Death Response Research Articles

MELK prevents radiofrequency ablation-induced immunogenic cell death and antitumor immune response by stabilizing FABP5 in hepatocellular malignancies

BackgroundRadiofrequency ablation (RFA) is an efficient treatment with unlimited potential for liver cancer that can effectively reduce patient mortality. Understanding the biological process related with RFA treatment is important for improving treatment strategy. This study aimed to identify the critical targets for regulating the efficacy of RFA.MethodsThe RFA treatment in hepatocellular carcinoma (HCC) tumor models in vivo, was analyzed by RNA sequencing technology. The heat treatment in vitro for HCC tumor cells was also constructed to explore the mechanism after RFA treatment in tumor cells. Nanoparticles with high affinity to tumor cells were applied as a new therapy to interfere with the expression of maternal embryonic leucine zipper kinase (MELK).ResultsIt was found that RFA treatment upregulated MELK expression, and MELK inhibition promoted RFA efficacy by immunogenic cell death and the antitumor response, including anti-tumoral macrophage polarization and increased CD8+ T cell cytotoxicity in HCC. Mechanically, MELK binds to fatty acid-binding protein 5 (FABP5), and affects its ubiquitination through the K48R pathway to increase its stability, thereby activating protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling axis to weaken the RFA-mediated antitumor effect. In addition, the synthesis of arginylglycylaspartic acid (RGD)-lipid nanoparticles (LNPs) targeting tumor cell-intrinsic MELK enhanced RFA efficacy in HCC.ConclusionMELK is a therapeutic target by regulating RFA efficacy in HCC, and targeting MELK via RGD-LNPs provides new insight into improving RFA efficacy in HCC clinical treatment and combating the malignant progression of liver cancer.

A high-valence bismuth(V) nanoplatform triggers cancer cell death and anti-tumor immune responses with exogenous excitation-free endogenous H2O2- and O2-independent ROS generation

Reactive oxygen species with evoked immunotherapy holds tremendous promise for cancer treatment but has limitations due to its dependence on exogenous excitation and/or endogenous H2O2 and O2. Here we report a versatile oxidizing pentavalent bismuth(V) nanoplatform (NaBiVO3-PEG) can generate reactive oxygen species in an excitation-free and H2O2- and O2-independent manner. Upon exposure to the tumor microenvironment, NaBiVO3-PEG undergoes continuous H+-accelerated hydrolysis with •OH and 1O2 generation through electron transfer-mediated BiV-to-BiIII conversion and lattice oxygen transformation. The simultaneous release of sodium counterions after endocytosis triggers caspase-1-mediated pyroptosis. NaBiVO3-PEG intratumorally administered initiates robust therapeutic efficacies against both primary and distant tumors and activates systemic immune responses to combat tumor metastasis. NaBiVO3-PEG intravenously administered can efficiently accumulate at the tumor site for further real-time computed tomography monitoring, immunotherapy, or alternative synergistic immune-radiotherapy. Overall, this work offers a nanomedicine based on high-valence bismuth(V) nanoplatform and underscores its great potential for cancer immunotherapy.

Laminaran potentiates cGAS-STING signaling to enhance antiviral responses.

Cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) signaling pathway, an essential element in the innate antiviral immune responses, has emerged as a key component of innate immune system to modulate type I IFNs production and response by recognizing both exogenous and endogenous DNA. Although some cGAS-STING signaling small molecule agonists have been developed, there are few natural polysaccharides reported to activate cGAS-STING signaling for the treatment of infectious diseases. Here, we reported that Laminaran, a low molecular weight β-glucan storage polysaccharide present in brown algae, potentiates cGAS-STING signaling to promote type I IFNs production and antiviral response. Laminaran enhanced cGAS-STING signaling mediated type I IFNs production and response both in human and murine cells upon HSV-1 infection or DNA mimics stimulation. Importantly, we found that Laminaran markedly inhibited Herpes simplex virus-1 (HSV-1) induced death and inflammatory responses and increased the induction of type I IFNs in C57BL/6J mice. Mechanistically, we found Laminaran inhibited autophagy and suppressed STING autophagic degradation to positively regulate cGAS-STING signaling response. Taken together, we uncovered the function of Laminaran in DNA triggered innate immunity by enhancing cGAS-STING signaling response. Laminaran might be a potential therapeutic candidate for viral infectious diseases.

Real-world data on utilization of neoadjuvant chemotherapy for muscle invasive bladder cancer: impact on surgical complications and oncological efficacy.

Recommended treatment of urothelial muscle-invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy, but there are challenges with low utilization of NAC. We aimed to evaluate the utilization of NAC, perioperative complications and oncological efficacy in a real-world setting. All patients operated with radical cystectomy at the University Hospital of North Norway during 2011-2021 for MIBC were included. NAC consisted of three cycles of dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (ddMVAC) every second week. Complications after cystectomy (Clavien-Dindo ≥ grade 3 within 30 days), histopathologic NAC response, cancer recurrence, relapse-free survival (RFS), overall survival (OS) and cause of death were reported. We included 124 patients, median observation time of 4 years. Fifty-nine patients (48%) received NAC. Most common causes for not receiving NAC were age ≥ 75 years (n = 38; 31%), cardiovascular disease (n = 7; 5.6%), and reduced kidney function (n = 6; 4.8%). Overall 34 patients (27%) had a ≥ grade 3 complication. The 5-year actuarial OS rate was higher among patients treated with NAC than those without NAC (67% vs. 45%, p = 0.02). Among NAC-treated patients, 29 (49%) were downstaged to non-muscle invasive stage (≤pT1), and the 5-year actuarial RFS and OS were higher among patients with ≤pT1 in the post-cystectomy specimen than those with ≥ pT2 (92% vs. 35%, and 94% vs. 39%, both p < 0.001). The utilization of NAC was high in this real-world setting. Treatment with ddMVAC with achieved downstaging to ≤pT1 was associated with considerably improved RFS and OS.

TEAD1 Prevents Necroptosis and Inflammation in Cisplatin-Induced Acute Kidney Injury Through Maintaining Mitochondrial Function.

Cisplatin is widely used for the treatment of solid tumors and its antitumor effects are well established. However, a known complication of cisplatin administration is acute kidney injury (AKI). In this study, we examined the role of TEA domain family member 1 (TEAD1) in the pathogenesis of cisplatin-induced AKI. TEAD1 expression was upregulated in tubular epithelial cells of kidneys with cisplatin-induced AKI. TEAD1 floxed mice (TEAD1CON) mice treated with cisplatin developed tubular cell damage and impaired kidney function. In contrast, proximal tubule specific TEAD1 knockout (TEAD1PKO) mice treated with cisplatin had enhanced tubular cell damage and kidney dysfunction. Additionally, TEAD1PKO mice treated with cisplatin had augmented necroptotic cell death and inflammatory response compared to TEAD1CON mice with cisplatin. Knockdown of TEAD1 in mouse tubular epithelial cells showed increased intracellular ROS levels, reduced ATP production and impaired mitochondrial bioenergetics compared to control cells treated with cisplatin. Mechanistically, TEAD1 interacts with peroxisomal proliferator-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, to promote mitochondrial function. Taken together, our results indicate TEAD1 plays an important role in the pathogenesis of cisplatin-induced AKI through regulation of necroptosis and inflammation, which is associated with mitochondrial metabolism. Therefore, TEAD1 may represent a novel therapeutic target for cisplatin-induced AKI.

Hyaluronic acid-functionalized supramolecular nanophotosensitizers for targeted photoimmunotherapy of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is recognized as a particularly aggressive subtype of breast cancer that is devoid of effective therapeutic targets. Immune checkpoint inhibitors (ICIs) have demonstrated promising results in TNBC treatment. Nonetheless, most patients either develop resistance to ICIs or fail to respond to them initially. Owing to its spatio-temporal precision and non-invasive nature, photoimmunotherapy offers a targeted therapeutic strategy for TNBC. Herein, we report hyaluronic acid (HA)-functionalized indocyanine green-based supramolecular nanoparticles (HGI NPs), with biodegradable characteristics, for high-performance photoacoustic imaging and targeted phototherapy for TNBC. Notably, HGI NPs can significantly gather in TNBC tissues because of the enhanced permeability and retention effect of the tumor, and the tumor-targeting properties of HA. The strong amplification of HGI nanoparticles triggers a significant immunogenic cell death (ICD) response when exposed to 808 nm light, thus shifting the immunosuppressive tumor microenvironment (iTME) into a tumor attack mode and ‘hot’ state. Antitumor experiments demonstrate the high efficiency of the supramolecular photosensitizers HGI NPs for TNBC elimination and good biosafety. This synergistic strategy reshapes the iTME and amplifies the antitumor immune response, providing a theoretical foundation for combining phototherapy and ICIs as potential treatments for TNBC.Graphical

Evaluating maternal death surveillance and response system in Sunyani Municipality of Bono region in Ghana from 2017-2021

IntroductionMaternal death rates in Ghana have decreased overall but remain high in rural areas. The Maternal Death Surveillance and Response System (MDSR) aims to eliminate preventable maternal deaths effectively. However, its effectiveness is less pronounced at district and subdistrict levels than at national and regional levels. Despite the requirement for periodic evaluation, there is a lack of evidence supporting these assessments. This study focuses on evaluating the MDSR in Sunyani Municipal.MethodsThe evaluation was conducted using a cross-sectional design, using both qualitative and quantitative approaches. Data from the District Health Information Management Systems (DHIMS) and the maternal death line list from January 2017 to December 2021 on maternal deaths were reviewed. Stakeholders, including health professionals, were interviewed. The means, proportions, and other statistical measures were calculated using Epi Info Version 7. Qualitative data underwent content analysis, and the results were visually presented in tables and flowcharts to illustrate the flow of surveillance information.ResultsMost respondents were female, constituting 51.4% (19/37), with midwives comprising the largest group at 32.4% (12/37). Approximately 75.7% (28/37) were able to explain how the surveillance data has been used for public health action. The notification and reporting process was clear to 85% (17/20) of respondents. Although 94.6% (35/37) expressed willingness to notify and participate in audits at facility and community levels, the audits remained facility-based. All facilities consistently reported maternal deaths, but data storage equipment was lacking. Approximately 80% (20/25) of forms were reported within 24 h, and 88% (22/25) were investigated within seven days. Only 68% (17/25) of forms were filled out correctly, with no municipal and facility-level line list. All reported deaths came from healthcare facilities, with no community-reported maternal deaths.ConclusionsThe MDSR system in Sunyani Municipal demonstrates high awareness and willingness to participate among healthcare providers but faces challenges in data accuracy and community engagement. Death audits remain facility-based, and the lack of community-reported maternal deaths and municipal-level line lists indicates gaps in comprehensive reporting and data management. To improve the system, it is recommended that community case searches be enhanced for better reporting and to address data management issues by ensuring proper data quality assessment.

Galacto-oligosaccharides alone and combined with lactoferrin impact the Kenyan infant gut microbiota and epithelial barrier integrity during iron supplementation in vitro

Aim: Iron supplementation to African weaning infants was associated with increased enteropathogen levels. While cohort studies demonstrated that specific prebiotics inhibit enteropathogens during iron supplementation, their mechanisms remain elusive. Here, we investigated the in vitro impact of galacto-oligosaccharides (GOS) and iron-sequestering bovine lactoferrin (bLF) alone and combined on the gut microbiota of Kenyan infants during low-dose iron supplementation. Methods: Different doses of iron, GOS, and bLF were first screened during batch fermentations (n = 3), and the effect of these factors was studied on microbiota community structure and activity in the new Kenyan infant continuous intestinal PolyFermS model. The impact of different fermentation treatments on barrier integrity, enterotoxigenic Escherichia coli (ETEC) infection, and inflammatory response was assessed using a transwell co-culture of epithelial and immune cells. Results: A dose-dependent increase in short-chain fatty acid (SCFA) production, Bifidobacterium and Lactobacillus /Leuconostoc /Pediococcus (LLP) growth was detected with GOS alone and combined with bLF during iron supplementation in batches. This was confirmed in the continuous PolyFermS model, which also showed a treatment-induced inhibition of opportunistic pathogens C. difficile and C. perfringens . In all tests, supplementation of iron alone and combined with bLF did not have a significant effect on microbiota composition and activity. We observed a strengthening of the epithelial barrier and a decrease in cell death and pro-inflammatory response during ETEC infection with microbiota fermentation supernatants from iron + GOS, iron + bLF, and iron + GOS + bLF treatments compared to iron alone. Conclusion: Overall, beneficial effects on infant gut microbiota were shown using advanced in vitro models for GOS alone and combined with bLF during low-dose iron supplementation.

Exploring the role and application of mitochondria in radiation therapy.

Mitochondria are pivotal in cellular energy metabolism, the oxidative stress response and apoptosis. Recent research has focused on harnessing their functions to enhance the efficacy of radiation therapy (RT). This review focuses on the critical functions and applications of mitochondria in radiation therapy, including the targeting of mitochondrial metabolism and the modulation of mitochondria-mediated cell death and immune responses. While these strategies have demonstrated considerable potential in preclinical studies to improve radiotherapy outcomes, challenges remain, such as optimizing drug delivery systems, ensuring safety and overcoming resistance to therapy.

HSP90 Family Members, Their Regulators and Ischemic Stroke Risk: A Comprehensive Molecular-Genetics and Bioinformatics Analysis.

Disruptions in proteostasis are recognized as key drivers in cerebro- and cardiovascular disease progression. Heat shock proteins (HSPs), essential for maintaining protein stability and cellular homeostasis, are pivotal in neuroperotection. Consequently, deepening the understanding the role of HSPs in ischemic stroke (IS) risk is crucial for identifying novel therapeutic targets and advancing neuroprotective strategies. Our objective was to examine the potential correlation between single nucleotide polymorphisms (SNPs) in genes that encode members of the Heat shock protein 90 (HSP90), small heat shock proteins (HSPB), and heat shock factors (HSF) families, and the risk and clinical characteristics of IS. 953 IS patients and 1265 controls from Central Russia were genotyped for nine SNPs in genes encoding HSP90AA1, HSFs, and HSPBs using the MassArray-4 system and probe-based polymerase chain reaction (PCR). In smokers, SNP rs1133026 HSPB8 increased the risk of IS (risk allele A, odds ratio (OR) = 1.43, 95% Confidence Interval (CI) 1.02-2.02, p = 0.035), and rs556439 HSF2 increased the brain infarct size (risk allele A, p = 0.02). In non-smokers, SNPs rs4279640 HSF1 (protective allele T, OR = 0.58, 95% CI 0.37-0.92, p = 0.02) and rs4264324 HSP90AA1 (protective allele C, OR = 0.11, 95% CI 0.01-0.78, p = 0.001) lowered the risk of recurrent stroke; SNP rs7303637 HSPB8 increased the age of onset of IS (protective allele T, p = 0.04). In patients with body mass index (BMI) ≥25, SNPs rs556439 HSF2 (risk allele A, OR = 1.33, 95% CI 1.04-1.69, p = 0.02) and rs549302 HSF2 (risk allele G, OR = 1.34, 95% CI 1.02-1.75, p = 0.03) were linked to a higher risk of IS. The primary molecular mechanisms through which the studied SNPs contribute to IS pathogenesis were found to be the regulation of cell death, inflammatory and oxidative stress responses.

Implementation status of maternal death surveillance and response system in Ethiopia: Evidence from a national-level system evaluation.

In Ethiopia, Maternal Death Surveillance and Response (MDSR) was integrated into the existing Integrated Disease Surveillance and Response (IDSR) system in 2014. Despite providing valuable evidence to inform policies and actions, system implementation has not been evaluated. Thus, a national-level evaluation was conducted to assess the level and status of system implementation. A national cross-sectional study was conducted using a multi-stage sampling approach in 2020. A total of 629 health facilities were included in the study. A modified tool, adapted from the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC), was employed to assess each functional component of the system, encompassing structure, core, supportive, and system attributes. The score for each component was based on Ethiopian Public Health Institute's mid-term evaluation metrics. To objectively evaluate the implementation status, a composite score of the Maternal Death Surveillance and Response Performance Index (MDSRPI) was calculated based on five performance indicators. Descriptive statistics, independent t-tests, and one-way analysis of variance (ANOVA) with Bonferroni correction were used to examine the variations in scores among the different characteristics. Of the total sample size, 82.5% (519/629) of health facilities were assessed. Among the assessed health facilities, 77.0% (400/519) fulfilled the criteria for final analysis. Accordingly, the overall readiness score was 44.9% (95% CI: 43.9% to 45.9%), which is rated as less functional. The structures of the system were rated at 51.7% (95% CI: 49.9% to 53.4%), and the system attributes were rated at 69.6% (95% CI: 68.0% to 71.2%), which were considered fairly functional. In contrast, the core functions were rated at 20.0% (95% CI: 18.9% to 21.1%), and the supportive functions were rated at 38.4% (95% CI: 36.4% to 40.4%), which were categorized as not functioning and less functional, respectively. Regionally, Tigray's overall readiness score (54.8%, 95% CI: 50.4-59.1%) was significantly higher than Oromia (41.6%, 95% CI: 40.2-43.0%, P = 0.0001), Amhara (47.7%, 95% CI: 43.9-45.9%, P = 0.05), and SNNPR (42.3%, 95% CI: 39.3-45.3, P = 0.0001). Additionally, Amhara's score was significantly higher than Oromia and SNNPR. Secondary-level healthcare facilities (49.6%, 95% CI: 45.7-53.7, P = 0.029) had a significantly higher readiness score compared to primary health facilities (44.6%, 95% CI: 43.5-45.6). The overall score for the Maternal Death Surveillance and Response Performance Index (MDSPI) was 33.9%. Despite the noticeable regional variation, the overall system readiness and status to implement MDSR were suboptimal, characterized by low representativeness, completeness, and community engagement. Efforts should be directed toward improving community surveillance and enhancing all components of the system to address regional variations and improve overall performance through triangulation and integration with various data sources.

Establishment of primary and immortalized fibroblasts reveals resistance to cytotoxic agents and loss of necroptosis-inducing ability in long-lived Damaraland mole-rats

AbstractThe Damaraland mole-rat (DMR; Fukomys damarensis) is a long-lived (~ 20 years) Bathyergid rodent that diverged 26 million years ago from its close relative, the naked mole-rat (NMR). While the properties of NMR cultured fibroblasts have been extensively studied and have revealed several unusual features of this cancer-resistant, long-lived species, comparative DMR studies are extremely limited. We optimized conditions for successfully culturing primary DMR skin fibroblasts and also established immortalized DMR cells using simian virus 40 early region expression. Like NMRs, DMR fibroblasts are more resistant than mice to various cytotoxins including heavy metals, DNA-damaging agents, oxidative stressors, and proteasome inhibitors. DMR genome sequencing analyses revealed the presence of premature stop codons in the master regulator genes of necroptosis, an inflammatory programmed cell death—receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), although these mutations have different locations to those found in the NMR. DMR cells, like NMR cells, did not show significantly increased cell death in response to necroptosis induction. Our data suggest that both Bathyergid species require species-specific cell culture conditions for optimized growth, display similar resistance to cytotoxins, and show loss-of-function mutations abrogating the ability to employ necroptosis. These shared traits may contribute to their evolved adaptations to their subterranean lifestyle and prolonged longevity. These convergent insights and valuable resource may be pertinent to biomedical research.

Research progress on metal pollutants inducing neurotoxicity through ferroptosis

It has been confirmed that exposure to various metal pollutants can induce neurotoxicity, which is closely associated with the occurrence and development of neurological disorders. Ferroptosis is a form of cell death in response to metal pollutant exposure and it is closely related to oxidative stress, iron metabolism and lipid peroxidation. Recent studies have revealed that ferroptosis plays a significant role in the neurotoxicity induced by metals such as lead, cadmium, manganese, nickel, and antimony. Lead exposure triggers ferroptosis through oxidative stress, iron metabolism disorder and inflammation. Cadmium can induce ferroptosis through iron metabolism, oxidative stress and ferroptosis related signaling pathways. Manganese can promote ferroptosis through mitochondrial dysfunction, iron metabolism disorder and oxidative stress. Nickel can promote ferroptosis by influencing mitochondrial function, disrupting iron homeostasis and facilitating lipid peroxidation in the central nervous system. Antimony exposure can induce glutathione depletion by activating iron autophagy, resulting in excessive intracellular iron deposition and ultimately causing ferroptosis. This article reviews the effects of metal pollutants on ferroptosis-related indicators and discusses the specific mechanisms by which each metal triggers ferroptosis. It provides a reference for identifying targets for preventing neurotoxicity and for developing treatment strategies for neurological disorders.

Propofol Suppresses Ferroptosis via Modulating eNOS/NO Signaling Pathway to Improve Traumatic Brain Injury.

This study aims to explore the neuroprotective effect of propofol in improving traumatic brain injury (TBI) by inhibiting ferroptosis through the modulation of the endothelial nitric oxide (NO) synthase (eNOS)/NO signaling pathway. The GSE173975 dataset was used to analyze the differentially expressed genes between TBI and sham surgery control groups in the short and long term. A TBI model was established in 2-month-old male SPF C57BL/6 mice by impact exposure of the exposed dura mater. After the establishment of the TBI model, propofol (30mg/kg) or saline was administered via intraperitoneal injection for intervention. Nissl staining and Perls staining were employed to assess neuronal function and iron deposition, respectively. Western blot technology was employed to detect the expression of proteins related to ferroptosis. Immunofluorescence staining of astrocytes and microglia was utilized to assess the neuroinflammatory response induced by TBI. The Morris water maze (MWM) and novel object recognition (NOR) tests were employed to assess cognitive dysfunction induced by TBI. Bioinformatics analysis revealed aberrant gene expression associated with iron transport, neuronal death, and inflammatory response in the initial stages of TBI. Long-term abnormalities were predominantly linked to genes involved in inflammatory response. Perls staining and protein expression analysis confirmed the occurrence of iron deposition and ferroptosis following TBI. Propofol treatment significantly reduced iron deposition and ferroptosis induced by TBI. Nissl staining demonstrated enhanced neuronal function, while TUNEL staining indicated reduced neuronal apoptosis. Immunofluorescence analysis demonstrated that propofol significantly reduced the proliferation of astrocytes and activation of microglia induced by TBI in the long term. The results of MWM and NOR tests indicated that propofol significantly improved the long-term cognitive dysfunction induced by TBI. Propofol exerts neuroprotective effects by increasing the expression of eNOS protein and the content of NO. The neuroprotective effects of propofol can be reversed by the eNOS inhibitor L-NAME. Propofol significantly improves the prognosis of TBI by inhibiting ferroptosis through the modulation of the eNOS/NO signaling pathway. The study results provide a scientific basis for the clinical use of propofol as a neuroprotective agent and offer a new direction for the development of new treatment strategies for TBI.

Ventral Hernia Repair With a Hybrid Absorbable-permanent Preperitoneal Mesh.

To analyze device safety and clinical outcomes of ventral hernia repair with the GORE SYNECOR Preperitoneal Biomaterial (PRE device), a permanent high-strength mesh with bioabsorbable web scaffold technology. This multicenter retrospective review analyzed device/procedure endpoints and patient-reported outcomes in patients treated for hernia repair ≥1 year from study enrollment. Included in this analysis were 148 patients with a mean age of 56 years; 66.2% met the Ventral Hernia Working Group grade 2 classification. Median hernia size was 30.0cm 2 and 58.8% of patients had an incisional hernia. Repairs were primarily a robotic (53.4%) or open approach (41.9%). All meshes were placed extraperitoneal. Procedure-related adverse events within 30 days occurred in 13 (8.8%) patients and included 7 (4.8%) patients with surgical site infection, 2 (1.4%) with surgical site occurrence (SSO), 4 (2.7%) requiring readmission, and 3 (2.0%) who had reoperation. The rate of SSO events requiring procedural intervention was 2.7% (4 patients) through 30 days and 3.4% (5 patients) at 12 months. The rate of procedure-related surgical site infection remained at 4.8% through 12 months (no further reports after 30d) and 3.4% for SSO (2 reports after 30d). There were no site-reported clinically diagnosed hernia recurrences throughout the study. Median patient follow-up including in-person visit, physical examination, reported adverse event, explant, death, and questionnaire response was 28 months (n = 148). Median patient follow-up with patient questionnaire was 36 months (n = 88). Use of the PRE device, which incorporates the proven advantages of both an absorbable synthetic mesh and the long-term durability of a permanent macroporous mesh, is safe and effective in complex ventral hernia repairs. When used in the retromuscular space, the combination of these 2 materials had lower wound complications and recurrence rates than either type of material alone.

Elucidation of the Active Agents in a West African Ground Herbal Medicine Formulation That Elicit Antimalarial Activities in In Vitro and In Vivo Models.

Agunmu (ground herbal medicine) is a form of West African traditional medicine consisting of a cocktail of herbs. The goal of this study is to evaluate a formulation of Agunmu made from M. indica, A. repens, E. chlorantha, A. boonei, and B. ferruginea, sold in the open market and commonly used for the treatment of malaria by the locals, for its antimalarial effects and to determine the active principles that may contribute to the antimalarial effect. The ethanolic extract obtained from this formulation (Ag-Iba) was analyzed, using TLC, LC-MS, and Tandem-MS techniques, to determine its phytochemical properties. The extract was tested in vitro against representative bacteria strains, cancer and normal human cell lines, and susceptible (D6) and resistant (W2) Plasmodium falciparum. In subsequent in vivo experiments, graded doses of the extract were used to treat mice infected with chloroquine-susceptible (NK-65) and chloroquine-resistant (ANKA) strains of Plasmodium berghei. Bacteria growth was monitored with a disc diffusion assay, cancer cell viability was determined with MTS assay, and percentage parasitemia and parasite clearance were determined by microscopy. Bound heme content, host mitochondria permeability transition (mPT) pore opening, F0F1-ATPase, and lipid peroxidation were determined via spectrophotometry. Indices of oxidative stress, anti-oxidant activities, toxicity, cell death, and inflammatory responses were obtained using biochemical and ELISA techniques. The histology of the liver and spleen was performed using the standard method. We elucidated the structures of the critical active principles in the extract to be flavonoids: kaempferol, quercetin, myricetin, and their glycosides with little or no detectable levels of the toxic Aristolochic acids that are found in Aristolochia repens, one of the components of the formulation. The extract also showed anti-plasmodial activity in in vitro and in vivo models. Furthermore, the extract dose-dependently decreased mitochondrial dysfunction, cell death, and inflammatory and oxidative damage but increased antioxidant potentials. Presumably, the active principles in the extract work as a combinatorial therapy to elicit potent antimalarial activity. Overall, our study unraveled the active components from a commercial herbal formulation that could be reformulated for antimalarial therapy.

Exploring variations in the implementation of a health system level policy intervention to improve maternal and child health outcomes in resource limited settings: A qualitative multiple case study from Uganda.

Despite growing literature, few studies have explored the implementation of policy interventions to reduce maternal and perinatal mortality in low- and middle-income countries (LMICs). Even fewer studies explicitly articulate the theoretical approaches used to understand contextual influences on policy implementation. This under-use of theory may account for the limited understanding of the variations in implementation processes and outcomes. We share findings from a study exploring how a health system-level policy intervention was implemented to improve maternal and child health outcomes in a resource limited LMIC. Our qualitative multiple case study was informed by the Normalization Process Theory (NPT). It was conducted across eight districts and among ten health facilities in Uganda, with 48 purposively selected participants. These included health care workers located at each of the cases, policy makers from the Ministry of Health, and from agencies and professional associations. Data were collected using semi-structured, in-depth interviews to understand uptake and use of Uganda's maternal and perinatal death surveillance and response (MPDSR) policy and were inductively and deductively analyzed using NPT constructs and subconstructs. We identified six broad themes that may explain the observed variations in the implementation of the MPDSR policy. These include: 1) perception of the implementation of the policy, 2) leadership of the implementation process, 3) structural arrangements and coordination, 4) extent of management support and adequacy of resources, 5) variations in appraisal and reconfiguration efforts and 6) variations in barriers to implementation of the policy. The variations in sense making and relational efforts, especially perceptions of the implementation process and leadership capacity, had ripple effects across operational and appraisal efforts. Adopting theoretically informed approaches to assessing the implementation of policy interventions is crucial, especially within resource limited settings.

Keratinocytes - Amplifiers of Immune Responses in Systemic Lupus Erythematosus.

Epithelial cells have been acknowledged as important players in autoimmune diseases by directing and enhancing inflammatory responses. Here, we summarize recent publications that examine keratinocyte (KC) dysfunction and its contribution to cutaneous and systemic disease in systemic lupus erythematosus patients. Chronic upregulation of type I interferon (IFN) in KCs is a feature of both lesional and nonlesional lupus skin. This IFN rich environment modulates epidermal cell death responses and promotes inflammatory responses to UV light exposure. In addition, newer technologies such as single cell RNA-seq are informing our understanding of lupus-specific intercellular crosstalk and how this contributes to disease. Recent discoveries in KC dysfunction in lupus skin include aberrant IFN responses to environmental stress, enhanced cytokine and chemokine secretion and epigenetic changes leading to increased cell death. Further research will enable precision therapies for lupus treatment.

The Antifungal Potential of Ozonated Extra-Virgin Olive Oil Against Candida albicans: Mechanisms and Efficacy.

The growing emergence of resistance mechanisms and side effects associated with antifungal agents highlight the need for alternative therapies. This study aims to investigate the antifungal potential of ozonated extra-virgin olive oil (EOO) against Candida albicans, with the goal of developing eco-friendly and highly effective treatments based on natural products. Antifungal activity was evaluated via cell viability and biofilm formation assays using Crystal Violet and Sytox green staining. The results showed that EOO reduced C. albicans viability in a dose-dependent manner, achieving over 90% cell death at a 3% (v/v) concentration. Transmission Electron Microscopy (TEM) revealed cell wall structural damage, and ROS levels increased by approximately 60% compared to untreated controls within 10 min of treatment. Additionally, the expression of autophagy-related genes atg-7 and atg-13was upregulated by 2- and 3.5-fold, respectively, after 15 min, suggesting a stress-induced cell death response. EOO also significantly inhibited hyphal formation and biofilm development, thus reducing C. albicans pathogenicity while preserving cell biocompatibility. EOO antifungal activity was also observed in the case of Candida glabrata. In conclusion, ozonated olive oil demonstrates potent antifungal activity against C. albicans by reducing cell viability, inhibiting hyphal and biofilm formation, and triggering oxidative stress and autophagy pathways. These findings position EOO as a promising alternative therapy for fungal infections.

Mechanisms regulating host cell death during Leishmania infection.

Parasites from the Leishmania genus are the causative agents of leishmaniasis and primarily reside within macrophages during mammalian infection. Their ability to establish intracellular infection provides a secure niche for proliferation while evading detection. However, successful multiplication within mammalian cells requires the orchestration of multiple mechanisms that control host cell viability. In contrast, innate immune cells, such as macrophages, can undergo different forms of cell death in response to pathogenic intracellular microbes. Thus, modulation of these different forms of host cell death is crucial for Leishmaniasis development. The regulation of host cell apoptosis, a form of programmed cell death, is crucial for sustaining parasites within viable host cells. Accordingly, several studies have demonstrated evasion of apoptosis induced by dermotropic and viscerotropic Leishmania species. Conversely, the prevention of pyroptosis, an inflammatory form of cell death, ensures the establishment of infection by silencing the release of mediators that could trigger massive proinflammatory responses. This manuscript explores how Leishmania regulates various host cell death pathways and overviews seminal studies on regulating host cell apoptosis by different Leishmania species.