2-CD58 interaction with blocking anti-CD2 mAb in HS skin organotypic cultures resulted in a profound reduction of the inflammatory gene signature and secretion of inflammatory cytokines and chemokines in the culture supernate. In summary, we show that a cellular network of heterogenous NKT and NK cell populations drives inflammation, tunnel formation and fibrosis in the pathogenesis of HS. Furthermore, CD2 blockade is a viable immunotherapeutic approach for the management of HS.

Integrative systems biology framework discovers common gene regulatory signatures in multiple mechanistically distinct inflammatory skin diseases.

More than 20% of the population across the world is affected by non-communicable inflammatory skin diseases including psoriasis, atopic dermatitis, hidradenitis suppurativa, rosacea, etc. Many of these chronic diseases are painful and debilitating with limited effective therapeutic interventions. However, recent advances in psoriasis treatment have improved the effectiveness and provide better management of the disease. This study aims to identify common regulatory pathways and master regulators that regulate molecular pathogenesis. We designed an integrative systems biology framework to identify the significant regulators across several inflammatory skin diseases. With conventional transcriptome analysis, we identified 55 shared genes, which are enriched in several immune-associated pathways in eight inflammatory skin diseases. Next, we exploited the gene co-expression-, and protein-protein interaction-based networks to identify shared genes and protein components in different diseases with relevant functional implications. Additionally, the network analytics unravels 55 high-value proteins as significant regulators in molecular pathogenesis. We believe that these significant regulators should be explored with critical experimental approaches to identify the putative drug targets for more effective treatments. As an example, we identified IKZF1 as a shared significant master regulator in three inflammatory skin diseases, which can serve as a putative drug target with known disease-derived molecules for developing efficacious combinatorial treatments for hidradenitis suppurativa, atopic dermatitis, and rosacea. The proposed framework is very modular, which can indicate a significant path of molecular mechanism-based drug development from complex transcriptomics data and other multi-omics data.

Epigenetic switch reshapes epithelial progenitor cell signatures and drives inflammatory pathogenesis in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a complex inflammatory skin disease with undefined mechanistic underpinnings. Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epidermal hyperproliferation and dysregulated inflammation in HS. When comparing to healthy epithelial stem/progenitor cells, in HS, we identified changes in gene signatures that revolve around the mitotic cell cycle, DNA damage response and repair, as well as cell-cell adhesion and chromatin remodeling. By reconstructing cell differentiation trajectory and CellChat modeling, we identified a keratinocyte population specific to HS. This population is marked by S100A7/8/9 and KRT6 family members, triggering IL1, IL10, and complement inflammatory cascades. These signals, along with HS-specific proinflammatory cytokines and chemokines, contribute to the recruitment of certain immune cells during the disease progression. Furthermore, we revealed a previously uncharacterized role of S100A8 in regulating the local chromatin environment of target loci in HS keratinocytes. Through the integration of genomic and epigenomic datasets, we identified genome-wide chromatin rewiring alongside the switch of transcription factors (TFs), which mediated HS transcriptional profiles. Importantly, we identified numerous clinically relevant inflammatory enhancers and their coordinated TFs in HS basal CD49fhigh cells. The disruption of the S100A enhancer using the CRISPR/Cas9-mediated approach or the pharmacological inhibition of the interferon regulatory transcription factor 3 (IRF3) efficiently reduced the production of HS-associated inflammatory regulators. Our study not only uncovers the plasticity of epidermal progenitor cells in HS but also elucidates the epigenetic mechanisms underlying HS pathogenesis.

Efficacy and safety of sodium-glucose cotransporter-2 inhibitors for heart failure with mildly reduced or preserved ejection fraction: a systematic review and meta-analysis of randomized controlled trials.

Aims: We sought to conduct a meta-analysis to evaluate the efficacy and safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with heart failure (HF) with preserved ejection fraction (HFpEF) and HF with mildly reduced ejection fraction (HFmrEF). Methods: We searched the Cochrane Library, MEDLINE (via PubMed), Embase, and ClinicalTrials.gov till March 2023 to retrieve all randomized controlled trials of SGLT2i in patients with HFpEF or HFmrEF. Risk ratios (RRs) and standardized mean differences (SMDs) with their 95% confidence intervals (95% CIs) were pooled using a random-effects model. Results: We included data from 14 RCTs. SGLT2i reduced the risk of the primary composite endpoint of first HF hospitalization or cardiovascular death (RR 0.81, 95% CI: 0.76, 0.87; I2 = 0%); these results were consistent across the cohorts of HFmrEF and HFpEF patients. There was no significant decrease in the risk of cardiovascular death (RR 0.96, 95% CI: 0.82, 1.13; I2 = 36%) and all-cause mortality (RR 0.97, 95% CI: 0.89, 1.05; I2 = 0%). There was a significant improvement in the quality of life in the SGLT2i group (SMD 0.13, 95% CI: 0.06, 0.20; I2 = 51%). Conclusion: The use of SGLT2i is associated with a lower risk of the primary composite outcome and a higher quality of life among HFpEF/HFmrEF patients. However, further research involving more extended follow-up periods is required to draw a comprehensive conclusion. Systematic Review Registration: PROSPERO (CRD42022364223).

Microneedle-mediated transdermal delivery of N-acetyl cysteine as a potential antidote for lewisite injury.

Lewisite is a chemical warfare agent intended for use in World War and a potential threat to the civilian population due to presence in stockpiles or accidental exposure. Lewisite-mediated skin injury is characterized by acute erythema, pain, and blister formation. N-acetyl cysteine (NAC) is an FDA-approved drug for acetaminophen toxicity, identified as a potential antidote against lewisite. In the present study, we have explored the feasibility of rapid NAC delivery through transdermal route for potentially treating chemical warfare toxicity. NAC is a small, hydrophilic molecule with limited passive delivery through the skin. Using skin microporation with dissolving microneedles significantly enhanced the delivery of NAC into and across dermatomed human skin in our studies. Microporation followed by application of solution (poke-and-solution) resulted in the highest in vitro delivery (509.84 ± 155.04 µg/sq·cm) as compared to poke-and-gel approach (474.91 ± 70.09 µg/sq·cm) and drug-loaded microneedles (226.89 ± 33.41 µg/sq·cm). The lag time for NAC delivery through poke-and-solution approach (0.23 ± 0.04 h) was close to gel application (0.25 ± 0.02 h), with the highest for drug-loaded microneedles (1.27 ± 1.16 h). Thus, we successfully demonstrated the feasibility of rapid NAC delivery using various skin microporation approaches for potential treatment against lewisite-mediated skin toxicity.

Fabrication of Direct Z-Scheme CoNiWO4/Ph-gC3N4 Heterocomposites: Enhanced Photodegradation of Bisphenol A and Anticancer Activity.

Photocatalysis is realized by the design of a visible-light-active catalyst with robust redox capacity and broad absorption. In this study, a series of novel Z-scheme CoNiWO4/Ph-gC3N4 photocatalysts are synthesized to improve their redox property and photocatalytic activity toward broad visible light absorption. An intimate stable heterojunction is made between cobalt-nickel tungstate (CoNiWO4) and phenyl-doped graphitic carbon nitride (Ph-gC3N4), and its physicochemical properties are studied. The bifunctional properties of all of the synthesized materials were assessed by studying the decomposition of bisphenol A (BPA) and methyl orange (MO) dye as model pollutants, followed by an evaluation of their anticancer activity on human lung cancer cell lines. The photocatalyst with 20 wt % CoNiWO4 heterocomposite showed an enhanced response toward the removal of cancerous cells. The synthesized pristine CoNiWO4 and Ph-gC3N4 exhibit well-matched band structures and, hence, make it easier to create a Z-scheme heterocomposite. This may increase the lifetime of photoinduced charge carriers with a high redox power, thereby improving their photocatalytic and anticancer activity. An extensive analysis of the mechanism demonstrates that hydroxyl radicals (•OH) and superoxide radical anions (•O2-) are responsible for the degradation of organic compounds via Z-scheme charge transfer approach. These findings point toward a new route for creating effective Co-Ni tungstate-based direct Z-scheme photocatalysts for various redox processes, particularly the mineralization of resistant organic molecules.

Altered sphingolipid pathway in SARS-CoV-2 infected human lung tissue.

Introduction: The SARS-CoV-2 mediated COVID-19 pandemic has impacted millions worldwide. Hyper-inflammatory processes, including cytokine storm, contribute to long-standing tissue injury and damage in COVID-19. The metabolism of sphingolipids as regulators of cell survival, differentiation, and proliferation has been implicated in inflammatory signaling and cytokine responses. Sphingosine-kinase-1 (SK1) and ceramide-synthase-2 (CERS2) generate metabolites that regulate the anti- and pro-apoptotic processes, respectively. Alterations in SK1 and CERS2 expression may contribute to the inflammation and tissue damage during COVID-19. The central objective of this study is to evaluate structural changes in the lung post-SARS-CoV-2 infection and to investigate whether the sphingolipid rheostat is altered in response to SARS-CoV-2 infection. Methods: Central and peripheral lung tissues from COVID-19+ or control autopsies and resected lung tissue from COVID-19 convalescents were subjected to histologic evaluation of airspace and collagen deposisiton, and immunohistochemical evaluation of SK1 and CERS2. Results: Here, we report significant reduction in air space and increase in collagen deposition in lung autopsy tissues from patients who died from COVID-19 (COVID-19+) and COVID-19 convalescent individuals. SK1 expression increased in the lungs of COVID-19+ autopsies and COVID-19 convalescent lung tissue compared to controls and was mostly associated with Type II pneumocytes and alveolar macrophages. No significant difference in CERS2 expression was noted. SARS-CoV-2 infection upregulates SK1 and increases the ratio of SK1 to CERS2 expression in lung tissues of COVID-19 autopsies and COVID-19 convalescents. Discussion: These data suggest an alteration in the sphingolipid rheostat in lung tissue during COVID-19, suggesting a potential contribution to the inflammation and tissue damage associated with viral infection.

The prevalence of depression and anxiety among Iranian people with multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: There is significant inconsistency regarding the prevalence rate of depression and anxiety among people with multiple sclerosis (MS) in Iran. We sought to conduct this comprehensive meta-analysis to assess the prevalence of depression and anxiety in Iranian multiple sclerosis patients. METHODS: A systematic search was conducted on 14 March 2023 in PubMed/MEDLINE, Web of Science, Scopus, Embase, and Iranian national databases. All studies assessing the prevalence of depression and anxiety among Iranian people with MS were included. We used the NEWCASTLE-OTTAWA tool for quality assessment. We pooled the prevalence of individual studies using the random effect model. RESULTS: Our systematic search showed 23 articles that meet the eligibility criteria. Most of the included studies were cross-sectional. The most used questionnaire to assess depression and anxiety were Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS), respectively. The overall prevalence of depression and anxiety among Iranian people with MS was 47% (95%CI: 39%-55%%, I2 =94%) and 51% (95%CI: 36%-66%%, I2 =97%), respectively. The results of subgroup and meta-regression analyses showed assessment scale used and the province was significantly associated with the prevalence of the outcomes. Tehran had the most studies published on this topic. The prevalence of depression and anxiety was highest in Kermanshah province. The funnel plot and Egger's regression test did not show a significant source of funnel plot asymmetry for depression (p-value = 0.8138), and anxiety (p-value = 0.8259). CONCLUSION: Our study indicates that a significant proportion of people with MS in Iran are affected by depression and anxiety.

Levels of brain-derived neurotrophic factor (BDNF) among patients with COVID-19: a systematic review and meta-analysis.

Many individuals have been suffering from consistent neurological and neuropsychiatric manifestations even after the remission of coronavirus disease (COVID-19). Brain-derived neurotrophic factor (BDNF) is a protein involved in the regulation of several processes, including neuroplasticity, neurogenesis, and neuronal differentiation, and has been linked to a range of neurological and psychiatric disorders. In this study, we aimed to synthesize the available evidence on the profile of BDNF in COVID-19. A comprehensive search was done in the Web of Science core collection, Scopus, and MEDLINE (PubMed), and Embase to identify relevant studies reporting the level of BDNF in patients with COVID-19 or those suffering from long COVID. We used the NEWCASTLE-OTTAWA tool for quality assessment. We pooled the effect sizes of individual studies using the random effect model for our meta-analysis. Fifteen articles were included in the systematic review. The sample sizes ranged from 16 to 183 participants. Six studies compared the level of BDNF in COVID-19 patients with healthy controls. The pooled estimate of the standardized mean difference in BDNF level between patients with COVID-19 and healthy individuals was - 0.84 (95% CI - 1.49 to - 0.18, p = 0.01, I2 = 81%) indicating a significantly lower BDNF level in patients with COVID-19. Seven studies assessed BDNF in different severity statuses of patients with COVID-19. The pooled estimate of the standardized mean difference in BDNF level was - 0.53 (95% CI - 0.85 to - 0.21, p = 0.001, I2 = 46%), indicating a significantly lower BDNF level in patients with more severe COVID-19. Three studies evaluated BDNF levels in COVID-19 patients through different follow-up periods. Only one study assessed the BDNF levels in long COVID patients. Sensitivity analyses did not alter the significance of the association. In this study, we showed a significant dysregulation of BDNF following COVID-19 infection. These findings may support the pathogenesis behind the long-lasting effects of this disease among infected patients. PROSPERO: CRD42023413536.

Novel LDLR Variant in Familial Hypercholesterolemia: NGS-Based Identification, In Silico Characterization, and Pharmacogenetic Insights.

BACKGROUND: Familial Hypercholesterolemia (FH) is a hereditary condition that causes a rise in blood cholesterol throughout a person's life. FH can result in myocardial infarction and even sudden death if not treated. FH is thought to be caused mainly by variants in the gene for the low-density lipoprotein receptor (LDLR). This study aimed to investigate the genetic variants in FH patients, verify their pathogenicity, and comprehend the relationships between genotype and phenotype. Also, review studies assessed the relationship between the LDLR null variants and the reaction to lipid-lowering therapy. METHODS: The study utilised high-throughput next-generation sequencing for genetic screening of FH-associated genes and capillary sequencing for cascade screening. Furthermore, bioinformatic analysis was employed to describe the pathogenic effects of the revealed novel variant on the structural features of the corresponding RNA molecule. RESULTS: We studied the clinical signs of hypercholesterolemia in a Saudi family with three generations of FH. We discovered a novel frameshift variant (c.666_670dup, p.(Asp224Alafs*43) in the LDLR and a known single nucleotide variant (c.9835A > G, p.(Ser3279Gly) in the APOB gene. It is thought that the LDLR variant causes a protein to be prematurely truncated, likely through nonsense-mediated protein decay. The LDLR variant is strongly predicted to be pathogenic in accordance with ACMG guidelines and co-segregated with the FH clinical characteristics of the family. This LDLR variant exhibited severe clinical FH phenotypes and was restricted to the LDLR protein's ligand-binding domain. According to computational functional characterization, this LDLR variant was predicted to change the free energy dynamics of the RNA molecule, thereby affecting its stability. This frameshift variant is thought to eliminate important functional domains in LDLR that are required for receptor recycling and LDL particle binding. We provide insight into how FH patients with a null variant in the LDLR gene respond to lipid-lowering therapy. CONCLUSIONS: The findings expand the range of FH variants and assist coronary artery disease preventive efforts by improving diagnosis, understanding the genotype-phenotype relationship, prognosis, and personalised therapy for patients with FH.