Tissue Tolerance Research Articles

Trends and hotspots in acupuncture treatment of rat models of stroke: a bibliometric analysis from 2004 to 2023.

Acupuncture is a widely used clinical treatment method, and studies have confirmed its therapeutic effects on stroke patients. It can also reduce the burden on patients and society. Acupuncture treatment is a complementary and preventive treatment for stroke. However, there has yet to be a visual bibliometric analysis of the field of acupuncture for stroke rat models. This study explores future trends, research hotspots, and frontiers in acupuncture for stroke rat models over the past 20 years through investigation and visualization. We collected literature data on acupuncture treatment of stroke in rats from the Web of Science Core Collection (WOSCC) database from January 1, 2004, to December 31, 2023. Import into CiteSpace (version 6.2.R4) and RStudio for analysis by author, country/region, affiliation, annual publication, keywords, and journal visualization. A total of 379 articles were retrieved, including articles from 16 countries, 258 research institutions, and 123 academic journals. The countries and institutions with the most publications were the People's Republic of China (338) and the Fujian University of Traditional Chinese Medicine (43). Tao, Jing had the highest number of co-citations (144). The keywords and co-citation clustering show the main research directions in the field, including "artery occlusion," "neural regeneration," "stimulation," "rapid tolerance," "receptor," "signaling pathway," "apoptosis," "oxidative stress," "inflammatory response," "endogenous neurogenesis," "tolerance of local cerebral ischemic tissues," "proliferation of reactive astrocytes" and "neuroprotective effect." The intervention combines classical acupuncture treatment and modern technology (electricity) with electroacupuncture as a new intervention modality. This study demonstrates the increasing research on acupuncture for treating stroke in rat models. The country/region with the most publications is the People's Republic of China. However, international cooperation still needs to be improved, and future researchers must strengthen international cooperation. In addition, in future studies, researchers should improve the overall quality of research results in this area and enhance research protocols.

60Co γ‐radiation at low‐dose level alters volatile compounds of blueberry during storage

Summary60Co γ‐radiation was applied to blueberry fruits in an effort to investigate a safe, eco‐friendly and effective blueberry preservation technique. However, the preservation effects were variable depending on tissue tolerance to irradiation doses. Moreover, irradiation may cause off‐odour. In this study, we examined the effects of three low doses of 60Co γ‐radiation on the physical and flavour attributes of blueberry. The results showed that 60Co γ‐radiation did not significantly improve fruit quality but extend the shelf life up to 15 days at 25 °C and 30 days at 4 °C. Compared with the control group, the preservation effect of 0.5–1.0 kGy irradiation treatment on blueberry fruit was not obvious before 15 days but maintained 65% of fruit firmness and reduced the loss of nutrients afterwards at 4 °C. At 25 °C, irradiation treatment caused up to a 150% increase in polyphenol oxidase activity, which was relevant to colour changes in late storage. Headspace Gas Chromatography Ion Mobility Spectrometry (HS‐GC‐IMS) was applied, and 33 volatile organic compounds (VOCs) in blueberry treated with different radiation doses were identified, including 11 esters, 8 aldehydes, 7 alcohols, 6 ketones and other substances, which increased with increasing radiation dose. Radiation reduced the green taste of blueberry and promoted their ripening. Radiation above the level of 1.02 kGy led to the flavour deterioration of blueberry such as ethyl trans‐2‐butenoate. The side effects of radiation on the aroma of blueberry could be offset by low‐temperature storage. Blueberry stored at 4 °C contained more aldehydes with a heavier fresh/green aroma. Six aromas were proposed to be characteristic odour markers of radiated blueberry.

Fibrin glue mediated direct delivery of radiation sensitizers results in enhanced efficacy of radiation treatment

PurposeRadiation therapy (RT) plays an important role in the treatment of glioblastoma multiforme (GBM). However, inherent intrinsic resistance of tumors to radiation, coupled with the need to consider the tolerance of normal tissues and the potential effects on neurocognitive function, impose constraints on the amount of RT that can be safely delivered. A strategy for augmenting the effectiveness of RT involves the utilization of radiation sensitizers (RS). Directly implanting RS-loaded fibrin glue (FG) into the tumor resection cavity would by-pass the blood brain barrier, potentially enhancing the impact of RT on tumor recurrence. This study investigated the ability of FG to incorporate and release, in non-degraded form, the radiation sensitizers 5-Fluorouracil (5FU) and Motexafin gadolinium (MGd).MethodsFG layers were created in a 24-well plate by combining thrombin, fibrinogen, and 5FU or MGd. Supernatants from these layers were collected at various intervals and added to F98 glioma spheroid cultures in 96-well plates. Radiation was applied either before or after RS application as single or fractionated dosages. Spheroid growth was monitored for 14 days.ResultsCombined treatment of FG-released 5FU and RT significantly inhibited spheroid growth compared to RS or RT as a single treatment. As a free drug, MGd demonstrated its efficacy in reducing spheroid volume, but had diminished potency as a released RS. Fractionated radiation was more effective than single dose radiation.ConclusionNon-degraded RS was released from the FG for up to 72 h. FG-released 5FU greatly increased the efficacy of radiation therapy.

Low Temperature Tolerance of Peach Flower Buds and Shoot Tissues Is Differentially Influenced by Freezing and High Temperature Exposure

In northern temperate zones, peach trees are vulnerable to cold temperature injury in the fall, particularly as climate change prolongs warm weather in the fall and potentially delays the onset of cold acclimation. Four experiments evaluated how cold acclimation of flower buds and shoot phloem, cambium, and xylem is affected by exposure to varying temperatures in the fall. One-year-old peach shoots from trees grown in Maine, USA, were collected from October through November, exposed to 1, 3, or 6 days of low, high, and freezing temperatures, and subjected to stepwise controlled freezing to about −30 °C. Injury was visually quantified as oxidative browning of flower buds and shoot tissues. High temperature exposure, even of a single day, decreased cold tolerance of flower buds and shoot tissues until late November, when high temperatures only minimally decreased cold hardiness. In mid-November, increasing the duration of high temperature exposure from 1 to 3 days decreased cambium and phloem hardiness, but hardiness in flower buds was not further decreased by the longer duration of 3 days. By late November, hardiness in flower buds, cambium, and phloem was less responsive to high temperature, and was increased by prior exposure to 6 days of freezing. After high temperature, xylem lost hardiness to a small degree in mid-October and late November, but in mid-November this occurred in only one experiment. In this study, deacclimation during high temperature in the fall was greater in cambium and phloem than in flower buds and at times greater than in xylem.

Understanding mechanisms for differential salinity tissue tolerance between quinoa and spinach: Zooming on ROS-inducible ion channels

Soil salinity is a worldwide issue and a major threat to global food security. Salinity tolerance is a complex mechanism that is conferred by numerous molecular, physiological, and biochemical traits. Of critical importance are plant’s ability to regulate redox balance without compromising reactive oxygen species (ROS) signalling and maintain cytosolic ion homeostasis. In this study, the mechanistic basis of K+ retention ability in leaf mesophyll (an important but highly sensitive plant tissue) was compared between halophytic quinoa and glycophytic spinach. Phenotypic data showed quinoa outperformed spinach under 100 to 500 mmol L−1 NaCl salinity. The major difference behind this differential salinity sensitivity was a differential K+ uptake in leaf mesophyll. Electrophysiological and molecular experiments revealed that a superior ability of mesophyll K+ retention in quinoa was conferred by three complementary mechanisms: (i) an intrinsically lower H+-ATPase activity in quinoa (potentially as an energy saving strategy); (ii) reduced sensitivity of K+ transporters to ROS; and (iii) increased sensitivity of ROS-inducible Ca2+-permeable channels. Moreover, the sensitivity of K+-transport systems to ROS was further examined in NaCl-acclimated quinoa and spinach plants. The key factors differentiating between K+ retention in acclimated leaf mesophyll was associated with the reduced sensitivity and gene expression of K+-permeable outward rectifying channel (GORK), Arabidopsis potassium transporter 1 (AKT1), and high affinity potassium transporter 5 (HAK5) to additional NaCl and ROS stress, along with the upregulation of ROS scavenging system. Taken together, our results showed that the tissue-specific and ROS-specific regulation of K+ retention are important for conferring salinity tolerant at least in the halophyte quinoa.

An international phase II trial and immune profiling of SBRT and atezolizumab in advanced pretreated colorectal cancer

BackgroundImmuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients.MethodsEligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling.ResultsSixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20–81 years]; 77% with liver metastases) were enrolled in five centers (France: n = 4, Spain: n = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9–11.6] and 1.4 months [95%CI:1.2–2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease (n = 38; 64%), partial (n = 3; 5%) and complete response (n = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses.ConclusionsThis study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy.Trial registrationEudraCT N°: 2015–005464-42; Clinicaltrial.gov number: NCT02992912.

Early life imprinting of intestinal immune tolerance and tissue homeostasis.

Besides its canonical role in protecting the host from pathogens, the immune system plays an arguably equally important role in maintaining tissue homeostasis. Within barrier tissues that interface with the external microenvironment, induction of immune tolerance to innocuous antigens, such as commensal, dietary, and environmental antigens, is key to establishing immune homeostasis. The early postnatal period represents a critical window of opportunity in which parallel development of the tissue, immune cells, and microbiota allows for reciprocal regulation that shapes the long-term immunological tone of the tissue and subsequent risk of immune-mediated diseases. During early infancy, the immune system appears to sacrifice pro-inflammatory functions, prioritizing the establishment of tissue tolerance. In this review, we discuss mechanisms underlying early life windows for intestinal tolerance with a focus on newly identified RORγt+ antigen-presenting cells-Thetis cells-and highlight the role of the intestinal microenvironment in shaping intestinal immune system development and tolerance.

Group 3 innate lymphoid cells in intestinal health and disease.

The gastrointestinal tract is an immunologically rich organ, containing complex cell networks and dense lymphoid structures that safeguard this large absorptive barrier from pathogens, contribute to tissue physiology and support mucosal healing. Simultaneously, the immune system must remain tolerant to innocuous dietary antigens and trillions of normally beneficial microorganisms colonizing the intestine. Indeed, a dysfunctional immune response in the intestine underlies the pathogenesis of numerous local and systemic diseases, including inflammatory bowel disease, food allergy, chronic enteric infections or cancers. Here, we discuss group 3 innate lymphoid cells (ILC3s), which have emerged as orchestrators of tissue physiology, immunity, inflammation, tolerance and malignancy in the gastrointestinal tract. ILC3s are abundant in the developing and healthy intestine but their numbers or function are altered during chronic disease and cancer. The latest studies provide new insights into the mechanisms by which ILC3s fundamentally shape intestinal homeostasis or disease pathophysiology, and often this functional dichotomy depends on context and complex interactions with other cell types or microorganisms. Finally, we consider how this knowledge could be harnessed to improve current treatments or provoke new opportunities for therapeutic intervention to promote gut health.

Moving forward to understand the alteration of physiological mechanism by seed priming with different halo-agents under salt stress.

Soil salinity hampers the survival and productivity of crops. To minimize salt-associated damages in plant, better salt management practices in agriculture have become a prerequisite. Seed priming with different halo-agents is a technique, which improves the primed plant's endurance to tackle sodium. Salt tolerance is achieved in tolerant plants through fundamental physiological mechanisms- ion-exclusion and tissue tolerance, and salt-tolerant plants may (Na+ accumulators) or may not (Na+ excluders) allow sodium movement to leaves. While Na+ excluders depend on ion exclusion in roots, Na+ accumulators are proficient Na+ managers that can compartmentalize Na+ in leaves and use them beneficially as inexpensive osmoticum. Salt-sensitive plants are Na+ accumulators, but their inherent tissue tolerance ability and ion-exclusion process are insufficient for tolerance. Seed priming with different halo-agents aids in 'rewiring' of the salt tolerance mechanisms of plants. The resetting of the salt tolerance mechanism is not universal for every halo-agent and might vary with halo-agents. Here, we review the physiological mechanisms that different halo-agents target to confer enhanced salt tolerance in primed plants. Calcium and potassium-specific halo-agents trigger Na+ exclusion in roots, thus ensuring a low amount of Na+ in leaves. In contrast, Na+-specific priming agents favour processes for Na+ inclusion in leaves, improve plant tissue tolerance or vacuolar sequestration, and provide the greatest benefit to salt-sensitive and sodium accumulating plants. Overall, this review will help to understand the underlying mechanism behind plant's inherent nature towards salt management and its amelioration with different halo-agents, which helps to optimize crop stress performance.

Neurologic Changes Induced by Whole-Brain Synchrotron Microbeam Irradiation: 10-Month Behavioral and Veterinary Follow-Up

PurposeNovel radiotherapy approaches have increased the therapeutic efficacy for malignant brain tumors over the last decades but the balance between therapeutic gain and radiotoxicity remains a medical hardship. Synchrotron Microbeam Radiation Therapy (MRT), an innovative technique, deposes extremely high (peak) doses in micron-wide, parallel microbeam paths, while the diffusing inter-beam (valley) doses lie in the range of conventional radiotherapy doses. In this study, we evaluated normal tissue toxicity of whole-brain microbeam irradiation (MBI) versus that of a conventional, hospital broad beam (hBB). Methods and MaterialsNormal Fischer rats (n=6-7/group) were irradiated with one of the two modalities, exposing the entire brain to 0, 5/200, 10/400, 13/520, 17/680 or 25/1000 Gy MBI valley/peak dose, or to 7, 10, 13, 17 or 25 Gy hBB dose. Two additional groups of rats received 10 Gy MBI valley dose coupled with 7 or 15 Gy BB dose (groups MBI17* and MBI25*). Behavioral parameters were evaluated for 10 months post irradiation, combined with veterinary observations. ResultsMBI peak doses of ≥680 Gy caused acute toxicity and death. Animals exposed to hBB or MBI dose-dependently gained less weight than controls; rats in the hBB25 and MBI25* groups deceased within 6 months post irradiation. Increasing doses of MBI caused hyperactivity but no other detectable behavioral alteration in our tests. Importantly, no health concerns were seen up to 17 Gy MBI valley dose. ConclusionsWhile acute toxicity of microbeam exposures depends on very high peak doses, late toxicity mainly relates to delivery of high MBI valley doses. MBI seems to elicit low impact on normal rat behavior but further tests are warranted to fully explore this hypothesis. However, high peak and valley doses are well tolerated from a veterinary point of view. This normal tissue tolerance to whole-brain, high-dose MBI reveals a promising avenue for MRT, i.e., therapeutic applications of microbeams which are poised for translation to a clinical environment.

PMI-controlled mannose metabolism and glycosylation determines tissue tolerance and virus fitness

Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered immunometabolic response cascade and reduces tissue damage. Safe and inexpensive D-mannose can compete with glucose for the same transporter and hexokinase. Such competitions suppress glycolysis, reduce mitochondrial reactive-oxygen-species and succinate-mediated hypoxia-inducible factor-1α, and thus reduce virus-induced proinflammatory cytokine production. The combinatorial treatment by D-mannose and antiviral monotherapy exhibits in vivo synergy despite delayed antiviral treatment in mouse model of virus infections. Phosphomannose isomerase (PMI) knockout cells are viable, whereas addition of D-mannose to the PMI knockout cells blocks cell proliferation, indicating that PMI activity determines the beneficial effect of D-mannose. PMI inhibition suppress a panel of virus replication via affecting host and viral surface protein glycosylation. However, D-mannose does not suppress PMI activity or virus fitness. Taken together, PMI-centered therapeutic strategy clears virus infection while D-mannose treatment reprograms glycolysis for control of collateral damage.

Autophagy differentially regulates tissue tolerance of distinct target organs in graft-versus-host disease models.

Tissue-intrinsic mechanisms that regulate severity of systemic pathogenic immune-mediated diseases, such as acute graft-versus-host disease (GVHD), remain poorly understood. Following allogeneic hematopoietic stem cell transplantation, autophagy, a cellular stress protective response, is induced in host nonhematopoietic cells. To systematically address the role of autophagy in various host nonhematopoietic tissues, both specific classical target organs of acute GVHD (intestines, liver, and skin) and organs conventionally not known to be targets of GVHD (kidneys and heart), we generated mice with organ-specific knockout of autophagy related 5 (ATG5) to specifically and exclusively inhibit autophagy in the specific organs. When compared with wild-type recipients, animals that lacked ATG5 in the gastrointestinal tract or liver showed significantly greater tissue injury and mortality, while autophagy deficiency in the skin, kidneys, or heart did not affect mortality. Treatment with the systemic autophagy inducer sirolimus only partially mitigated GVHD mortality in intestine-specific autophagy-deficient hosts. Deficiency of autophagy increased MHC class I on the target intestinal epithelial cells, resulting in greater susceptibility to damage by alloreactive T cells. Thus, autophagy is a critical cell-intrinsic protective response that promotes tissue tolerance and regulates GVHD severity.

Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), for which therapeutic options are limited. Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA sequencing, we identified a lipocalin-2 (LCN2)-expressing neutrophil population in mice with intestinal aGVHD. Transfer of LCN2-overexpressing neutrophils or treatment with recombinant LCN2 reduced aGVHD severity, whereas the lack of epithelial or hematopoietic LCN2 enhanced aGVHD severity and caused microbiome alterations. Mechanistically, LCN2 induced insulin-like growth factor 1 receptor (IGF-1R) signaling in macrophages through the LCN2 receptor SLC22A17, which increased interleukin-10 (IL-10) production and reduced major histocompatibility complex class II (MHCII) expression. Transfer of LCN2-pretreated macrophages reduced aGVHD severity but did not reduce graft-versus-leukemia effects. Furthermore, LCN2 expression correlated with IL-10 expression in intestinal biopsies in multiple cohorts of patients with aGVHD, and LCN2 induced IGF-1R signaling in human macrophages. Collectively, we identified a LCN2-expressing intestinal neutrophil population that reduced aGVHD severity by decreasing MHCII expression and increasing IL-10 production in macrophages. This work provides the foundation for administration of LCN2 as a therapeutic approach for aGVHD.

Desiccation tolerance in the resurrection plant Barbacenia graminifolia involves changes in redox metabolism and carotenoid oxidation.

Desiccation tolerance in vegetative tissues enables resurrection plants to remain quiescent under severe drought and rapidly recover full metabolism once water becomes available. Barbacenia graminifolia is a resurrection plant that occurs at high altitudes, typically growing on rock slits, exposed to high irradiance and limited water availability. We analyzed the levels of reactive oxygen species (ROS) and antioxidants, carotenoids and its cleavage products, and stress-related phytohormones in fully hydrated, dehydrated, and rehydrated leaves of B. graminifolia. This species exhibited a precise adjustment of its antioxidant metabolism to desiccation. Our results indicate that this adjustment is associated with enhanced carotenoid and apocarotenoids, α-tocopherol and compounds of ascorbate-glutathione cycle. While α-carotene and lutein increased in dried-leaves suggesting effective protection of the light-harvesting complexes, the decrease in β-carotene was accompanied of 10.2-fold increase in the content of β-cyclocitral, an apocarotenoid implicated in the regulation of abiotic stresses, compared to hydrated plants. The principal component analysis showed that dehydrated plants at 30 days formed a separate cluster from both hydrated and dehydrated plants for up to 15 days. This regulation might be part of the protective metabolic strategies employed by this resurrection plant to survive water scarcity in its inhospitable habitat.

OP02 IL23R-CAR-Tregs: creating a therapeutic breakthrough for Crohn’s Disease

Abstract Background Regulatory T cells (Tregs) are key immunomodulators to maintain immune homeostasis and self-tolerance, including in the intestine. Disrupted immune homeostasis is associated with Crohn’s Disease (CD) pathogenesis. As a living drug, Treg therapy is a promising treatment for restoring immune balance and achieving durable tissue tolerance in the diseased intestine. By targeting a disease-relevant protein, Interleukin-23 receptor (IL23R), we engineered Tregs expressing IL23R-chimeric antigen receptor (CAR) to create IL23R-CAR-Tregs for treating CD. Methods IL23R protein expression in CD intestine was verified by immunohistochemical analysis. Tonic signaling and CAR-specific activation were quantified during the IL23R-CAR screening. The IL23R-CAR-Treg phenotype was assessed by monitoring the expression of FoxP3 and Helios transcription factors, and the demethylation status of FoxP3 Treg-specific demethylated region (TSDR). The suppressive function of IL23R-CAR-Tregs was evaluated using in vitro assays and a colitis mouse model. The functionality of IL23R-CAR-Tregs were further assessed using intestinal biopsy-derived cells from CD patients in an in vitro activation assay. Transcriptomic and proteomic analyses were performed to associate molecular profiles with IL23R-CAR-Treg activation. Results Our highly potent IL23R-CAR lead candidate displays negligible tonic signalling and a strong signal-to-noise ratio. The resulting IL23R-CAR-Tregs maintain their regulatory phenotype with high FoxP3 and Helios expression and TSDR demethylation during in vitro expansion, CAR-specific stimulation, and in the presence of proinflammatory cytokines. In accordance with their regulatory phenotype, IL23R-CAR-Tregs exhibit CAR-dependent suppressive activity, promote a tolerogenic environment, and protect mice from colitis. The expression of IL23R was also confirmed in the intestinal mucosa from CD patients. Importantly, IL23R-CAR-Tregs elicit activation following exposure to intestinal biopsy-derived cells from CD, demonstrating the engagement and potency of IL23R-CAR towards their target in CD. We also identified molecular profiles that correlated with IL23R-CAR activation and, more broadly, showed their potential to monitor IL23R-CAR-Treg activity in CD patients. Conclusion Our results demonstrate that an IL23R-CAR-Treg product could be a promising therapy for CD patients, with the potential long-term benefits of immune tolerance.

Neural tissue tolerance to synthetic dural mater graft implantation in a rabbit durotomy model.

In neurosurgical interventions, effective closure of the dura mater is essential to prevent cerebrospinal fluid leakage and minimize post-operative complications. Biodegradable synthetic materials have the potential to be used as dura mater grafts owing to their regenerative properties and low immunogenicity. This study evaluated the safety of ArtiFascia, a synthetic dura mater graft composed of poly(l-lactic-co-caprolactone acid) and poly(d-lactic-co-caprolactone acid), in a rabbit durotomy model. Previously, ArtiFascia demonstrated positive local tolerance and biodegradability in a 12-month preclinical trial. Here, specialized stains were used to evaluate potential brain damage associated with ArtiFascia use. Histochemical and immunohistochemical assessments included Luxol Fast Blue, cresyl Violet, Masson's Trichrome, neuronal nuclei,, Glial Fibrillary Acidic Protein, and ionized calcium-binding adaptor molecule 1 stains. The stained slides were graded based on the brain-specific reactions. The results showed no damage to the underlying brain tissue for either the ArtiFascia or control implants. Neither inflammation nor neuronal loss was evident, corroborating the safety of the ArtiFascia. This approach, combined with previous histopathological analyses, strengthens the safety profile of ArtiFascia and sets a benchmark for biodegradable material assessment in dura graft applications. This study aligns with the Food and Drug Administration guidelines and offers a comprehensive evaluation of the potential neural tissue effects of synthetic dura mater grafts.

Neuroprotective effect of hypoxic-hypercapnic training. Review

The neuroprotective effects of hypercapnia, especially with hypoxia combined, interested in the context of nerve cells forming protective mechanisms. Hypercapnia not only acts as a potent neuroprotector but also increases tissue tolerance to ischemia and reperfusion. Hypercapnic effects are based on many different mechanisms including energy metabolism modulation, adaptive signaling pathways activation, histological damage reduction, pro-inflammatory factors, angiogenesis activation, and activation of synthetic processes in neurons. The summarized data indicate prospects for further research to better understand the molecular and physiological aspects of neuroprotection during hypercapnia and hypoxia, as well as to determine the conditions under which the best neuroprotective effect is achieved with a subsequent reduction in neurological deficits. __________________________________________________________________________________________ Keywords: hypercapnia, hypoxia, neuroprotection, permissive hypercapnia, ischemia, stroke

Prevention of lipid droplet accumulation by DGAT1 inhibition ameliorates sepsis-induced liver injury and inflammation

Lipid droplet (LD) accumulation in cells and tissues is understood to be an evolutionarily conserved tissue tolerance mechanism to prevent lipotoxicity caused by excess lipids; however, the presence of excess LDs has been associated with numerous diseases. Sepsis triggers the reprogramming of lipid metabolism and LD accumulation in cells and tissues, including the liver. The functions and consequences of sepsis-triggered liver LD accumulation are not well known. Experimental sepsis was induced by CLP (caecal ligation and puncture) in mice. Markers of hepatic steatosis, liver injury, hepatic oxidative stress, and inflammation were analysed using a combination of functional, imaging, lipidomic, protein expression and immune-enzymatic assays. To prevent LD formation, mice were treated orally with A922500, a pharmacological inhibitor of DGAT1. We identified that liver LD overload correlates with liver injury and sepsis severity. Moreover, the progression of steatosis from 24h to 48h post-CLP occurs in parallel with increased cytokine expression, inflammatory cell recruitment and oxidative stress. Lipidomic analysis of purified LDs demonstrated that sepsis leads LDs to harbour increased amounts of unsaturated fatty acids, mostly 18:1 and 18:2. An increased content of lipoperoxides within LDs was also observed. Conversely, the impairment of LD formation by inhibition of the DGAT1 enzyme reduces levels of hepatic inflammation and lipid peroxidation markers and ameliorates sepsis-induced liver injury. Our results indicate that sepsis triggers lipid metabolism alterations that culminate in increased liver LD accumulation. Increased LDs are associated with disease severity and liver injury. Moreover, inhibition of LD accumulation decreased the production of inflammatory mediators and lipid peroxidation while improving tissue function, suggesting that LDs contribute to the pathogenesis of liver injury triggered by sepsis. Sepsis is a complex life-threatening syndrome caused by dysregulated inflammatory and metabolic host responses to infection. The observation that lipid droplets may contribute to sepsis-associated organ injury by amplifying lipid peroxidation and inflammation provides a rationale for therapeutically targeting lipid droplets and lipid metabolism in sepsis.

Separation of GVL from GVHD -location, location, location.

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for various hematologic malignancies. However, alloimmune response is a double-edged sword that mediates both beneficial graft-versus-leukemia (GVL) effects and harmful graft-versus-host disease (GVHD). Separation of GVL effects from GVHD has been a topic of intense research to improve transplant outcomes, but reliable clinical strategies have not yet been established. Target tissues of acute GVHD are the skin, liver, and intestine, while leukemic stem cells reside in the bone marrow. Tissue specific effector T-cell migration is determined by a combination of inflammatory and chemotactic signals that interact with specific receptors on T cells. Specific inhibition of donor T cell migration to GVHD target tissues while preserving migration to the bone marrow may represent a novel strategy to separate GVL from GVHD. Furthermore, tissue specific GVHD therapy, promoting tissue tolerance, and targeting of the tumor immune microenvironment may also help to separate GVHD and GVL.

Absence of MHC Class I Expression on Target Cells Exacerbates Iron Dependent CD4+ T Cell Mediated Killing

Introduction: Little is known about the target-cell intrinsic features that affect tissue susceptibility to T-cell mediated cell death. The major histocompatibility complex (MHC) Class I presents antigens to CD8+ T cells, while MHC class II presents antigens to CD4+ T cells, and this process is critical for infectious, tumor, auto- and allo -immunity. However, MHC Class I has been suggested to have a non-canonical role iron metabolism, but whether it plays a role in tissue tolerance to CD4+ T cell mediated damage is not known. Herein, we investigated the role of MHC Class I on target cells in CD4+ T-cell mediated damage to intestinal epithelial cells (IECs) utilizing clinically relevant models of T-cell mediated gastrointestinal damage from Graft-versus-Host Disease (GVHD), a major complication of allogeneic stem cell transplantation. Methods: Because MHC class I is expressed on all nucleated cells, to specifically assess the role of MHC Class I on IECs, we generated and utilized intestine-specific MHC Class I knockout mice (B2m∆IEC) as recipients for MHC Class II-disparate bm12–>B2m∆IEC allogeneic stem cell transplant (allo-SCT). We utilized flow cytometry, immunological, molecular and biochemical assays to assess cell death pathways and tissue damage in IECs. We performed mechanistic studies to assess the role of iron and utilized clinically relevant iron chelation treatment to assess survival after treatment. Results: Here, we demonstrate that absence of MHC Class I on target cells exacerbates CD4+ T cell mediated killing of IECs leading to greater mortality in the KO animals than WT recipients (P<0.01) (Fig.1). Compared with wild-type (WT) mice, B2m∆IEC mice, despite an increase in mortality following MHC II disparate allo-SCT, did not demonstrate significant changes in T cell activation, or antigen presentation. In vitro co-culture cell killing assays demonstrate that B2m knockout cells have increased cell death compared with WT cells when co-cultured with activated bm12 CD4+ T cells. Because B2m knockout mice have increased liver iron deposition, we hypothesized that the increase in GI damage might be a consequence of iron related cell death in the IECs in B2m∆IEC mice. We demonstrate that absence of B2m on the intestine is sufficient to drive an increase in tissue iron levels in the liver and intestine. Furthermore, B2m∆IEC allo-recipient mice demonstrated increased intracellular labile iron in IECs. Given the increased mortality in B2m∆IEC allo-recipient mice and the increase in intracellular iron in IECs, we investigated the role of iron-dependent cell death, ferroptosis. We show that IECs from B2m∆IEC allo-recipient mice have increased ferroptosis compared with WT animals (P<0.05). Finally, chelation of iron with administration of clinically utilized iron chelator (Deferasirox) ameliorated excess mortality from GVHD in the B2m∆IEC mice. Conclusion: Absence of MHC Class I expression on target cells exacerbates CD4+ T cell mediated killing by enhancing iron dependent ferroptosis. These data demonstrate that in contrast to immunological paradigm, class I regulates CD4+ T cell mediated cytotoxicity even as it is essential for CD8+ T cell immunity.