Animal Models Of Injury Research Articles

Comparative Effects of Monascin and Monascinol Produced by Monascus pilosus SWM-008 on Pro-Inflammatory Factors and Histopathological Alterations in Liver and Kidney Tissues in a Streptozotocin–Nicotinamide-Induced Rat Model

Monascinol (Msol), an analog of monascin (MS) produced by Monascus pilosus, possesses potential anti-inflammatory properties. This study compares the effects of M. pilosus SWM-008 fermented red mold rice, which contains the functional components MS and Msol, on liver and kidney damage related to diabetic complications in rats. An animal model of liver and kidney injury was induced by an intraperitoneal injection of streptozotocin (STZ) at 65 mg/kg body weight combined with nicotinamide (NA) at 150 mg/kg body weight. Our findings indicate that Msol significantly reduces STZ-NA induced pro-inflammatory markers, including interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) in both liver and kidney tissues. Significant improvements were noted in the histopathological assessments. Msol was more effective than MS in suppressing renal IL-1β and COX-2 expressions. In summary, the findings indicate that Msol shows potential as a novel therapeutic agent for treating liver and kidney injuries associated with diabetic complications.

Trefoil factor protein 3 (TFF3) as a guardian of the urinary bladder epithelium.

Trefoil factor family (TFF) peptides have been examined primarily in the gastrointestinal tract, where they play an important role in the epithelial regeneration. The therapeutic effects of TFFs, particularly the TFF3 protein, have been well studied in humans and in animal models of gastrointestinal injury, whereas little is known about their occurrence and function in the urinary bladder. In this study, we investigated the presence, location, and function of Tff3 in the urinary bladders of wild-type mice (Tff3WT) and compared them with Tff3 knockout mice (Tff3KO) using molecular and microscopic methods at the light and electron microscopic level. Our results show that Tff3 is expressed in the superficial cells of the urothelium, where it colocalizes with the uroplakin UP1b as one of the fundamental structural components of the apical plasma membrane, which is an important component of the blood-urine permeability barrier. Analysis of the urothelium with experimentally induced injury revealed that injury is more severe in Tff3KO mice and urothelial regeneration is attenuated compared with Tff3WT mice, suggesting that Tff3 plays a fine-tuned role in homeostasis and protection of the urothelium. This study provides the first data on the precise location and function of Tff3 in the bladder epithelium.

Therapeutic potential of melatonin-pretreated human dental pulp stem cells (hDPSCs) in an animal model of spinal cord injury

Dental pulp stem cells (DPSCs) show potential for treating neurodegenerative and traumatic diseases due to their neural crest origin. Melatonin (MT), an endogenous neurohormone with well-documented anti-inflammatory and antioxidant properties, has shown promising results with MSCs in terms of engraftment, proliferation, and neuronal differentiation in animal SCI models. However, the effects of melatonin preconditioning on human dental pulp stem cells (hDPSCs) for SCI treatment remain unclear. This study investigates the impact of melatonin preconditioning on hDPSCs engraftment, neural differentiation, and neurological function in rats with SCI. Forty-two male Sprague–Dawley rats were divided into six groups: Control, Sham, Model, Vehicle, Lesion Treatment A (SCI + hDPSCs), and Lesion Treatment B (SCI + MT-hDPSCs). After obtaining hDPSCs, stem cells were evaluated using flow cytometry. Cell viability was assessed using the MTT assay. SCI was induced in the Model, Vehicle, Lesion Treatment A, and Lesion Treatment B groups. The Lesion Treatment A and B groups received hDPSCs and hDPSCs pretreated with melatonin, respectively, 1 week after SCI, while the Vehicle group received only an intravenous injection of DMEM to simulate treatment. The other groups were used for behavioral testing. Immunohistochemistry (IHC) was employed to assess hDPSCs engraftment and differentiation at the SCI site. Motor function across the six groups was evaluated using the Basso, Beattie, and Bresnahan (BBB) score. Histological studies and cell counts confirmed hDPSCs implantation at the injury site, with a significantly higher presence in the MT-hDPSCs compared to hDPSCs (p < 0.01). IHC revealed that hDPSCs and MT-hDPSCs differentiated into neurons and astrocytes, with greater differentiation observed in the MT-hDPSCs compared to the hDPSCs (p < 0.01 and p < 0.05, respectively). Functional improvement was noted in both SCI + hDPSCs and SCI + MT-hDPSCs groups compared to SCI and Vehicle groups from Week 4 onward (p < 0.001). Significant differences were also observed between the SCI + hDPSCs and SCI + MT-hDPSCs groups starting from Week 7 (p < 0.01). Preconditioning hDPSCs with melatonin enhances engraftment, neuronal differentiation, and greater performance improvement compared to hDPSCs alone in the SCI animal model.

Improved intracochlear biopolymeric drug delivery system: an in vivo study

Background The delivery of drugs into the inner ear is a challenging field of study due to the complex cochlear anatomy and physiology. The creation of an intracochlear device that allows for short- and long-term intracochlear delivery of the drugs with a minimal invasive technology is needed to prevent or treat conditions that can potentially prevent the development of permanent hearing loss. Aim This study intends to test the efficacy of DXM-infused PLGA microneedles created in our laboratory in an in vivo animal model of acute ototoxic injury. Material and Methods Twenty-four male Norway Brown rats were randomized into four groups, three of which groups received an intratympanic injection of ethacrynic acid and kanamycin. Two of these groups underwent the placement of an intracochlear microneedle blended or not with dexamethasone, and two groups underwent implantation of a plain microneedle, one of without prior exposure to the ototoxic agent to confirm in vivo biocompatibility. Animals were then followed with a weekly auditory brainstem response testing until day 28 after surgical intervention. Result and Conclusion Our intracochlear device demonstrated biocompatibility and produced no hearing changes after its implantation in the control group. Inserted DXM-blended microneedles prevented hearing deterioration in those animals exposed to an ototoxic environment.

The Protective Effects of Mito-TEMPO on Acetaminophen-induced Hepatotoxicity: A Systematic Review

Background: Acetaminophen overdose is a leading cause of acute liver failure glob-ally. Current treatment options, primarily N-acetylcysteine (NAC), have limitations. Mito-TEMPO (Mito-T), a mitochondria-targeted antioxidant, has shown potential in preclinical stud-ies. This systematic review evaluated the evidence for Mito-T's hepatoprotective effects against acetaminophen-induced liver injury. Methods: We conducted a comprehensive search of databases and grey literature following PRISMA guidelines. Studies published between 2000 and 2023 on Mito-T and acetaminophen-induced hepatotoxicity in animal models were included. Data on study characteristics, inter-ventions, outcomes, and risk of bias were extracted. Results: Six high-quality studies were included. Mito-T administration significantly reduced serum alanine transaminase (ALT) levels, a marker of liver injury, compared to controls. Mito-T also protects against hepatocellular necrosis, apoptosis, and mitochondrial dysfunction. These effects were likely mediated by Mito-T's ability to scavenge reactive oxygen and nitrogen spe-cies within mitochondria. Conclusion: This review provides strong evidence that Mito-T effectively protects against ac-etaminophen-induced liver injury in animal models. Mito-T’s mechanisms of action address a critical pathophysiological pathway in acetaminophen toxicity. While limitations, including the use of animal models and potential for publication bias, exist, the findings suggest Mito-T holds promise as a novel therapeutic option. Further studies are needed to assess Mito-T's safety, pharmacokinetics, and optimal dosing in humans. Clinical trials comparing Mito-T against NAC are warranted if toxicity profiles are favorable. Additionally, investigating Mito-T's po-tential in other diseases involving oxidative stress is crucial.

P53/HIF-1α regulates neuronal aging and autophagy in spinal cord ischemia/reperfusion injury

ObjectionSpinal cord injury (SCI)-induced hindlimb dysfunction affects the physical and mental health of patients. There is growing evidence suggesting that the recovery capacity of elderly SCI patients is poorer than that of young individuals. However, the specific molecular mechanisms remain unclear. MethodsRNA expression profiles of SCI samples were collected from the GEO database, and key genes involved in the progression of SCI were identified by the limma package in R software. A diagnostic model based on SCIDEG was constructed using LASSO regression analysis. Subsequently, correlation analysis was conducted to identify biological pathways influenced by the key genes. Furthermore, SCI animal models were established in different age groups to examine the expression of relevant genes and verify the molecular mechanism of p53/HIF-1α axis. ResultsWe initially identified 34 ischemia-hypoxia-related genes potentially involved in the progression of SCI. Subsequently, we constructed a diagnostic model based on SCIDEGs using LASSO regression analysis. This model highlighted 9 key genes (TP53, SFTPA1, MASP2, KRT14, IL9, HIF1A, HGFAC, FUT7, and ALPP), which demonstrated high diagnostic accuracy in both the training set (AUC=1) and the validation set (AUC=0.855). Further cross-analysis with ischemia-reperfusion-related datasets confirmed the involvement of HIF1A and TP53. We also observed significant enrichment of HIF1A in organoids composed of mature neurons, which induced neuronal damage. In subsequent spinal cord injury animal models of different age groups, we found that HIF-1α expression was downregulated in the spinal cord tissues of elderly animals. Additionally, we discovered that TP53 activation induces cellular senescence in aging neurons and suppresses HIF-1α expression and autophagy levels within these cells. ConclusionIn summary, our study suggests that the p53/HIF-1α signaling pathway plays a critical role in regulating neuronal aging and autophagy in the pathogenesis of SCI. Importantly, HIF-1α may represent a promising therapeutic target for SCI treatment.

P292 Human umbilical cord mesenchymal stem cells-derived extracellular vesicles as a therapeutic approach to ameliorate bladder injury in animal models of radiation cystitis

P292 Human umbilical cord mesenchymal stem cells-derived extracellular vesicles as a therapeutic approach to ameliorate bladder injury in animal models of radiation cystitis

Rapidly in situ forming antibiotic-free injectable hydrogel wound dressing for eradicating drug-resistant bacterial infections in human skin organoids

The rising prevalence of global antibiotic resistance evokes the urgent requirement to explore the alternative antimicrobial candidates. It is of great significance to overcome these serious threats of multidrug-resistant bacterial infections and difficult-to-heal cutaneous wounds to human health. Herein, we proposed a rapidly in situ forming innovative antibiotic-free hydrogel dressing with excellent biocompatibility, easy injectability, strong tissue adhesion and superior antibacterial activity against drug-resistant bacteria. An octa-armed poly(ethylene glycol) amine (Octa-PEG-NH2) was quickly crosslinked with a green industrial microbicide tetrakis (hydroxymethyl) phosphonium chloride (THPC) to form an antibacterial hydrogel (OPTH) by simple mixing without any other initiators or crosslinkers. A significant broad-spectrum antibacterial efficacy was demonstrated against Gram-positive Staphylococcus aureus (S. aureus), Gram-negative Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA). Significantly, benefiting from its flexible injectability and reliable tissue adhesion, the excellent antibacterial performances were further evidenced by employing human-induced pluripotent stem cell (iPSC)-derived skin organoids in a 3D culture system and rat animal wound models in vivo with MRSA infection, thus allowing for reepithelization promotion and wound healing. Collectively, the findings not only propose a facile gelatinization strategy for readily accessible antibiotic-free hydrogel dressings for effective MRSA therapy but also hold great clinical translation potential in obliterating multi-pathogenic bacteria and accelerating wound healing.

A novel Non-rodent animal model of hydrochloric acid-induced acute and chronic lung injury

Hydrochloric acid is one of the most prevalent and hazardous chemicals. Accidental spills occur in industrial plants or during transportation. Exposure to HCl can induce severe health impairment, including acute and chronic pulmonary diseases. We have previously described the molecular, structural, and functional aspects of the development of chronic lung injury and pulmonary fibrosis caused by intratracheal instillation of HCl in mice. Although mouse models of human disease have many advantages, rodents are evolutionary far from human and exhibit significant anatomical and physiological differences. Genetic and anatomic similarities between rabbits and humans are significantly higher. Rabbit models of HCl-induced lung injury have been used sparsely to evaluate acute lung injury. In this study, for the first time, we utilized rabbits as a model of HCl-induced pulmonary fibrosis and chronic lung injury. We present molecular, histological, and functional evidence that demonstrate the utility of using this model for studying new pharmaceutics against pulmonary fibrosis.

The SIRT6/BAP1/xCT signaling axis mediates ferroptosis in cisplatin-induced AKI

BackgroundCisplatin is extensively utilized in clinical settings for treating solid tumors; However, its use is restricted because of the kidney damage caused by side effects. Moreover, currently, no effective medications have been approved to prevent or treat acute kidney injury induced by cisplatin. Our research indicates that sirtuin 6 (SIRT6) can inhibit ferroptosis induced by cisplatin, and the use of SIRT6 agonists can alleviate acute kidney injury caused by cisplatin. MethodsAn animal model of cisplatin-induced acute kidney injury (AKI) was established, followed by RNA sequencing to identify potential differentially expressed genes (DEGs) and associated pathways. To explore the role of SIRT6 in this model, SIRT6 knockout mice were generated, and recombinant adeno-associated virus was employed to achieve SIRT6 overexpression in the mice. In vitro, cells were cultured in a cisplatin-containing medium to establish a cisplatin-induced cell model. The function of SIRT6 was further investigated by overexpressing or knocking down the gene using lentiviral plasmids. To elucidate the underlying molecular mechanisms, we employed RNA sequencing, performed bioinformatics analyses, and conducted chromatin immunoprecipitation assays. ResultsRNA sequencing and Western blot analyses revealed a significant reduction in SIRT6 expression in mice with cisplatin-induced acute kidney injury (AKI). Enhancing SIRT6 expression improved renal function, reduced ferroptosis, and mitigated kidney damage, whereas SIRT6 knockout exacerbated kidney injury and heightened ferroptosis. Mechanistically, RNA sequencing, bioinformatics analysis, and chromatin immunoprecipitation assays demonstrated that SIRT6 inhibits ferroptosis by reducing the acetylation of histone H4K9ac at the BAP1 promoter. Furthermore, in vitro studies demonstrated that the SIRT6 agonist UBCS039 can alleviate cisplatin-induced acute kidney injury, highlighting its potential therapeutic role in mitigating cisplatin's damaging effects. However, further research is needed to fully elucidate the underlying mechanisms and to validate these findings in vivo. ConclusionOur findings underscore the critical role of the SIRT6/BAP1/xCT axis in regulating ferroptosis, particularly via the downregulation of SIRT6, in the context of cisplatin-induced acute kidney injury (AKI). This suggests that SIRT6 could be a promising therapeutic target for treating cisplatin-induced AKI. However, additional research is required to explore the specific mechanisms and fully assess the therapeutic potential of SIRT6 in this context.

Promotion of Epithelial Healing in Oral Mucositis by hESC-Derived Mesenchymal Stem Cells via the PI3K/AKT Pathway

Introduction: Oral mucositis (OM) is a common and debilitating side effect of cancer therapies such as radiotherapy, chemotherapy, hematopoietic cell transplant, or their combinations. Method: This study focused on the reparative effects of human embryonic stem cell-derived mesenchymal stem cells (hESC-MSCs) in OM and possible mechanisms. An ulcer model was created in the rat buccal mucosa to mimic an in vivo animal model of OM mucosal injury, and hESC-MSCs were injected 48h later to assess their reparative effects. In vitro, the efficacy of hESC-MSCs in regulating apoptosis and proliferation in LPS- or 5-fluorouracil (5-FU)-injured HaCaT cells was studied using a transwell coculture system. Subsequently, the PI3K inhibitor LY24002 was used to assess whether hESC-MSCs regulated injured HaCaT cells through the PI3K/AKT pathway. In vivo, we found that hESC-MSCs injection promoted OM healing in rats through the acceleration of re-epithelialization and a decrease in apoptosis. Results: In vitro, our findings revealed that the hESC-MSCs treatment led to a reduction in the quantity of HaCaT cells undergoing apoptosis. Western blot analysis revealed that hESC-MSCs activated AKT, resulting in increased protein levels of PCNA and BCL-2 and decreased protein levels of Bax and Caspase-3 whereas LY294002 reversed these changes. Conclusion: These findings suggest that hESC-MSCs promoted OM wound healing by stimulating the proliferation of epithelial cells and inhibiting their apoptosis in rat models. Furthermore, hESC-MSCs might mediate the PI3K/AKT pathway to modulate apoptosis/proliferation injured by LPS or 5-FU in HaCaT cells.

Evaluation of the Wound Healing Potential of Aloe Vera Leaf Extract Containing Carbopol 934 as a Gelling Agent and Comparing with Sodium CMC and HPMC on Surgically Induced in Wound Wister Rats: A Preclinical Study

ABSTRACT Introduction: The restricted injury can occur in any tissue or organ and is caused by an external source. The toughness and adaptability of the delivery system are enhanced by the synthetic hydrophilic, biocompatible, and biodegradable stable polymer known as carbopol 934. Aloe vera is a plant belonging to the Liliaceae family that releases anthraquinones, a bitter liquid that has medicinal qualities. Aim: The current study is to determine if aloe vera gel containing Carbopol 934 can cure wounds in animal models used in experiments. Need of the Study: This review will offer a thorough examination of recent studies on the medicinal use of Aloe vera gel. Further study is required to establish the mechanism of action because certain areas, such as wound healing, have not received much attention in the scientific community. However, these biological materials must first be appropriately isolated and identified. Materials and Methods: Various centralizations of Carbopol 934, sodium CMC, and HPMC will be attempted, and lastly, gel that showed great spreadability and consistency will be chosen for wound mending properties of homegrown Aloe vera gel.

Swertia cincta and its main active ingredients regulate the PPAR-α pathway in anti-cholestatic liver injury

Ethnopharmacological relevanceSwertia cincta is a traditional remedy for cholestasis commonly utilised in Yunnan, China. Despite its widespread use, the specific active components and underlying mechanisms of action remain poorly understood. Aim of this studyThis study aimed to investigate the therapeutic properties, mechanisms, and active compounds of Swertia cincta in an animal model of cholestasis induced by alpha-naphthylisothiocyanate (ANIT). Materials and methodsUHPLC/Q-TOF-MS and high-performance liquid chromatography (HPLC) were utilised to analyse the blood components of Swertia cincta. An ANIT-induced cholestatic liver injury animal model was established, and metabolomics was employed to explore the potential mechanisms of Swertia cincta in treating cholestatic liver injury. Hepatocellular injury induced by taurochenodeoxycholic acid was evaluated in vitro, and key bioactive components of Swertia cincta for cholestatic liver injury treatment were identified and confirmed using the ANIT-induced mouse model. ResultsThe established HPLC method demonstrates good specificity and reproducibility, enabling the simultaneous determination of six components in Swertia cincta. Results from serum biochemical indicators and liver pathology analysis indicated that Swertia cincta exhibits promising anti-cholestasis liver injury effects. Specifically, gentiopicroside, loganic acid, and isoorientin were identified as key active ingredients in treating cholestatic liver injury. Their mechanism of action primarily involves regulating PPAR-α, FXR, CYP3A4, NTCP, CAR, and CPT2. By modulating PPAR-α and bile acid metabolism-related proteins, reducing pro-inflammatory factors, enhancing bile acid transport, and promoting fatty acid oxidation to reduce lipid accumulation, Swertia cincta exerts protective and therapeutic effects against cholestatic liver injury. Notably, gentian bitter glycosides appear to be the most critical components for this effect. ConclusionSwertia cincta may improve cholestatic liver injury by activating the peroxisome proliferator-activated receptor alpha pathway, and the key active compounds were gentiopicroside, loganic acid, and isoorientin.

Phosphatidylserine-mediated uptake of extracellular vesicles by hepatocytes ameliorates liver ischemia-reperfusion injury.

Compelling evidence suggests that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) promote regeneration in animal models of liver injury by delivering signaling molecules. However, their target cells and uptake mechanism remain elusive. In this study, MSC-EVs were intravenously administered in a mouse model of liver ischemia-reperfusion injury (IRI). Our results revealed that MSC-EVs exhibit enhanced liver targeting in IRI mice, and injured hepatocytes display a greater capacity for MSC-EV uptake. We found that phosphatidylserine (PS) displayed on the exterior of injured hepatocytes promotes MSC-EV internalization, possibly by binding to MFGE8, a protein expressed on the MSC-EV membrane. Furthermore, the therapeutic effect of MSC-EVs on liver IRI is highly dependent on this PS-mediated uptake pathway. Our findings provide evidence that MSC-EVs preferentially target injured hepatocytes, relying on a PS-dependent uptake route to exert hepatoprotective effects, which are critical for the future design of EV-based therapeutic strategies for liver IRI.

Melatonin Alleviates Albumin-Induced Tubular Cell Injury by Activating Clock-Controlled Nuclear Enriched Abundant Transcript 1-Mediated Proliferation.

The pleiotropic and protective effects of melatonin have been demonstrated in a variety of animal models of renal injury. While coding RNAs regulated by melatonin in renal tissues are well identified, the functional involvement of long noncoding RNAs (lncRNAs) in melatonin signaling remains undefined. This study identified nuclear enriched abundant transcript 1 (NEAT1), a clock-controlled lncRNA that was upregulated by melatonin through the BMAL1/CLOCK heterodimer in renal tubular epithelial cells (TECs). Mechanistic studies showed that melatonin enhanced NEAT1 expression via increasing BMAL1 stability and thereby the enrichment of BMAL1 on NEAT1's promoter. Further studies have revealed that NEAT1 promotes the proliferation of TECs by increasing levels of H3K27ac and H3K4me1 at the promoter regions of the proliferation gene MKI67. Treatment of albumin-injured TECs with melatonin promoted proliferation by transactivating NEAT1 and restoring the expression levels of core clock genes and MKI67. Moreover, melatonin treatment ameliorated proteinuria, hypoalbuminemia, and fibrotic lesions, which was correlated with increased levels of core clock genes, H3K27ac, Mki67, and Neat1 in experimental MN kidneys. Melatonin mediates a novel regulatory axis, BMAL1-NEAT1-MKI67, in TEC proliferation, establishing potential therapeutic targets for MN and other renal diseases.

Akkermansia muciniphila improve cognitive dysfunction by regulating BDNF and serotonin pathway in gut-liver-brain axis

BackrgroundAkkermansia muciniphila, a next-generation probiotic, is known as a cornerstone regulating the gut-organ axis in various diseases, but the underlying mechanism remains poorly understood. Here, we revealed the neuronal and antifibrotic effects of A. muciniphila on the gut-liver-brain axis in liver injury.ResultsTo investigate neurologic dysfunction and characteristic gut microbiotas, we performed a cirrhosis cohort (154 patients with or without hepatic encephalopathy) and a community cognition cohort (80 participants in one region for three years) and validated the existence of cognitive impairment in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced hepatic injury mouse model. The effects of the candidate strain on cognition were evaluated in animal models of liver injury. The expression of brain-derived neurotrophic factor (BDNF) and serotonin receptors was accessed in patients with fibrosis (100 patients) according to the fibrosis grade and hepatic venous pressure gradient. The proportion of A. muciniphila decreased in populations with hepatic encephalopathy and cognitive dysfunction. Tissue staining techniques confirmed gut-liver-brain damage in liver injury, with drastic expression of BDNF and serotonin in the gut and brain. The administration of A. muciniphila significantly reduced tissue damage and improved cognitive dysfunction and the expression of BDNF and serotonin. Isolated vagus nerve staining showed a recovery of serotonin expression without affecting the dopamine pathway. Conversely, in liver tissue, the inhibition of injury through the suppression of serotonin receptor (5-hydroxytryptamine 2A and 2B) expression was confirmed. The severity of liver injury was correlated with the abundance of serotonin, BDNF, and A. muciniphila.ConclusionsA. muciniphila, a next-generation probiotic, is a therapeutic candidate for alleviating the symptoms of liver fibrosis and cognitive impairment.Graphical

Comparison of Autologous and Allogeneic Adipose-Derived Stem Cells in Kidney Transplantation: Immunological Considerations and Therapeutic Efficacy.

Regenerative medicine shows significant potential in treating kidney diseases through the application of various types of stem and progenitor cells, including mesenchymal stem cells (MSCs), renal stem/progenitor cells, embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). Stem cells possess the unique ability to repair injured organs and improve impaired functions, making them a key element in the research of therapies for kidney tissue repair and organ regeneration. In kidney transplantation, reperfusion injury can cause tissue destruction, leading to an initially low glomerular filtration rate and long-term impact on function by creating irreversible interstitial fibrosis. MSCs have proven useful in repairing early tissue injury in animal models of kidney, lung, heart, and intestine transplantation. The use of stem cell therapies in solid organ transplantation raises the question of whether autologous or allogeneic cells should be preferred. Adipose-derived stem cells (ASCs), characterized by the lack of HLA Class II molecules and low expression of HLA Class I and co-stimulatory signals, are considered immune-privileged. However, the actual risk of graft rejection associated with allogeneic ASCs remains unclear. It has been demonstrated that donor-derived ASCs can promote the development of Treg cells in vitro, and some degree of tolerance induction has been observed in vivo. Nevertheless, a study comparing the efficacy of autologous and allogeneic ASCs in a rat model with a total MHC mismatch for kidney transplantation showed that donor-derived administration of ASCs did not improve the grafts' survival and was associated with increased mortality through an immunologically mediated mechanism. Given the lack of data, autologous ASCs appear to be a safer option in this research context. The aim of this review was to examine the differences between autologous and allogeneic ASCs in the context of their application in kidney transplantation therapies, considering potential immune reactions and therapeutic efficacy. Some have argued that ASCs harvested from end-stage renal disease (ESRD) patients may have lower regenerative potential due to the toxic effects of uremia, potentially limiting their use in transplantation settings. However, evidence suggests that the beneficial properties of ASCs are not affected by uremia or dialysis. Indeed, some investigators have demonstrated that ASCs harvested from chronic kidney disease (CKD) patients exhibit normal characteristics and function, maintaining consistent proliferative capacity and genetic stability over time, even after prolonged exposure to uremic serum Furthermore, no differences were observed in the response of ASCs to immune activation or their inhibitory effect on the proliferation of alloantigen-activated peripheral blood mononuclear cells between patients with normal or impaired renal function. This review presents the current achievements in stem cell research aimed at treating kidney diseases, highlighting significant progress and ongoing efforts in the development of stem cell-based therapies. Despite the encouraging results, further research is needed to overcome the current limitations and fully realize the potential of these innovative treatments. Advances in this field are crucial for developing effective therapies that can address the complex challenges associated with kidney damage and failure.

Metabolomics and pathways analyses in traumatic brain injury animal model

Traumatic brain injury (TBI), a progressive neurological disease caused by physical injury to the brain tissue, impacting its functions. This study employed metabolomics based on untargeted mass spectrometry method to examine plasma specimens from well-established mouse models with induced TBI (n = 6) and control mice (n = 6). The objective was to assess the metabolomics profile and the associated biochemical pathways in TBI. There was a noticeable segregation between TBI and reference groups (Q2 = 0.342, R2 = 0.993), according to orthogonal partial least square-discriminant analysis, indicating significant difference in metabolic expression. Moreover, 102 metabolites were significantly altered in TBI mice; 59 were upregulated, while 43 were downregulated in TBI mice. Correspondingly, the TBI model showed a significant dysregulation in number of key metabolic pathways, including metabolism of glycerophospholipids, linoleic acid, glycine, serine, threonine, pyrimidine, tryptophan, nicotinate and nicotinamide. Additionally, isoleucyl-asparagine, 2′-deoxyinosine triphosphate, diglycosyl diacylglycerols (25:0/26/2), and phosphatidylethanolamine (24:0/22:4) demonstrated excellent performance for TBI detection with an area under the curve ≥ 0.8. This study identified putative plasma biomarkers of TBI and highlighted the dysregulated biochemical pathways, providing valuable clinical insights into TBI research.

Neuroprotective Effect of Melatonin in a Neonatal Hypoxia-Ischemia Rat Model Is Regulated by the AMPK/mTOR Pathway.

Melatonin has been shown to be neuroprotective in different animal models of neonatal hypoxic-ischemic brain injury. However, its exact molecular mechanism of action remains unknown. Our aim was to prove melatonin's short- and long-term neuroprotection and investigate its role on the AMPK (AMP-activated protein kinase)/mTOR (mammalian target of rapamycin) pathway following neonatal hypoxic-ischemic brain injury. Seven-day-old Wistar rat pups were exposed to hypoxia-ischemia, followed by melatonin or vehicle treatment. Detailed analysis of the AMPK/mTOR/autophagy pathway, short- and long-term neuroprotection, myelination, and oligodendrogenesis was performed at different time points. At 7 days after hypoxia-ischemia, melatonin-treated animals showed a significant decrease in tissue loss, increased oligodendrogenesis, and myelination. Long-term neurobehavioral results showed significant motor improvement following melatonin treatment. Molecular pathway analysis showed a decrease in the AMPK expression, with a significant increase at mTOR's downstream substrates, and a significant decrease at the autophagy marker levels in the melatonin group compared with the vehicle group. Melatonin treatment reduced brain area loss and promoted oligodendrogenesis with a clear improvement of motor function. We found that melatonin associated neuroprotection is regulated via the AMPK/mTOR/autophagy pathway. Considering the beneficial effects of melatonin and the results of our study, melatonin seems to be an optimal candidate for the treatment of newborns with hypoxic-ischemic brain injury in high- as well as in low- and middle-income countries.

Impact of airway closure and lung collapse on inhaled nitric oxide effect in acute lung injury: an experimental study

BackgroundEfficacy of inhaled therapy such as Nitric Oxide (iNO) during mechanical ventilation may depend on airway patency. We hypothesized that airway closure and lung collapse, countered by positive end-expiratory pressure (PEEP), influence iNO efficacy. This could support the role of an adequate PEEP titration for inhalation therapy. The main aim of this study was to assess the effect of iNO with PEEP set above or below the airway opening pressure (AOP) generated by airway closure, on hemodynamics and gas exchange in swine models of acute respiratory distress syndrome. Fourteen pigs randomly underwent either bilateral or asymmetrical two-hit model of lung injury. Airway closure and lung collapse were measured with electrical impedance tomography as well as ventilation/perfusion ratio (V/Q). After AOP detection, the effect of iNO (10ppm) was studied with PEEP set randomly above or below regional AOP. Respiratory mechanics, hemodynamics, and gas-exchange were recorded.ResultsAll pigs presented airway closure (AOP > 0.5cmH2O) after injury. In bilateral injury, iNO was associated with an improved mean pulmonary pressure from 49 ± 8 to 42 ± 7mmHg; (p = 0.003), and ventilation/perfusion matching, caused by a reduction in pixels with low V/Q and shunt from 16%[IQR:13–19] to 9%[IQR:4–12] (p = 0.03) only at PEEP set above AOP. iNO had no effect on hemodynamics or gas exchange for PEEP below AOP (low V/Q 25%[IQR:16–30] to 23%[IQR:14–27]; p = 0.68). In asymmetrical injury, iNO improved pulmonary hemodynamics and ventilation/perfusion matching independently from the PEEP set. iNO was associated with improved oxygenation in all cases.ConclusionsIn an animal model of bilateral lung injury, PEEP level relative to AOP markedly influences iNO efficacy on pulmonary hemodynamics and ventilation/perfusion match, independently of oxygenation.