Mouse Model Of Injury Research Articles

β2 integrin regulates neutrophil trans endothelial migration following traumatic brain injury

Neutrophils are the first responders among peripheral immune cells to infiltrate the central nervous system following a traumatic brain injury (TBI), triggering neuroinflammation that can exacerbate secondary tissue damage. The precise molecular controls that dictate the inflammatory behavior of neutrophils post-TBI, however, remain largely elusive. Our comprehensive analysis of the molecular landscape surrounding the trauma in TBI mice has revealed a significant alteration in the abundance of β2 integrin (ITGB2), predominantly expressed by neutrophils and closely associated with immune responses. Using the fluid percussion injury (FPI) mouse model, we investigated the therapeutic efficacy of Rovelizumab, an agent that blocks ITGB2. The treatment has demonstrated significant improvements in neurologic function in TBI mice, attenuating blood–brain barrier permeability, mitigating oxidative stress and inflammatory mediator release, and enhancing cerebral perfusion. Moreover, ITGB2 blockade has effectively limited the adherence, migration, and infiltration of neutrophils, and has impeded the formation of neutrophil extracellular traps (NETs) upon their activation. Finally, it was demonstrated that ITGB2 mediates these effects mainly through its interaction with intercellular adhesion molecule-1 (ICAM 1) of endotheliocyte. These findings collectively illuminate ITGB2 as a crucial molecular switch that governs the adverse effects of neutrophils post-TBI and could be targeted to improve clinical outcome in patients.

Sevoflurane alleviates intestinal ischemia-reperfusion injury in aged mice.

Sevoflurane is a widely used inhalation anesthetic during the perioperative period. Recent studies have suggested that sevoflurane has an enteroprotective effect, but its mechanism is unclear. To explore the mechanism of sevoflurane in intestinal ischemia-reperfusion injury, an intestinal ischemia-reperfusion injury mouse model was established. First, intestinal ischemia-reperfusion injury was compared between aged and young mice. The results showed that intestinal ischemia-reperfusion injury caused pathological intestinal injury and disrupted the intestinal mucosal barrier. The aged mice had more severe intestinal ischemia-reperfusion injury than the young mice and therefore had a lower survival rate. The aged mice subsequently received sevoflurane via inhalation. Sevoflurane alleviated the pathological injury to the intestinal mucosa and repaired the function of the intestinal mucosal barrier in aged mice, thus increasing the level of intestinal mucosal hypoxia-inducible factor-1α and improving the survival rate of aged mice. However, preoperative administration of the hypoxia-inducible factor-1α inhibitor BAY87-2243 could counteract the enteroprotective effect of sevoflurane and lower the expression level of heme oxygenase-1, a downstream antioxidant enzyme of hypoxia-inducible factor-1α. Our findings suggest that sevoflurane alleviates intestinal ischemia-reperfusion injury in aged mice by repairing the intestinal mucosal barrier through the activation of hypoxia-inducible factor-1α/heme oxygenase-1, providing a new target for the treatment of intestinal ischemia-reperfusion injury in aged mice.

Synergistic effects of neural stem cells and ibrutinib on neural tissue repair and functional recovery in a contusion mouse model of spinal cord injury.

Modulating the immune response following spinal cord injury (SCI) is vital for establishing a conducive microenvironment that supports the survival and engraftment of transplanted neural stem/progenitor cells (NSPCs). Building on our prior findings of ibrutinib's immunotherapeutic potential in acute SCI, this study investigates the impact of ibrutinib administration on NSPC survival, fate and their potential synergistic effects on tissue repair and motor function in a contusive mouse model of SCI. Green fluorescence expressing NSPCs were transplanted into the lesion site with or without concurrent ibrutinib administration. Over four weeks, comprehensive assessments included behavioral evaluations, lesion volume measurements, and analyses of the survival, fate, and migration patterns of the transplanted cells. The results revealed that ibrutinib and NSPCs individually reduced lesion volume and improved motor functions. However, their combination significantly accelerated and enhanced motor recovery. Furthermore, ibrutinib improved cell viability, increasing markers for oligodendrocyte and neuroblast while concurrently diminishing the expression of astrocyte marker glial fibrillary acidic protein (GFAP). In conclusion, the combined utilization of ibrutinib and NSPC transplantation presents a promising strategy for enhancing tissue repair, promoting functional recovery, and positively modulating cell behaviors in the context of SCI.

Discovery and optimization of 1,2,4-triazole derivatives as novel ferroptosis inhibitors.

Ferroptosis is a novel form of regulated cell death characterized by iron-dependent lipid ROS accumulation, which is associated with various diseases, including acute organ injury, neurodegenerative disorders, and cancer. Pharmacological inhibition of ferroptosis has great potential for the treatment of these diseases. However, the clinical translation of many ferroptosis inhibitors is hindered by their inadequate activity or suboptimal pharmacokinetic profiles. In this study, several 1,2,4-triazole derivatives were identified as novel ferroptosis inhibitors through phenotypic screening of our in-house compound library. Among these compounds, NY-26 was found to significantly inhibit RSL3-induced ferroptosis in 786-O cells with nanomolar level (EC50=62nM). The antiferroptotic activity of NY-26 was further validated across multiple cell lines. Mechanistic studies revealed that NY-26 inhibits ferroptosis through its intrinsic free radical-trapping antioxidant capacity. Additional results demonstrated that the triazole derivatives could effectively ameliorate ferroptosis-related pathological conditions in a mouse model of ConA-induced acute liver injury. Taken together, NY-26, tethering a novel 1,2,4-triazole scaffold, could be an effective ferroptosis inhibitor with great therapeutic potential for further investigation.

Engineered S. cerevisiae-pYD1-ScFv-AFB1 mitigates aflatoxin B1 toxicity via bio-binding and intestinal microenvironment repair.

The highly toxic aflatoxin B1 (AFB1) is considered one of the primary risk factors for hepatocellular carcinoma, while effective measures after AFB1 exposure remain to be optimized. This study utilized cell-surface-display technique to construct an engineered S. cerevisiae-pYD1-ScFv-AFB1 (S.C-AF) that specifically binds AFB1, and verified the potential mechanism of S.C-AF in vivo through AFB1-induced (gastric perfused with 0.3mg/kg/d AFB1 per day) liver injury mouse model. In this experiment, the C57BL/6 mouse model of AFB1-induced liver injury was treated with S.C (gastric perfused with 1×109CFU/mL S.C per day) and S.C-AF (gastric perfused with 1×109CFU/mL S.C-AF per day) for 4 weeks, respectively. With probiotic properties optimized, S.C.-AF achieved an in vitro AFB1 binding capacity 1.7 times higher than S. cerevisiae. Furthermore, S.C-AF could alleviate AFB1-induced liver injury by reducing proinflammatory cytokine secretion and apoptotic protein expression, enhancing antioxidative capacity via Nrf2 activation, and simultaneously reversing intestinal tight junction protein deficiency, increasing intestinal barrier permeability, and improving intestinal dysbiosis caused by AFB1 exposure. S.C-AF alleviates AFB1-induced liver lesions, which might be a novel intervention to mitigate aflatoxin toxicity.

Cucurbitacin IIb mitigates concanavalin A-induced acute liver injury by suppressing M1 macrophage polarization.

Cucurbitacins are a class of triterpenoid compounds extracted from plants and possess various pharmacological applications. Cucurbitacin IIb (CuIIb), extracted from the medicinal plant Hemsleya amabilis (Cucurbitaceae), has served as a traditional Chinese medicine for the treatment of bacterial dysentery and intestinal inflammation. CuIIb has been shown to exhibit anti-inflammatory activity; however, the protective effect of CuIIb against concanavalin A (Con A)-induced acute liver injury (ALI) and the fundamental mechanism remain unelucidated. In this study, we established an acute liver injury mouse model using Con A to investigate the effects of CuIIb on ALI. The results revealed that CuIIb significantly reduced serum aminotransferase levels and increased the survival rate of mice. Additionally, CuIIb effectively attenuated hepatocyte apoptosis, hepatic histopathological damage, and oxidative stress. Notably, CuIIb inhibited the polarization of M1 macrophages in vivo and in vitro. Moreover, the expression levels of pro-inflammatory cytokines related to M1 macrophages, such as interleukin (IL)-12, IL-1β, IL-6 and tumor necrosis factor-α (TNF-α), were reduced. CuIIb regulated M1 macrophage activation by modulating the nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways. Conclusively, these results demonstrated that CuIIb significantly prevented Con A-induced ALI by suppressing M1 macrophage polarization via the MAPK and NF-κB signaling pathways, demonstrating the potential use of CuIIb for ALI treatment.

Transcriptome-Wide Analysis of N6-Methyladenosine-Modified Long Noncoding RNAs in Particulate Matter-Induced Lung Injury

Background: N6-methyladenosine (m6A) modification plays a crucial role in the regulation of diverse cellular processes influenced by environmental factors. Nevertheless, the involvement of m6A-modified long noncoding RNAs (lncRNAs) in the pathogenesis of lung injury induced by particulate matter (PM) remains largely unexplored. Methods: Here, we establish a mouse model of PM-induced lung injury. We utilized m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq) to identify differentially expressed m6A peaks on long non-coding RNAs (lncRNAs). Concurrently, we performed lncRNA sequencing (lncRNA-seq) to determine the differentially expressed lncRNAs. The candidate m6A-modified lncRNAs in the lung tissues of mice were identified through the intersection of the data obtained from these two sequencing approaches. Results: A total of 664 hypermethylated m6A peaks on 644 lncRNAs and 367 hypomethylated m6A peaks on 358 lncRNAs are confirmed. We use bioinformatic tools to analyze the potential functions and pathways of these m6A-modified lncRNAs, revealing their involvement in regulating inflammation, immune response, and metabolism-related pathways. Three key m6A-modified lncRNAs (lncRNA NR_003508, lncRNA uc008scb.1, and lncRNA ENSMUST00000159072) are identified through a joint analysis of the MeRIP-seq and lncRNA-seq data, and their validation is carried out using MeRIP-PCR and qRT-PCR. Analysis of the coding-non-coding gene co-expression network reveals that m6A-modified lncRNAs NR_003508 and uc008scb.1 participate in regulating pathways associated with inflammation and immune response. Conclusions: This study first provides a comprehensive transcriptome-wide analysis of m6A methylation profiling in lncRNAs associated with PM-induced lung injury and identifies three pivotal candidate m6A-modified lncRNAs. These findings shed light on a novel regulatory mechanism underlying PM-induced lung injury.

Angiotensin-Converting Enzyme 2 Enhances Autophagy via the Consumption of miR-326 in a Mouse Model of Acute Lung Injury.

Angiotensin-converting enzyme 2 (ACE2) has been reported to exert a protective effect in acute lung injury (ALI), though its underlying mechanism remains incompletely understood. In this study, ACE2 expression was found to be upregulated in a mouse model of ALI induced by lipopolysaccharide (LPS) injection. ACE2 knockdown modulated the severity of ALI, the extent of autophagy, and the mTOR pathway in this model. ACE2 regulated liver kinase B1 (LKB1) gene expression by sequestering miR-326, thereby alleviating ALI severity through enhanced autophagy. In cell-based experiments, miR-326 was shown to regulate ACE2 and LKB1 expression and autophagy. Overexpression of ACE2 disrupted miR-326's regulatory effect on LKB1, suggesting that LKB1 may function as an endogenous sponge for miR-326. These findings imply that elevated ACE2 expression in lung could play enhance the autophagy via the consumption of miR-326.

Profiling and bioinformatics analyses of circular RNAs in myocardial ischemia/reperfusion injury model in mice.

Myocardial ischemia/reperfusion (I/R) injury, which is associated with high morbidity and mortality, is a main cause of unexpected myocardial injury after acute myocardial infarction. However, the underlying mechanism remains unclear. Circular RNAs (circRNAs), which are formed from protein-coding genes, can sequester microRNAs or proteins, modulate transcription and interfere with splicing. Authoritative studies suggest that circRNAs may play an important role in myocardial I/R injury. To explore the role and mechanism of circRNAs in myocardial I/R injury. We constructed a myocardial I/R injury model using ligation of the left anterior descending coronary artery, and evaluated the success of the validated model using triphenyltetrazolium chloride and hematoxylin-eosin staining. Then, left ventricular samples from different groups were selected for mRNA-sequence, and differential gene screening was performed on the obtained results. The differentially obtained mRNAs were divided into up-regulated and down-regulated according to their expression levels, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis were performed, respectively. Then, the obtained circRNA and microRNA (miRNA) were paired for analysis, and the binding sites of miRNA and mRNA were virtual screened. Finally, the obtained circRNA, miRNA and mRNA were constructed by ceRNA mutual most useful network. We used an RNA sequencing array to investigate the expression signatures of circRNAs in myocardial I/R injury using three samples from the I/R group and three samples from the sham group. A total of 142 upregulated and 121 downregulated circRNAs were found to be differentially expressed (fold change ≥ 2, P < 0.05). GO and KEGG functional analyses of these circRNAs were performed. GO analysis revealed that these circRNAs were involved mainly in cellular and intracellular processes. KEGG analysis demonstrated that 6 of the top 20 pathways were correlated with cell apoptosis. Furthermore, a circRNA-miRNA coexpression network and ceRNA network based on these genes were constructed, revealing that mmu-circ-0001452, mmu-circ-0001637, and mmu-circ-0000870 might be key regulators of myocardial I/R injury. This research provides new insights into the mechanism of myocardial I/R, which mmu-circ-0001452, mmu-circ-0001637, and mmu-circ-0000870 are expected to be new therapeutic targets for myocardial I/R injury.

Extracellular calreticulin regulates fibrogenic and immunogenic properties of hepatic stellate cells.

Liver fibrosis is a persistent damage repair response triggered by various etiological factors, resulting in an excessive accumulation of extracellular matrix (ECM). Activated hepatic stellate cells (HpSCs) are the primary source of ECM proteins. Therefore, specifically targeting HpSCs has become a crucial approach for treating liver fibrosis. Calreticulin (CRT) is a molecular chaperone mainly located in the endoplasmic reticulum (ER), regulating protein folding and calcium homeostasis. Recently, CRT has gained much attention for its role outside the ER, particularly at the cell surface and extracellular space, acting as an immunomodulatory protein. The current study investigates the role of extracellular CRT in hepatic injury and its effects on HpSCs. Elevated levels of circulating CRT were observed in mouse models of liver injury, suggesting that hepatic injury may trigger CRT release. Extracellular CRT was found to moderately inhibit HpSC viability and induce morphological changes. Additionally, CRT treatment led to a decrease in α-smooth muscle actin and an upregulation of matrix metalloproteinase-2 and -9, indicating a potential fibrolytic effect. Immunomodulatory activities of CRT were also noted, as it increased cytokine expression in both macrophages and HpSCs. These effects were partially mediated through low-density lipoprotein receptor-related protein 1 (LRP1), as evidenced by altered cytokine expression upon co-treatment with a known LRP1 ligand receptor-associated protein (RAP). Overall, this study elucidates the complex role of extracellular CRT in liver injury and its potential impact on HpSC behavior and immune responses.

ROS-differentiated release of Apelin-13 from hydrogel comprehensively treats myocardial ischemia-reperfusion injury.

Treatment of myocardial ischemia-reperfusion (MI/R) injury still faces the lack of clinically approved drugs. Apelin-13 is a highly promising drug candidate of MI/R injury, but hampered by its extremely short half-life in plasma. This calls for efficient and smart delivering system for Apelin-13 delivery, but has not been reported. Herein, a reactive oxygen species (ROS)-responsive hydrogelator YFF-TK-FFY is designed, which co-assembles with Apelin-13 to form the peptide hydrogel Apelin-13@Gel TK. This hydrogel responds to ROS at varying levels in the surrounding environment of MI/R and releases Apelin-13 at different rates. In an MI/R injury mouse model, Apelin-13@Gel TK rapidly releases Apelin-13 in response to the high ROS in the core area of MI/R injury, efficiently reducing cardiomyocyte apoptosis within three days. In the ROS-low border zone, Apelin-13@Gel TK provides a slow and sustained release of Apelin-13, promoting angiogenesis and lymphatic remodeling, and facilitating the resolution of inflammation in the later repair stage after MI/R injury. By offering a spatiotemporally controlled drug release in response to ROS gradients in the MI/R microenvironment, this smart hydrogel presents a promising therapeutic strategy for effective treatment of MI/R injury.

N-acetyl-tryptophan in Acute Kidney Injury after Cardiac Surgery.

Cardiac surgery-associated acute kidney injury is a common serious complication after cardiac surgery. Currently, there are no specific pharmacological therapies. Our understanding of its pathophysiology remains preliminary. A total of 2504 patients with and without acute kidney injury (AKI) following cardiac surgery were enrolled. High-performance liquid chromatography coupled with mass spectrometry was used for untargeted analysis of metabolites in plasma, identifying significant differential metabolites. Subsequently, a tandem liquid chromatography-mass spectrometry-based approach using isotope-labeled standard addition was performed for targeted analysis of the metabolic marker N-acetyl-tryptophan. The function of N-acetyl-tryptophan was determined using different kidney injury mouse models and epithelial cellular models. Transcriptome sequencing, surface plasmon resonance and protein mutation were employed to explore the mechanism of N-acetyl-tryptophan on the kidney. We identified a total of 32 differential metabolites related to AKI occurrence based on a cohort of 1042 patients. Among them, N-acetyl-tryptophan was elevated in plasma of patients with cardiac surgery-associated acute kidney injury compared with those who do not develop AKI after cardiac surgery. The higher level of N-acetyl-tryptophan in plasma was confirmed by accurate targeted quantification. N-acetyl-tryptophan exhibited kidney protective effects in ischemia/reperfusion-, cisplatin-, and unilateral ureteral obstruction-induced kidney injury mouse models. Mechanistically, N-acetyl-tryptophan exerted kidney protective effects by interacting with KEAP1 at 483 and 508 sites, resulting in Nrf2 nuclear translocation and the transcription of proteasome genes. N-acetyl-tryptophan plays a key role in kidney protection.

Cryopreserved human alternatively activated macrophages promote resolution of acetaminophen-induced liver injury in mouse

Acute liver failure is a rapidly progressing, life-threatening condition most commonly caused by an overdose of acetaminophen (paracetamol). The antidote, N-acetylcysteine (NAC), has limited efficacy when liver injury is established. If acute liver damage is severe, liver failure can rapidly develop with associated high mortality rates. We have previously demonstrated that alternatively, activated macrophages are a potential therapeutic option to reverse acute liver injury in pre-clinical models. In this paper, we present data using cryopreserved human alternatively activated macrophages (hAAMs)—which represent a potential, rapidly available treatment suitable for use in the acute setting. In a mouse model of APAP-induced injury, peripherally injected cryopreserved hAAMs reduced liver necrosis, modulated inflammatory responses, and enhanced liver regeneration. hAAMs were effective even when administered after the therapeutic window for NAC. This cell therapy approach represents a potential treatment for APAP overdose when NAC is ineffective because liver injury is established.

NaHS modulates astrocytic EAAT2 expression to impact SNI-induced neuropathic pain and depressive-like behaviors

The potential role of hydrogen sulfide (H2S) in the modulation of neuropathic pain is increasingly recognized. This study investigated the therapeutic effect of intraperitoneal injection of the H2S donor sodium hydrosulfide (NaHS) on neuropathic pain. Utilizing the spared nerve injury (SNI) model in mice, the research investigates the role of astrocytes and the excitatory neurotransmitter glutamate in chronic pain. The findings reveal that sodium hydrosulfide (NaHS), an H2S donor, effectively enhances the mechanical pain threshold and thermal pain escape latency in SNI mice. The study further demonstrates NaHS’s potential in reducing glutamate levels in the spinal cord and the discharge frequency of neurons in the primary somatosensory cortex hindlimb region (S1HL) brain area, suggesting a novel therapeutic approach for neuropathic pain through the modulation of astrocyte function and EAAT2 expression.

Extracellular vesicle-mediated VEGF-A mRNA delivery rescues ischaemic injury with low immunogenicity.

Lackluster results from recently completed gene therapy clinical trials of VEGF-A delivered by viral vectors have heightened the need to develop alternative delivery strategies. This study aims to demonstrate the pre-clinical efficacy and safety of extracellular vesicles (EVs) loaded with VEGF-A mRNA for the treatment of ischaemic vascular disease. After encapsulation of full-length VEGF-A mRNA into fibroblast-derived EVs via cellular nanoporation (CNP), collected VEGF-A EVs were delivered into mouse models of ischaemic injury. Target tissue delivery was verified by in situ analysis of protein and gene expression. Functional rescue was confirmed by in vivo imaging and histology. The safety of single and serial delivery was demonstrated using immune-based assays. VEGF-A EVs were generated with high mRNA content using a CNP methodology. VEGF-A EV administration demonstrated expression of exogenous VEGF-A mRNA by in situ RNA hybridization and elevated protein expression by western blot, microscopy, and enzyme-linked immunosorbent assay. Mice treated with human VEGF-A EVs after femoral or coronary artery ligation exhibited heightened neovascularization in ischaemic tissues with increased arterial perfusion and improvement in left ventricular function, respectively. Serial delivery of VEGF-EVs in injured skin showed improved wound healing with repeat administration. Importantly, as compared with adeno-associated viral and lipid nanoparticle VEGF-A gene therapy modalities, murine VEGF-A EV delivery did not trigger innate or adaptive immune responses at the injection site or systemically. This study demonstrated that VEGF-A EV therapy offers efficient, dose-dependent VEGF-A protein formation with low immunogenicity, resulting in new vessel formation in murine models of ischaemic vascular disease.

Interleukin-6 is significantly increased in severe pneumonia after allo-HSCT and might induce lung injury via IL-6/sIL-6R/JAK1/STAT3 pathway.

Severe pneumonia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with high mortality. Given that cytokine, including Interleukin-6 (IL-6), play a critical role in immune-mediated organ injury in patients with severe COVID-19, we hypothesized that cytokines may also contribute to the pathogenesis of severe pneumonia after allo-HSCT. This study aimed to investigate the role of IL-6 in severe pneumonia post-allo-HSCT and explore its underlying mechanism. Serum cytokine levels were prospectively measured in patients with severe and non-severe pneumonia following allo-HSCT. A mouse model of acute lung injury (ALI) and in vitro experiment using primary murine pulmonary microvascular endothelial cells (PMVECs) were conducted to assess the effects of IL-6 blockade, the mechanism of IL-6 in ALI, and immune-induced ALI. Serum IL-6 and sIL-6R levels were higher in the severe pneumonia group than in the non-severe group and were associated with disease progression. In a mouse model, preventive IL-6 blockade reduced ALI and improved survival. In vitro, the IL-6 trans-signaling complex caused more severe damage to mouse PMVECs than the classical signaling pathway. Soluble glycoprotein 130 and ruxolitinib effectively blocked the JAK1/STAT3 pathway activated by IL-6 trans-signaling in mouse PMVECs and reduced downstream inflammatory responses. IL-6 levels were elevated in patients with severe pneumonia after allo-HSCT and were linked to disease progression. This injury may be driven by the IL-6/sIL-6R/JAK1/STAT3 pathway. This preliminary study suggests that targeting the IL-6 trans-signaling pathway may be a promising therapeutic approach for severe pneumonia/ALI following allo-HSCT.

Silencing of lncRNA Gm26917 Attenuates Alveolar Macrophage-mediated Inflammatory Response in LPS-induced Acute Lung Injury Via Inhibiting NKRF Ubiquitination.

The inflammatory response mediated by alveolar macrophages plays a crucial role in the development of acute lung injury. Numerous studies have reported that lncRNAs are highly expressed in acute lung injury in mouse models and cell lines, and acute lung injury (ALI) can be effectively alleviated by targeting these lncRNAs. The aim of this study was to explore the mechanism by LncRNA Gm26917 regulates the inflammatory response in alveolar macrophages during acute lung injury mouse model. We initially observed a significant upregulation of Gm26917 expression in both ALI conditions and in MH-S cells treated with LPS. Furthermore, the silencing of Gm26917 via lentivirus-mediated methods conferred protection against LPS-induced ALI. Additionally, siRNA-mediated knockdown of Gm26917 attenuated LPS-induced inflammatory responses and modulated the function of alveolar macrophages. Subsequent mechanistic studies revealed that Gm26917 interacts with NKRF, and its knockdown suppressed NKRF ubiquitination, thereby enhancing NKRF binding to p50 and subsequently inhibiting the NF-κB signaling pathway. In conclusion, our findings demonstrate that silencing Gm26917 can mitigate LPS-induced ALI by modulating the NF-κB signaling pathway in alveolar macrophages through interactions with NKRF.

Weekly administration of betulinic acid prevents development of chronic renal failure from acute renal failure in folic acid-induced mouse model of kidney injury.

Betulinic acid (BA) has been shown to exhibit various pharmacological activities and it has shown the protective effect on acute renal failure (ARF) and chronic renal failure (CRF); however, no reports are available on its effect on ARF-CRF transition. Therefore, we aimed to investigate the effects of BA on ARF-CRF transition. A single dose of250 mg/kg body weight (BW) intraperitoneal injection of folic acid was given in mice for inducing ARF-CRF transition (injury group; I) on day 1. Further, excess of these mice received BA at 30 mg/kg BW dose for 3 days (on days 1, 2, 3) in one group (IT3) and for 7 days (on days 1, 2, 3, 7, 14, 21, 28) in another group (IT7). All mice were sacrificed on day 28. Mice in injury group (I) showed elevated serum creatinine along with oxidative stress markers like urine nitrite, tissue lipid peroxidation, nitrotyrosine and fibrotic markers such as tissue α-smooth muscle actin and matrix metalloproteinase-2 activity. They had attenuated levels of urine creatinine and tissue reparative cytokines viz. interleukin-4 and interleukin-13. Excess of fibroblasts and extracellular matrix in the interstitia and periglomerular area in microscopy further support these findings. Seven days of BA treatment regimen (IT7) significantly improved serum and urine parameters accompanied by reduced oxidative stress, improved reparative cytokines and lesser maladaptive matrix deposition. The above findings reveal that weekly BA treatment regimen has potential to prevent development of CRF after ARF.

Hydrogen Sulfide Promotes Functional Endometrium Recovery via Regulating Pyroptosis in Severe Endometrial Injury: A Prospective Laboratory Based Randomized Control Trial

Background: Severe endometrial injury constitutes a significant risk to female fertility, often leading to the development of intrauterine adhesions. Pyroptosis, a form of programmed cell death associated with inflammation, is initiated by the cleavage of gasdermin family proteins by caspase, which has been implicated in endometrial injury. In recent years, hydrogen sulfide (H2S), a gaseous signaling molecule, exerts significant regulatory effects on pyroptosis in diverse pathological processes. The aim of this study is to elucidate the role of H2S in facilitating functional recovery of the endometrium following injury in a murine model. Methods: A prospective laboratory based randomized control trial was performed to evaluate the protective role of H2S in endometrial injury. Ethanol-induced endometrial injury mouse models were established and H2S donor sodium hydrosulfide (NaHS) was randomly administered to the injured mice. Western blot analysis was conducted to assess changes in the expression of endogenous H2S metabolism and pyroptosis-related markers and histological analysis (Hematoxylin &amp; Eosin and Masson staining) was employed to examine alterations in endometrial morphology. Finally, a fertility test was performed to evaluate the restoration of the uterine function. Results: Following endometrial injury, the expression of key endogenous H2S enzymes-cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MST)-is significantly reduced, while the levels of pyroptosis-related proteins are elevated (p &lt; 0.05). However, treatment with H2S resulted in an increase in the expression of endogenous H2S enzymes and a decrease in pyroptosis-associated proteins compared to the Model group (p &lt; 0.05). Moreover, endometrial morphology and embryo count showed the most pronounced improvement in the H2S treatment group (p &lt; 0.05). Conclusions: This study confirms the therapeutic efficacy of H2S in facilitating the recovery of injured endometrium and revealed its potential therapeutic mechanism, offering a promising therapeutic avenue for patients with severe endometrial injury.

Protective Effects of Schizochytrium Microalgal Fatty Acids on Alcoholic Liver Disease: A Network Pharmacology and In Vivo Study.

This study aimed to elucidate the hepatoprotective mechanisms of microalgal fatty acids (MFA) from Schizochytrium against alcoholic liver disease (ALD) through network pharmacology and invivo analysis. Network pharmacology and molecular docking methodologies were employed to predict the potential mechanisms of MFA against ALD. To substantiate these predictions, an acute alcoholic liver injury mouse model was utilized to assess the impact of MFA on serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), total protein (TP), and albumin (ALB). Additionally, liver histopathology and the expression levels of phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT) protein were evaluated. Seven active ingredients and 53 potential targets (including 7 core targets) for ALD treatment were identified in MFA. Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that these seven core targets are implicated in various biological pathways, notably those associated with cancer, viral infections, and the PI3K/AKT signaling pathway. Furthermore, molecular docking studies demonstrated that docosahexaenoic acid and docosapentaenoic acid in MFA exhibited strong binding affinity for these seven crucial targets. Animal experiments demonstrated that administration of MFA significantly decreased the levels of AST, ALT, and ALP, while increasing the levels of ALB and TP in mice with acute alcoholic liver injury. Moreover, MFA ameliorated liver tissue pathology and markedly down-regulated the expression of PI3K and AKT proteins in the liver. These results suggest that MFA may possess therapeutic potential for ALD by targeting multiple pathways, with its mechanisms likely involving the inhibition of the PI3K/AKT signaling pathway.