Tissue Damage Research Articles

Lacidipine, thiamine pyrophosphate and their combination on the ocular ischemic syndrome induced by bilateral common carotid artery ligation

AIM: To investigate the effect of lacidipine, thiamine pyrophosphate (TPP) and the combination of lacidipine and TPP against oxidative and inflammatory eye damage induced by bilateral common carotid artery ligation in rats. METHODS: Male albino Wistar rats were categorized as those who underwent sham surgery (SG), right and left common carotid cross-clamping and unclamping procedure (CCU), lacidipine+CCU (LCCU), TPP+CCU (TCCU), and combination of lacidipine and TPP (LTC)+CCU (LTCCU). One hour before anesthesia, the LCCU (n=6) received lacidipine (4 mg/kg, orally) and the TCCU (n=6) received TPP (20 mg/kg, intraperitoneally). The SG (n=6) and CCU (n=6) received the same volume of distilled water from the same route. After anesthesia (60 mg/kg ketamine, intraperitoneally), the necks of the rats were opened in the midline. Ischemia was created for 10min by placing clips on the right and left common carotid arteries. Rats in the SG only underwent subcutaneous incision. After 10min, the clips were removed and reperfusion was achieved for six days. Then, the animals were euthanized (120 mg/kg ketamine, intraperitoneally) and the levels of oxidant, antioxidant and proinflammatory cytokines in the eye tissues were determined. The retinal tissue of the eye was also examined histopathologically. RESULTS: Lacidipine, TPP, and LTC significantly prevent the increase in malondialdehyde, tumor necrosis factor-alpha, interleukin-1β (IL-1β), and IL-6 levels, decrease in total glutathione levels, superoxide dismutase and catalase activities and histopathological retinal damage in eye tissue induced by bilateral common carotid artery ligation in rats. The impact of these drugs on protection is determined to be LTC>lacidipine>TPP. CONCLUSION: As a result of the study, it is concluded that LTC may be more effective than lacidipine and TPP alone in treating ocular ischemic syndrome.

Sildenafil and furosemide nanoparticles as a novel pharmacological treatment for acute renal failure in rats.

Hospitalized patients often develop acute renal failure (ARF), which causes severe morbidity and death. This research investigates the potential renoprotective benefits of sildenafil and furosemide in glycerol-induced ARF, and measures kidney function metrics in response to nanoparticle versions of these medications. Inducing ARF is commonly done by injecting 50% glycerol intramuscularly. Rats underwent a 24-h period of dehydration and starvation before slaughter for renal function testing. We investigated urine analysis, markers of oxidative stress, histology of kidney tissue, immunohistochemistry analysis of caspase-3 and interleukin-1 beta (IL-1 β), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), which are specific indicators of kidney tissue damage. The results of our study showed that the combination of sildenafil and furosemide, using both traditional and nanoparticle formulations, had a greater protective effect on the kidneys compared to using either drug alone. The recovery of renal tissue indicators, serum markers, and urine markers, which are indicative of organ damage, provides evidence of improvement. This was also indicated by the reduction in KIM-1 and NGAL tubular expression. The immunohistochemistry tests showed that the combination therapy, especially with the nanoforms, greatly improved the damaged cellular changes in the kidneys, as shown by higher levels of caspase-3 and IL-1β. According to the findings, a glycerol-induced rat model demonstrates that sildenafil and furosemide, either alone or in combination, in conventional or nanoparticulate forms, improve ARF dysfunction. The synergistic nanoparticulate compositions show remarkable effectiveness. This observation highlights the possible therapeutic implications for ARF treatment.

Ginseng-DF ameliorates intestinal mucosal barrier injury and enhances immunity in immunosuppressed mice by regulating MAPK/NF-κB signaling pathways.

Dietary fiber (DF) has a good application prospect in effectively restoring the integrity of the intestinal mucosal barrier. Ginseng-DF has good physicochemical properties and physiological activity and shows positive effects in enhancing immunity. The aim of this study was to investigate the protective effect of Ginseng-DF on intestinal mucosal barrier injury induced by cyclophosphamide (CTX) in immunosuppressed mice and its possible mechanism. The effects of Gginseng-DF on immune function in mice were studied by delayed-type hypersensitivy, lymphocyte proliferation assay and NK cytotoxicity assay, the T lymphocyte differentiation and intestinal barrier integrity were analyzed by flow cytometry and western blot. Ginseng-DF (2.5% and 5%) could attenuate the inhibition of DTH response by CTX, promote the transformation and proliferation of lymphocytes, and stimulate NK effector cell activity. At the same time, Ginseng-DF could restore the proportion of CD4+/CD8+ T lymphocytes induced by CTX to different extents, improved spleen tissue damage, promoted the secretion of immunoglobulin IgG, and enhanced body immunity. More importantly, Ginseng-DF could up-regulate the contents of TNF-α, IFN-γ, IL-6 and IL-1β in serum and intestine of immunosuppressed mice to maintain the balance between Th1/Th2 cytokines, and improve the permeability of intestinal mucosal barrier. Meanwhile, Ginseng-DF could reduce intestinal epithelial cell apoptosis and improve intestinal adaptive immunity in CTX-induced immunosuppressed mice by regulating MAPK/NF-κB signaling pathway. Ginseng-DF can be used as a safe dietary supplement to enhance body immunity and reduce intestinal mucosal injury caused by CTX.

M1-type polarized macrophage contributes to brain damage through CXCR3.2/CXCL11 pathways after RGNNV infection in grouper.

The vertebrate central nervous system (CNS) is the most complex system of the body. The CNS, especially the brain, is generally regarded as immune-privileged. However, the specialized immune strategies in the brain and how immune cells, specifically macrophages in the brain, respond to virus invasion remain poorly understood. Therefore, this study aimed to examine the potential immune response of macrophages in the brain of orange-spotted groupers (Epinephelus coioides) following red-spotted grouper nervous necrosis virus (RGNNV) infection. We observed that RGNNV induced macrophages to produce an inflammatory response in the brain of orange-spotted grouper, and the macrophages exhibited M1-type polarization after RGNNV infection. In addition, we found RGNNV-induced macrophage M1 polarization via the CXCR3.2- CXCL11 pathway. Furthermore, we observed that RGNNV triggered M1 polarization in macrophages, resulting in substantial proinflammatory cytokine production and subsequent damage to brain tissue. These findings reveal a unique mechanism for brain macrophage polarization, emphasizing their role in contributing to nervous tissue damage following viral infection in the CNS.

Polyphyllin I alleviates neuroinflammation after cerebral ischemia–reperfusion injury via facilitating autophagy-mediated M2 microglial polarization

Microglial activation and polarization play a central role in poststroke inflammation and neuronal damage. Modulating microglial polarization from pro-inflammatory to anti-inflammatory phenotype is a promising therapeutic strategy for the treatment of cerebral ischemia. Polyphyllin I (PPI), a steroidal saponin, shows multiple bioactivities in various diseases, but the potential function of PPI in cerebral ischemia is not elucidated yet. In our study, the influence of PPI on cerebral ischemia–reperfusion injury was evaluated. Mouse middle cerebral artery occlusion (MCAO) model and oxygen–glucose deprivation and reoxygenation (OGD/R) model were constructed to mimic cerebral ischemia–reperfusion injury in vivo and in vitro. TTC staining, TUNEL staining, RT-qPCR, ELISA, flow cytometry, western blot, immunofluorescence, hanging wire test, rotarod test and foot-fault test, open-field test and Morris water maze test were performed in our study. We found that PPI alleviated cerebral ischemia–reperfusion injury and neuroinflammation, and improved functional recovery of mice after MCAO. PPI modulated microglial polarization towards anti-inflammatory M2 phenotype in MCAO mice in vivo and post OGD/R in vitro. Besides, PPI promoted autophagy via suppressing Akt/mTOR signaling in microglia, while inhibition of autophagy abrogated the effect of PPI on M2 microglial polarization after OGD/R. Furthermore, PPI facilitated autophagy-mediated ROS clearance to inhibit NLRP3 inflammasome activation in microglia, and NLRP3 inflammasome reactivation by nigericin abolished the effect of PPI on M2 microglia polarization. In conclusion, PPI alleviated post-stroke neuroinflammation and tissue damage via increasing autophagy-mediated M2 microglial polarization. Our data suggested that PPI had potential for ischemic stroke treatment.

The Anti-Inflammatory Effect of Nigella sativa Toothpaste on Porphyromonas gingivalis Bacteria Through Decreased TNF-α, MMP-9, PGE-2 Expression in Wistar Rats.

The main principle in preventing periodontal disease is to improve oral hygiene. The bacteria that cause the onset of periodontal disease, one of which is the Porphyromonas gingivalis bacterium, causes inflammation. Persistent inflammation causes tissue damage and alveolar bone resorption by secreting proinflammatory cytokines, matrix metalloproteinase-9 (MMP-9), prostaglandin E2 (PGE-2), and anti-inflammatory cytokines. In this case, preventive treatment is needed, such as using toothpaste that contains anti-inflammatories so that the progression of the disease does not get worse. The traditional ingredient currently being developed is Nigella sativa, which has anti-inflammatory properties. Therefore, this study analyzes the potential of toothpaste containing Nigella sativa on the expression of tumor necrosis factor-α (TNF-α), MMP-9, and PGE-2 in the Wistar rat model induced by Porphyromonas gingivalis bacteria. This study aims to prove the potential of Nigella sativa toothpaste to decrease the expression of PGE-2, TNF-α, and MMP-9 in the gingiva of rats induced by Porphyromonas gingivalis bacteria. Forty-five healthy male Wistar rats were used, consisting of the negative control group, which was only injected with Porphyromonas gingivalis bacteria ATCC3322. The positive control group was given enzyme toothpaste, and the treatment group was assigned 1 mg of Nigella sativa paste using a microbrush for 30 seconds on the gingiva incisors mandibular with a circular motion, given two times a day for a week. Immunohistochemical to see the expression of TNF-α, PGE-2, and MMP-9. Parametric comparative analysis using a one-way analysis of variance test was performed to analyze differences between groups. Nigella sativa toothpaste significantly reduced proinflammatory cytokines, as seen through the expression of TNF-α, PGE-2, and MMP-9 on days 3, 5, and 7 (p <0.05). In the limit of studied animal model, this trial indicates that giving toothpaste with black seed extract (Nigella sativa) could inhibit inflammatory mediators, as seen from the decreased expression of MMP-9, TNF-α, and PGE-2 seen from the 3rd, 5th, and 7th days.

Computational identification of potential bioactive compounds from Triphala against alcoholic liver injury by targeting alcohol dehydrogenase.

Alcoholic liver injury resulting from excessive alcohol consumption is a significant social concern. Alcohol dehydrogenase (ADH) plays a critical role in the conversion of alcohol to acetaldehyde, leading to tissue damage. The management of alcoholic liver injury encompasses nutritional support and, in severe cases liver transplantation, but potential adverse effects exist, and effective medications are currently unavailable. Natural products with their potential benefits and historical use in traditional medicine emerge as promising alternatives. Triphala, a traditional polyherbal formula demonstrates beneficial effects in addressing diverse health concerns, with a notable impact on treating alcoholic liver damage through enhanced liver metabolism. The present study aims to identify potential active phytocompounds in Triphala targeting ADH to prevent alcoholic liver injury. Screening 119 phytocompounds from the Triphala formulation revealed 62 of them showing binding affinity to the active site of the ADH1B protein. Promising lipid-like molecule from Terminalia bellirica, (4aS, 6aR, 6aR, 6bR, 7R, 8aR, 9R, 10R, 11R, 12aR, 14bS)-7, 10, 11-trihydroxy-9-(hydroxymethyl)-2, 2, 6a, 6b, 9, 12a-hexamethyl-1, 3, 4, 5, 6, 6a, 7, 8, 8a, 10, 11, 12, 13, 14b-tetradecahydropicene-4a-carboxylic acid showed high binding efficiency to a competitive ADH inhibitor, 4-Methylpyrazole. Pharmacokinetic analysis further confirmed the drug-likeness and non-hepatotoxicity of the top-ranked compound. Molecular dynamics simulation and MM-PBSA studies revealed the stability of the docked complexes with minimal fluctuation and consistency of the hydrogen bonds throughout the simulation. Together, computational investigations suggest that (4aS, 6aR, 6aR, 6bR, 7R, 8aR, 9R, 10R, 11R, 12aR, 14bS)-7, 10, 11-trihydroxy-9-(hydroxymethyl)-2, 2, 6a, 6b, 9, 12a-hexamethyl-1, 3, 4, 5, 6, 6a, 7, 8, 8a, 10, 11, 12, 13, 14b-tetradecahydropicene-4a-carboxylic acid from the Triphala formulation holds promise as an ADH inhibitor, suggesting an alternative therapy for alcoholic liver injury.

Epigallocatechin-3-gallate attenuates the sulfamethoxazole-induced immunotoxicity and reduces SMZ residues in Procambarus clarkii

Sulfamethoxazole (SMZ) is a commonly used antibiotic in aquaculture, and its residues in water bodies pose a significant threat to aquatic organisms in the water environment. In the present study, epigallocatechin-3-gallate (EGCG), a catecholamine, was used to mitigate the immunotoxicity caused by SMZ exposure in Procambarus clarkii. EGCG reduced the apoptosis rate, which was elevated by SMZ exposure, and increased the total hemocyte count. Simultaneously, EGCG enhanced the activities of enzymes related to antibacterial and antioxidant activities, such as superoxide dismutase (SOD), catalase (CAT), lysozyme (LZM), acid phosphatase (ACP), and GSH, which were decreased following SMZ exposure. Hepatopancreatic histology confirmed that EGCG ameliorated SMZ-induced tissue damage caused by SMZ exposure. In addition to EGCG attenuating SMZ-induced immunotoxicity in crayfish, we determined that EGCG can effectively reduce SMZ residues in crayfish exposed to SMZ. In addition, at the genetic level, the expression levels of genes related to the immune response in hemocytes were disrupted after SMZ exposure, and EGCG promoted their recovery and stimulated an increase in the expression levels of metabolism-related transcripts in hemocytes. The transcriptome analysis was conducted, and “phagosome” and “apoptosis” pathways were shown to be highlighted using Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. To the best of our knowledge, this is the first study to confirm that EGCG attenuates SMZ-induced immunotoxicity in aquatic animals and reduces SMZ residues in aquatic animals exposed to SMZ. Our study contributes to the understanding of the mechanisms by which EGCG reduces the immunotoxicity of antibiotic residues in aquatic animals. Environmental ImplicationSulfamethoxazole (SMZ) is a commonly utilized antibiotic in aquaculture, the misuse and overuse of this antibiotic have resulted in the accumulation of SMZ in aquatic environments, thereby posing a significant threat to aquatic organisms. This study firstly confirmed that EGCG can attenuate the SMZ-induced immunotoxicity in aquatic animals and reduce SMZ residues in aquatic animals exposed to SMZ. This study contributes to fully understand the mechanisms of EGCG in the reducing the content of antibiotics in aquatic products and the immunotoxicity of antibiotic residues on aquatic animals.

Lack of the IFN-γ signal leads to lethal Orientia tsutsugamushi infection in mice with skin eschar lesions.

Scrub typhus is an acute febrile disease due to Orientia tsutsugamushi (Ot) infection and can be life-threatening with organ failure, hemorrhage, and fatality. Yet, little is known as to how the host reacts to Ot bacteria at early stages of infection; no reports have addressed the functional roles of type I versus type II interferon (IFN) responses in scrub typhus. In this study, we used comprehensive intradermal (i.d.) inoculation models and two clinically predominant Ot strains (Karp and Gilliam) to uncover early immune events. Karp infection induced sequential expression of Ifnb and Ifng in inflamed skin and draining lymph nodes at days 1 and 3 post-infection. Using double Ifnar1-/-Ifngr1-/- and Stat1-/- mice, we found that deficiency in IFN/STAT1 signaling resulted in lethal infection with profound pathology and skin eschar lesions, which resembled to human scrub typhus. Further analyses demonstrated that deficiency in IFN-γ, but not IFN-I, resulted in impaired NK cell and macrophage activation and uncontrolled bacterial growth and dissemination, leading to metabolic dysregulation, excessive inflammatory cell infiltration, and exacerbated tissue damage. NK cells were found to be the major cellular source of innate IFN-γ, contributing to the initial Ot control in the draining lymph nodes. In vitro studies with dendritic cell cultures revealed a superior antibacterial effect offered by IFN-γ than IFN-β. Comparative in vivo studies with Karp- and Gilliam-infection revealed a crucial role of IFN-γ signaling in protection against progression of eschar lesions and Ot infection lethality. Additionally, our i.d. mouse models of lethal infection with eschar lesions are promising tools for immunological study and vaccine development for scrub typhus.

Comparative Analysis of Circulating Metabolomic Profiles Identifies Shared Metabolic Alterations Across Distinct Multi-Stressor Military Training Operations.

Military training provides insight into metabolic responses under unique physiological demands that can be comprehensively characterized by global metabolomic profiling to identify potential strategies for improving performance. This study identified shared changes in metabolomic profiles across three distinct military training exercises varying in magnitude and types of stress. Blood samples collected before and after three real or simulated military training exercises were analyzed using the same untargeted metabolomic profiling platform. Exercises included a three-week survival school course (ST, n=36), a four-day arctic cross country ski march (AT, n=24), and a 28-day controlled diet- and exercise-induced energy deficit (CED, n=26). Log2-fold changes of >±1 in 191, 121 and 64 metabolites were identified in the ST, AT and CED datasets, respectively. Most metabolite changes were within lipid (57-63%) and amino acid metabolism (18-19%) pathways, and changes in 87 were shared across studies. The largest and most consistent increases in shared metabolites were found in acylcarnitine, fatty acid, ketone, and glutathione metabolism pathways, whereas the largest decreases were in diacylglycerol and urea cycle metabolism pathways. Multiple shared metabolites were consistently correlated with biomarkers of inflammation, tissue damage, and anabolic hormones across studies. These three studies of real and simulated military training revealed overlapping alterations in metabolomic profiles despite differences in environment and the stressors involved. Consistent changes in metabolites related to lipid metabolism, ketogenesis and oxidative stress suggest a potential common metabolomic signature associated with inflammation, tissue damage and suppression of anabolic signaling that may characterize unique physiological demands of military training.

Acacetin Attenuates Sepsis-induced Acute Lung Injury via NLRC3-NF-κB Pathway.

Acacetin, a flavonoid derived compound has been recognized for its diverse biological activities, such as anti-oxidative and anti-inflammatory effects. Acute lung injury (ALI) is a severe condition characterized by respiratory insufficiency and tissue damage, commonly triggered by pneumonia and severe sepsis. These conditions induce an inflammatory response via Toll-like receptor 4 (TLR4) signaling activation. This study explored acacetin's therapeutic potential against lipopolysaccharide (LPS) induced ALI in mice, focusing on its ability to modulate the NF-κB pathway via regulation of the Nod-like receptor family CARD domain containing 3 (NLRC3), a signal sensor that plays an important role in the regulation of inflammation and the maintenance of homeostasis. Our findings revealed that high-dose acacetin reduced the mortality rate of ALI mice, significantly ameliorated LPS-induced lung pathological changes, reduced lung edema, and decreased the expression of inflammatory mediators in lung tissues. This protective impact of acacetin appears to stem form its capacity to enhance NLRC3 expression, which, intern, can inhibit the activation of NF-κB and subsequently inhibit the production of inflammatory mediators. NLRC3 deficiency inhibits the protective effect of acacetin on ALI mice. Molecular docking also verified that acacetin tightly bound acacetin to NLRC3. Additionally, acacetin was found to influence macrophage recruitment dynamics via NLRC3, inhibiting the overactivation of NLRC3-NF-κB related pathways. Taken together, our results indicate that acacetin inhibited LPS-induced acute lung injury and macrophage overrecruitment to the lungs in mice by upregulating NLRC3.

Lactobacillus delbrueckii subsp. bulgaricus Alleviates Acute Injury in Hypoxic Mice

Acute mountain sickness (AMS) is a common ailment in high-altitude areas caused by the body’s inadequate adaptation to low-pressure, low-oxygen environments, leading to organ edema, oxidative stress, and impaired intestinal barrier function. The gastrointestinal tract, being the first to be affected by ischemia and hypoxia, is highly susceptible to injury. This study investigates the role of Lactobacillus delbrueckii subsp. bulgaricus in alleviating acute hypoxic-induced intestinal and tissue damage from the perspective of daily consumed lactic acid bacteria. An acute hypoxia mouse model was established to evaluate tissue injury, oxidative stress, inflammatory responses, and intestinal barrier function in various groups of mice. The results indicate that strain 4L3 significantly mitigated brain and lung edema caused by hypoxia, improved colonic tissue damage, and effectively increased the content of tight junction proteins in the ileum, reducing ileal permeability and alleviating mechanical barrier damage in the intestines due to acute hypoxia. Additionally, 4L3 helped to rebalance the intestinal microbiota. In summary, this study found that Lactobacillus delbrueckii subsp. bulgaricus strain 4L3 could alleviate acute intestinal damage caused by hypoxia, thereby reducing hypoxic stress. This suggests that probiotic lactic acid bacteria that exert beneficial effects in the intestines may alleviate acute injury under hypoxic conditions in mice, offering new insights for the prevention and treatment of AMS.

Decoction derived from Allium ascalonicum L. bulbs and Sojae Semen Praeparatum alleviates wind-cold-type common cold via Nrf2/HO-1 pathway and modulation of Lactobacillus murinus level

BackgroundCong-Chi decoction (CCD) is made using Allium ascalonicum L. (shallot) bulbs and Sojae Semen Praeparatum (SSP). Shallot bulbs and SSP are both used regularly in traditional Chinese medicine; however, there are no recent pharmacological studies on their synergistic effects. Despite their roles in the treatment of the common cold for thousands of years, their pharmacological mechanisms of action against wind-cold-type common cold are yet to be explored comprehensively.MethodsA mouse model was standardized using wind-cold modeling equipment to study the anti-inflammatory, antioxidant, and antiapoptotic effects of CCD. Then, 16S rRNA sequencing was employed to analyze the association between Lactobacillus murinus and changes in body temperature. Additionally, the antipyretic effects of L. murinus were validated via animal experiments.ResultsThe results indicate that CCD improves the symptoms of wind-cold by reducing fever, levels of pro-inflammatory factors, and cellular apoptosis, as well as increasing the blood leukocyte and lymphocyte counts, thereby alleviating lung tissue damage. The effects of CCD are mediated by upregulation of pulmonary Nrf2 and HO-1 expressions, thereby reducing oxidative damage in the lungs, in addition to other anti-inflammatory mechanisms. Furthermore, CCD increases the abundance of L. murinus in the intestinal tract. The animal experiments confirm that L. murinus ameliorates fever in mice.ConclusionCCD exhibits remarkable antioxidant and anti-inflammatory properties for effectively treating wind-cold-type common cold. Furthermore, its regulatory effects on L. murinus represent a novel mechanism for product development.

Advancing crush syndrome management: the potent role of Sodium zirconium cyclosilicate in early hyperkalemia intervention and survival enhancement in a rat model

Background: Crush Syndrome (CS), a severe trauma resulting from prolonged muscle compression, is commonly seen in large-scale disasters such as earthquakes. It not only causes localized tissue damage but also triggers electrolyte imbalances, particularly hyperkalemia, increasing the risk of early mortality. This study aims to assess the early intervention effects of Sodium Zirconium Cyclosilicate (SZC) on hyperkalemia in rat CS model.Methods: A rat CS model was established using a self-developed multi-channel intelligent small-animal crush injury platform. Rats in the experimental groups were treated with varying doses of SZC before compression and immediately post-decompression. The efficacy of SZC was evaluated by continuous monitoring of blood potassium levels and survival rates. Serum creatinine (Cre) and blood urea nitrogen (BUN) levels were analyzed, and renal damage was assessed through histopathological examination.Results: SZC treatment significantly reduced blood potassium levels and improved survival rates in rats. Compared to the placebo group, the SZC-treated rats showed a significant decrease in blood potassium levels at 6 and 12 h post-decompression, maintaining lower levels at 24 h. Biochemical analysis indicated no significant impact of SZC on renal function, with no notable differences in Cre and BUN levels between groups. Histopathological findings revealed similar levels of renal damage in both groups.Conclusion: SZC demonstrates significant early intervention effects on hyperkalemia in a rat model of crush injury, effectively improving survival rates without adverse effects on renal function. These results provide a new strategic direction for the clinical treatment of Crush Syndrome and lay the foundation for future clinical applications.

Cell-free DNA in patients with sepsis: long term trajectory and association with 28-day mortality and sepsis-associated acute kidney injury

IntroductionOutcome-prediction in patients with sepsis is challenging and currently relies on the serial measurement of many parameters. Standard diagnostic tools, such as serum creatinine (SCr), lack sensitivity and specificity for acute kidney injury (AKI). Circulating cell-free DNA (cfDNA), which can be obtained from liquid biopsies, can potentially contribute to the quantification of tissue damage and the prediction of sepsis mortality and sepsis-associated AKI (SA-AKI).MethodsWe investigated the clinical significance of cfDNA levels as a predictor of 28-day mortality, the occurrence of SA-AKI and the initiation of renal replacement therapy (RRT) in patients with sepsis. Furthermore, we investigated the long-term course of cfDNA levels in sepsis survivors at 6 and 12 months after sepsis onset. Specifically, we measured mitochondrial DNA (mitochondrially encoded NADH-ubiquinone oxidoreductase chain 1, mt-ND1, and mitochondrially encoded cytochrome C oxidase subunit III, mt-CO3) and nuclear DNA (nuclear ribosomal protein S18, n-Rps18) in 81 healthy controls and all available samples of 150 intensive care unit patients with sepsis obtained at 3 ± 1 days, 7 ± 1 days, 6 ± 2 months and 12 ± 2 months after sepsis onset.ResultsOur analysis revealed that, at day 3, patients with sepsis had elevated levels of cfDNA (mt-ND1, and n-Rps18, all p&amp;lt;0.001) which decreased after the acute phase of sepsis. 28-day non-survivors of sepsis (16%) had higher levels of cfDNA (all p&amp;lt;0.05) compared with 28-day survivors (84%). Patients with SA-AKI had higher levels of cfDNA compared to patients without AKI (all p&amp;lt;0.05). Cell-free DNA was also significantly increased in patients requiring RRT (all p&amp;lt;0.05). All parameters improved the AUC for SCr in predicting RRT (AUC=0.88) as well as APACHE II in predicting mortality (AUC=0.86).ConclusionIn summary, cfDNA could potentially improve risk prediction models for mortality, SA-AKI and RRT in patients with sepsis. The predictive value of cfDNA, even with a single measurement at the onset of sepsis, could offer a significant advantage over conventional diagnostic methods that require repeated measurements or a baseline value for risk assessment. Considering that our data show that cfDNA levels decrease after the first insult, future studies could investigate cfDNA as a “memoryless” marker and thus bring further innovation to the complex field of SA-AKI diagnostics.

Considerations on the Evolutionary Biology and Functions of Eosinophils: What the 'Haeckel'?

The origins and evolution of the eosinophilic leukocyte has received only scattered attention since Paul Ehrlich first named this granulocyte. Studies suggest that myeloperoxidase, expressed by granulocytes, and eosinophil peroxidase diverged some 60-70 million years ago, but invertebrate to vertebrate evolution of the eosinophil lineage is unknown. Vertebrate eosinophils have been characterized extensively in representative species at light microscopic, ultrastructural, genetic, and biochemical levels. Understanding of eosinophil function continues to expand and includes to date regulation of "Local Immunity And/Or Remodeling/Repair" (the so-called LIAR hypothesis), modulation of innate and adaptive immune responses, maintenance of tissue and metabolic homeostasis, and under pathologic conditions, inducers of tissue damage, repair, remodeling, and fibrosis. This contrasts with their classically considered primary roles in host defense against parasites and other pathogens, and involvement in T-helper 2 inflammatory and immune responses. The eosinophils' early appearance during evolution and continued retention within the innate immune system across taxa illustrate their importance during evolutionary biology. However, successful pregnancies in eosinophil-depleted humans/primates treated with biologics, host immune responses to parasites in eosinophil-deficient mice, and the absence of significant developmental or functional abnormalities in eosinophil-deficient mouse strains under laboratory conditions, raise questions of the continuing selective advantages of the eosinophil lineage in mammals and humans. The objectives of this review are to provide an overview on evolutionary origins of eosinophils across the animal kingdom, discuss some of their main functions in the context of potential evolutionary relevance, and highlight the need for further research on eosinophil functions and functional evolution.

Unstable Distal Tibia Fracture Management By Anatomically Contoured Plate With Mipo Technique

Background: Fracture at distal tibia is a notorious fracture and difficult to manage. This fracture can be managed conservatively or operatively. Minimally invasive percutaneous osteosynthesis (MIPO) technique can be applied in distal tibia fracture and it usually provides better outcome. This technique ensures minimal soft tissue damage, preserves periosteum and hematoma of the fracture. As the fracture site is not opened, indirect fracture reduction technique is applied. This study tries to evaluate the outcome of MIPO technique application in distal tibia fracture management. Methods: The study was cross sectional study and was carried out on 20 patients during the period of January 2019 to July 2021 in orthopaedic department of Combined Military Hospital (CMH), Dhaka. During this tenure all patients who fulfilled the inclusion and exclusion criteria was included in the study. All had close fracture. Follow up interval was at 2 weeks then 06 weeks, thereafter at 3 months, 6 month and 12 months' time from the date of operation. Data were collected and evaluated in terms of bony union and postoperative complications. Results: 12 patients i.e. 60% were male and same percentage of patient had fracture at right lower limb. Mode of trauma was mostly road traffic accidents (RTA) and fall from height. 40 years was mean age of the patients. It was 07 weeks mean partial weight bearing time and 14 weeks mean full weight bearing time. Mean radiological union time was seen at 18 weeks. Non union or delayed union did not happen in any case. But ankle stiffness (3/20) was most commonly found postoperative complications. Conclusion: For distal tibia fracture MIPO technique is a better treatment option as it gives good outcome and fewer complications. Bangladesh Armed Forces Med J Vol 56 No (1) June 2023, pp 1-6

A commentary on studies of brain iron accumulation during ageing.

Brain iron content is widely reported to increase during "ageing", across multiple species from nematodes, rodents (mice and rats) and humans. Given the redox-active properties of iron, there has been a large research focus on iron-mediated oxidative stress as a contributor to tissue damage during natural ageing, and also as a risk factor for neurodegenerative disease. Surprisingly, however, the majority of published studies have not investigated brain iron homeostasis during the biological time period of senescence, and thus knowledge of how brain homeostasis changes during this critical stage of life largely remains unknown. This commentary examines the literature published on the topic of brain iron homeostasis during ageing, providing a critique on limitations of currently used experimental designs. The commentary also aims to highlight that although much research attention has been given to iron accumulation or iron overload as a pathological feature of ageing, there is evidence to support functional iron deficiency may exist, and this should not be overlooked in studies of ageing or neurodegenerative disease.

Cartilage Collagen Neoepitope C2C Expression in the Articular Cartilage and Its Relation to Joint Tissue Damage in Patients with Knee Osteoarthritis

Pathological cleavage of type II collagen (Col2) and generation of Col2 neoepitopes can serve as useful molecular markers of the progression of osteoarthritis (OA). One of such potential biomarkers is type II collagen neoepitope C2C. The aim of this study was to correlate the degree of articular cartilage damage in OA patients with C2C expression in histological samples of tissues removed during total knee replacement. Cartilage samples were obtained from 27 patients ranging in age from 55 to 66 years. In each patient, medial and lateral tibia plateau samples were analyzed according to the OARSI histopathology grading system. The C2C expression was evaluated on histological slides by semi-quantitative analysis using ImageJ Fiji 2.14.0 software. Spearman’s rank correlation analysis revealed a positive weak correlation (rho = 0.289, p = 0.0356) between the histological grade of tissue damage and the percentage of C2C staining. In addition, a highly significant positive correlation (rho = 0.388, p = 0.0041) was discovered between the osteoarthritis score (combining the histological grade of damage with the OA macroscopic stage) and the percentage of C2C staining in the samples. The C2C expression was detected in all the regions of the articular cartilage (i.e., the superficial zone, mid zone, deep zone and tidemark area, and the zone of calcified cartilage). Our findings imply that local expression of C2C correlates with the articular cartilage damage in OA-affected knees. This confirms that C2C can be used as a prospective marker for assessing pathological changes in the OA course and OA clinical trials.

The Role of Mesenchymal Stem Cells Secretome in Regeneration of Thyroid Tissue Damage after Thyroid Lobectomy: A Literature Review

Mesenchymal Stem Cells (MSC) are a type of stem cell that is multipotent and originates from the mesoderm and ectoderm at an early stage of development and can differentiate into: 1. Ectodermal derivatives such as: neurons, keratocytes and keratinocytes; 2. Endodermal derivatives such as: hepatocytes and pancreatic β cells. MSCs were first discovered in the bone marrow, but in recent research they have been found in many other body tissues, such as the lungs, pancreas, liver, adipose tissue, synovial tissue, muscles, bones, amniotic fluid and umbilical cord blood. MSCs vary in content, accessibility, proliferation ability, immunomodulatory capacity, and the cytokines they secrete, and have different therapeutic potential based on different sources. Recent evidences showed that even the secreted factor including secretome, microvesicles, or exosomes alone without the cell may repair damaged tissue in various conditions. In this review, we summarize the latest research which aims to provide an overview of the influence of the mesenchymal stem cells secretome in regenerating damaged follicular thyroid tissue after thyroid lobectomy, so that in the future research can be carried out on this matter to minimize complications after thyroid lobectomy, can even regenerate follicular thyroid tissue, and can be an option treatment to help overcome the current challenges of hormone replacement therapy.