Proliferation Of Kupffer Cells Research Articles

Further Insights into The Pathogenic Mechanisms of Haemotropic Mycoplasma ovis.

In this study, we examined the effects of experimental intraperitoneal infection with haemotropic Mycoplasma ovis (0.5 mL of blood containing 80% parasitaemia) on selected serum biomarkers and cellular pathology in mice. After infection, M. ovis cells appeared in the blood films within one week. A dose-dependent peak of parasitemia was observed during the 3rd-week post-infection (pi), with a significant decrease in mean PCV between treatment versus control group at week 3 (t 14 = -3.693, P < 0.02), week 5 (t 14 = -2.096, P = 0.055), and week 7 (t 14 = -4.329, P = 0.001). There was a significantly (t 8 = -2.330, P = 0.048) lower serum oestrogen in treatment (10.38 ± 5.07) than control (17.43 ± 4.48), while serum progesterone was significantly (t 8 = 5.415, P = 0.001) increased in treatment (27.37 ± 2.17) than control (15.92 ± 4.20). Serum haptoglobin was significantly (t 8 = 8.525, P < 0.01) lower in treatment (8.72 ± 1.49) than control (18.16 ± 1.98) while the SAA was significantly (t 8 = 3.362, P = 0.01) higher in treatment (16.79 ± 2.71) than control (11.59 ± 2.15). Prominent lesions observed in the ovary include degeneration, necrosis, vacuolation, and hypertrophy of the lutein cells in corpora lutea. In the lymph nodes, diffused cellular hyperplasia of the lymphoid tissue in the cortex. In the liver, degeneration and necrosis accompanied by leucocytic cellular infiltration and Kupffer cell proliferation within the sinusoids. There were diffused leucocytic infiltrations and proliferative lesions in the glomerulus of the kidneys. The disturbance in progesterone and ovarian pathology highlights the potential role of haemotropic M. ovis in reproductive disorders. The observed changes in biomarkers and cellular reactions following M. ovis infection in the mouse may be further advanced in sheep and goats.

The analysis of the histomorphometric characteristics and ultrastructural features of the liver in response to environmental cycle desynchronization in the wild desert rodent (Gerbillus tarabuli)

The architecture of the hepatic tissue in the nocturnal wild desert rodent (Gerbillus tarabuli) subjected to a shifted LD (Light/Dark) cycle was investigated using transmission electron microscopy and histomorphometry. Investigation involved two groups: the control group (n = 5), exposed to the regular LD cycle (LD: 12:12), and the shifted group (n = 5), exposed to the LD regimen with a prolonged light phase of 8 h, in a day by day alternation with regular LD cycle (LD: 12:12 / LD: 20:4) during 12 weeks. Histological examination showed in the shifted group disorganization of hepatocyte trabeculae, sinusoidal dilatation, and inflammatory cell infiltration around the portal tracts. Morphometric results revealed hypertrophy of hepatocytes with a size of 29.83 ± 1.69 μm vs. 17.52 ± 0.81 μm and of their nuclei diameter with 8.69 ± 0.25 μm vs. 6.55 ± 0.15 μm. This increase is highly significant (p&lt;0.001) and represents an increase of 70.17% and 32.67%, respectively. We also noticed a significant increase in the number of binucleated cells compared to the control group with an average of 9.73 ± 0.98 vs. 5.53 ± 0.38 binucleated hepatocytes per area unit, respectively. Ultrastructural analysis corroborated the histological findings, confirming the installation of inflammatory foci, characterized by portal and intraparenchymal infiltration of leukocytes, proliferation of Kupffer cells and stellate cells, as well as an expansion of collagen fiber deposits. Electron microscopy also revealed in the shifted group some hepatocytic lesional features represented by vacuolar or liquefied cytoplasm associated with degenerative mitochondria and a rarefaction of organelles in addition to an abundance of lysosomes. Additionally, strong glycogen depletion was observed at the metabolic level. This study showed that 12 weeks of lengthening the light phase of the LD cycle, corresponding to the gerbil's resting period, had a discernible impact on hepatocellular activity, making G. tarabuli an interesting model to study the influence of artificial light at night as a circadian rhythm disruptor.

Pathological Effects of Aflatoxin on Hepatic Tissue of Rats, Experimental Study

The objective of studying this research is to discuss the pathological influence of aflatoxin on hepatic tissue. Aflatoxin was produced in this work using Aspergillus flavus. The samples were mixed with Potato Dextrose Agar (PDA) and left to incubate at a temperature of 28 ± 2°C for three to five days. We employed the fungal species for further usage once they were incubated. The AF was made via a fermentation process with Aspergillus parasitcus and rice, After the rice had fermented properly, it was steams to destroy the fungus, dried, and pulverised into a powder. The AF concentration in rice residue was determined using a TLC fluorometric densitometer on TLC spots. Ten rats from each of the two experimental groups—"G1 Control" (fed a baseline diet without AF) and "AF" (fed a different diet)—were randomly assigned to participate in the study. Group 2 rats were given 25 μg of AF daily. This study's duration was ninety days. Then, blood specimens were drawn by heart puncture using a syringe to determine serum enzyme levels. The animals were sacrificed in order to get tissue samples as well enzyme levels were assessed in serum specimens that had been centrifuged at 4000 × g for 15 minutes at 4 °C. The levels of AST, ALT, and GGT were determined using a spectrophotometer and a kit that was received from Biolabo. Liver samples were collected from rats after scarification, embedded in paraffin wax, and fixed with 10% neutralised formaldehyde. Hematoxylin and eosin were used for staining. The AF-treated group had substantially high levels of those enzymes compare to the control group (p &lt; 0.05). G2 demonstrated that macrophage aggregations in the liver parenchyma constitute granulomatous lesions. Another portion showed hepatocyte apoptosis, which is defined by dense nuclei in the hepatocyte's irregular esonophilic cytoplasm, and a necrotic region with pyknosis or no nuclei at all. A portion of the liver of rats that were treated with aflatoxin showed proliferation of kupffer cells together with a few clusters of mononuclear cells around the major vein. In conclusion, Aflatoxin can affect of liver tissue histology as well as liver enzymes such as ALT, AST as well as GGT.

Simulated microgravity altered the gene expression profiles and inhibited the proliferation of Kupffer cells in the early phase by downregulating LMO2 and EZH2

Microgravity is a primary challenge that need to overcome, when human travel to space. Our study provided evidence that Kupffer cells (KCs) are sensitive to simulated microgravity (SMG), and no similar research report has been found in the literature. Using transcriptome sequencing technology, it was showed that 631 genes were upregulated and 801 genes were downregulated in KCs after treatment under SMG for 3 days. The GO analysis indicated that the proliferation of KCs was affected when exposed to SMG for 3 days. CCK-8 assay confirmed that the proliferation of KCs was inhibited in the third day under the environment of SMG. Furthermore, we identified 8 key genes that affect the proliferation of KCs and predicted 2 transcription factors (TFs) that regulate the 8 key genes. Significantly, we found that microgravity could affect the expression of LMO2 and EZH2 to reduce the transcription of Racgap1, Ccna2, Nek2, Aurka, Plk1, Haus4, Cdc20, Bub1b, which resulting in the reduction in KCs proliferation. These finding suggested that the inhibition of KCs proliferation under microgravity may influence the homeostasis of liver, and LMO2 and EZH2 can be the targets in management of KCs’ disturbance in the future practice of space medicine.

Morphological and Histological Impacts of Bisphenol A on Chicken Embryos

The aim of the current study was to investigate the morphological and histological effects of Bisphenol A on chicken Ross 308 during embryonic development A total of 150 eggs were randomly divided into five groups: negative control, positive control injected with con oil and treatment groups administered with different concentrations of Bisphenol A (0.005, 0.02 and 0.1 microliters/egg). The eggs were injected on the second day of incubation and the evaluation was conducted on days 10 and 21 of incubation. Our results showed different abnormal observations at both ages of incubation including skin redness, presence of hemorrhagic spots on the head and around the eyes, congenital anomalies in the upper and lower limbs, chick lethargy and inflammation, particularly in the caudal region. Additionally, there was a clear paralysis in a chicken aged 21 days. Microscopically, there were changes in the liver structure representing congestion in the central vein, mild focal intercellular changes in hepatocytes, few necrosis and atrophy of hepatic cords. At day 21, there was also dispersed hemorrhagic, inflammatory infiltration slight proliferation of Kupffer cells, fatty degeneration, irregularity of hepatocytes and hepatic cords as well as cloudy swelling.

Biochemical and histopathological changes in livers of rats poisoned with aluminum phosphide and treated with carrot extract.

The experimental studies of Aluminum Phosphide (AP) poisoning in rats revealed several clinical and pathological signs such as hemorrhage, sinusoidal dilatation, bile stasis, centrilobular necrosis, Kupffer cell hyperplasia, infiltration by mononuclear cells, and fatty infiltration in the liver tissues. This paper aimed to show the impact of carrots on the toxic effect of AP on the livers of adult rats (female). To investigate some biochemical and histopathological changes effects of AP in rats, sixty white female rats were equally divided into four groups, the first group (G1) was administered orally with 3mg/kg/ body weight of AP, the second group (G2) was orally treated with AP and 10% carrot extract at the same time. The third group (G3) administrated 10% carrot extract only. The fourth (G4) group was the negative control and was treated with distilled water only. The experiments continued for a month at the animal house of the Veterinary Medicine College of Baghdad University. The results revealed that high levels of liver enzymes and bilirubin were induced in G1 with decreasing total protein levels. The pathological examination revealed the presence of marked proliferation of Kupffer cells in G1 livers. However, the G2 group showed slight infiltration of lymphocytes in sinusoids. The pathological changes in the livers of G3 group showed slight cloudy swelling in hepatocytes compared with the normal texture of hepatocytes in G4. The data of this experiment showed that treatment with carrot extract significantly decreases the elevation in the level of liver function enzymes in animal poisoned with AP. In addition, treatment with carrot extract reduces the severe damage in the hepatic tissue that occurred in rats treated with AP only. In general, it could be concluded that treatment with carrot extract provides a remedial effect against the hepatotoxicity that is resulted from exposure to AP.

Kupffer cells heterogeneity and replacement by monocyte-derived KCs contributes to visceral leishmaniasis resistance

Abstract Visceral leishmaniasis (VL) is a potentially fatal disease transmitted by sand fly bites and caused by Leishmania (L. donovani/L. infantum) protozoa. Kupffer cells (KCs) are the liver embryonic resident macrophages (emKCs), characterized by Clec4f and Tim4 expression and their sessile behavior within the liver sinusoids. KCs maintain their numbers via self-proliferation during homeostasis but can be replaced by monocyte-derived cells (moKCs) during inflammation. In the murine VL model, KCs are important for both initial parasite growth and granuloma formation, the latter being associated with the eventual protective response. The objective of our study is to investigate KC proliferation, migration, death, and their replacement by moKCs in VL. We found that KC proliferation was enhanced at 19 d.p.i., while at 42 d.p.i. the granulomas cores contained mixed KC clonal lineages and were located outside the liver sinusoids. At the same time point, Clec4f and Tim4 expression was reduced, and we found evidence of KC apoptosis and ferroptosis. Parabiotic mice demonstrated KC populations that bore either congenic marker, and CCR2 −/−infected mice showed enhanced frequencies of emKCs, reduced frequencies of moKCs, and higher parasite loads compared to WT mice. Reduction of ferroptosis in BACH1 −/−mice resulted in lower frequencies of moKCs. Collectively, our data indicates that KCs migrate to the liver parenchyma to form granulomas, facilitating their activation by other immune cells, and that KC death results in their partial replacement by moKCs, contributing to increased parasite killing. Thus, KC heterogeneity is an important hallmark of hepatic resistance in VL. Funded by the Division of Intramural Research, NIAID.

In situ expansion and reprogramming of Kupffer cells elicit potent tumoricidal immunity against liver metastasis.

Liver metastasis represents one of the most frequent malignant diseases with no effective treatment. Functional reprogramming of Kupffer cells (KCs), the largest population of hepatic macrophages, holds promise for treating liver cancer, but remains seldom exploited. Taking advantage of the superior capacity of KCs to capture circulating bacteria, we report that a single administration of attenuated Escherichia coli producing clustered regularly interspersed short palindromic repeats CasΦ (CRISPR/CasΦ) machinery enables efficient editing of genes of interest in KCs. Using intravital microscopy, we observed a failure of tumor control by KCs at the late stage of liver metastasis due to KC loss preferentially in the tumor core and periphery, resulting in inaccessibility of these highly phagocytic macrophages to cancer cells. Simultaneous disruption of MafB and c-Maf expression using the aforementioned engineered bacteria could overcome KC dysfunction and elicit remarkable curative effects against several types of metastatic liver cancer in mice. Mechanistically, bacterial treatment induced massive proliferation and functional reprogramming of KCs. These cells infiltrated into the tumor, dismantled macrometastases by nibbling cancer cells, and skewed toward proinflammatory macrophages to unleash antitumor T cell responses. These findings provide an immunotherapy strategy that could be applicable for treating liver metastasis and highlight the therapeutic potential of targeting tissue-resident macrophages in cancer.

Acute Toxicity Effect of Crude Leaves Extract of Thevetia peruviana on Full Blood Count and some Organs of Clarias gariepinus Juveniles

Background: Many toxicity studies have shown that heamatological and histological alterations are widely used as good bioindicators in determining the effect of toxicants on fish. This study investigated the acute toxicity effects of the leaf extract of Thevetia peruviana on full blood count parameters and some organs of Clarias gariepinus juveniles”. Methods: One hundred and twenty C. gariepinus mixed sex juveniles were exposed to acute con-centrations (0.63, 1.25, 2.50, 5.00, and 10.00g/L ) of leave extract of T. peruviana in twelve 20 L capacity rectangular glass tanks with six treatments and bi-replicated. Blood for full blood count was collected through cardiac puncture while gills and liver were excised and analyzed for histo-pathological alterations. Results: PCV, RBC, Hb, Neu, and Lym of C. gariepinus juveniles inversely decreased while WBC directly increased with acute concentrations of T. peruviana leaves extract. The microscopic examination of the gills revealed concentration-dependent histo-architectural alterations expressed as epical clubbing, haemorrhage, desquamation, atrophy, and complete erosion of secondary lamel-lae. The liver showed moderate to severe concentration-dependent histopathological lesions typi-fied by hypertrophy, atrophy, necrosis, kupffer cell proliferation, and hepatocellular degenerations. Conclusion: Given the alterations in the blood, gills and liver noted in this study, the invasive growth of the T. peruviana plant should be controlled to minimize unwanted fish kill.

Nigella sativa seeds mitigate the hepatic histo-architectural and ultrastructural changes induced by 4-nonylphenol in Clarias gariepinus

Due to its prevalence in aquatic environments and potential cytotoxicity, 4-nonylphenol (4-NP) has garnered considerable attention. As a medicinal plant with numerous biological activities, Nigella sativa (black seed or black cumin) seed (NSS) is widely utilized throughout the world. Consequently, this study aimed to examine the potential protective effects of NSS against 4-NP-induced hepatotoxicity in African catfish (Clarias gariepinus). To achieve this objective, 18 fish (351 ± 3 g) were randomly divided into three equal groups for 21 days. The first group serves as a control which did not receive any treatment except the basal diet. The second and third groups were exposed to 4-NP at a dose of 0.1 mg L−1 of aquarium water and fed a basal diet only or supplemented with 2.5% NSS, respectively. The histological, histochemical, and ultrastructural features of the liver were subsequently evaluated as a damage biomarker of the hepatic tissue. Our results confirmed that 4-NP was a potent hepatotoxic agent, as 4-NP-intoxicated fish exhibited many lesions. Steatohepatitis, ballooning degeneration, sclerosing cholangitis, and coagulative necrosis of melanomacrophagecenters (MMCs) were observed. Hemosiderin, lipofuscin pigments, and proliferation of fibroblasts, kupffer cells, and telocytes were also demonstrated in the livers of 4-NP-intoxicated fish. In addition, decreased glycogen content and increased collagen deposition were observed in the hepatic tissue. Hepatocytes exhibited ultrastructural alterations in the chromatin, rough endoplasmic reticulum, smooth endoplasmic reticulum, mitochondria, lysosomes, and peroxisomes. Co-administration of 2.5% NSS to 4-NP-intoxicated fish significantly reduced these hepatotoxic effects. It nearly preserved the histological, histochemical, and ultrastructural integrity of hepatic tissue.

Rutin and Hesperidin Revoke the Hepatotoxicity Induced by Paclitaxel in Male Wistar Rats via Their Antioxidant, Anti-Inflammatory, and Antiapoptotic Activities.

Paclitaxel, one of the most effective chemotherapeutic drugs, is used to treat various cancers but it is exceedingly toxic when used long-term and can harm the liver. This study aimed to see if rutin, hesperidin, and their combination could protect male Wistar rats against paclitaxel (Taxol)-induced hepatotoxicity. Adult male Wistar rats were subdivided into 5 groups (each of six rats). The normal group was orally given the equivalent volume of vehicles for 6 weeks. The paclitaxel-administered control group received intraperitoneal injection of paclitaxel at a dose of 2 mg/Kg body weight twice a week for 6 weeks. Treated paclitaxel-administered groups were given paclitaxel similar to the paclitaxel-administered control group together with oral supplementation of rutin, hesperidin, and their combination at a dose of 10 mg/Kg body weight every other day for 6 weeks. The treatment of paclitaxel-administered rats with rutin and hesperidin significantly reduced paclitaxel-induced increases in serum alanine transaminase, aspartate transaminase, lactate dehydrogenase, alkaline phosphatase, and gamma-glutamyl transferase activities as well as total bilirubin level and liver lipid peroxidation. However, the levels of serum albumin, liver glutathione content, and the activities of liver superoxide dismutase and glutathione peroxidase increased. Furthermore, paclitaxel-induced harmful hepatic histological changes (central vein and portal area blood vessel congestion, fatty changes, and moderate necrotic changes with focal nuclear pyknosis, focal mononuclear infiltration, and Kupffer cell proliferation) were remarkably enhanced by rutin and hesperidin treatments. Moreover, the elevated hepatic proapoptotic mediator (caspase-3) and pro-inflammatory cytokine (tumor necrosis factor-α) expressions were decreased by the three treatments in paclitaxel-administered rats. The cotreatment with rutin and hesperidin was the most effective in restoring the majority of liver function and histological integrity. Therefore, rutin, hesperidin, and their combination may exert hepatic protective effects in paclitaxel-administered rats by improving antioxidant defenses and inhibiting inflammation and apoptosis.

The Contribution of Hepatic Macrophage Heterogeneity during Liver Regeneration after Partial Hepatectomy in Mice.

Methods In the present study, we investigated hepatic macrophage heterogeneity in murine liver regeneration after 2/3 PHx through immunofluorescence staining, fluorescence-activated cell sorting analysis, and quantitative reverse transcription-polymerase chain reaction. Results Our research showed that Kupffer cells reduced rapidly in the early PHx and restored gradually depending on local proliferation and replenishment from infiltrating monocyte-derived macrophages. The ratio of ly6Chi to ly6Clo subset of macrophages in the liver changed dynamically, and hepatic macrophage function exhibits a significant difference in different stages of liver regeneration. Moreover, blocking infiltrating monocyte-derived macrophage recruitment augmented Kupffer cell proliferation but impaired the restoration of the hepatic macrophage pool, which led to delayed hepatocyte mitosis and liver regeneration. Conclusions Our data suggest that hepatic macrophage changes dynamically in origin and function during liver regeneration following PHx and macrophage-targeted liver regeneration should consider macrophage heterogeneity.

Heterogeneity and Function of Kupffer Cells in Liver Injury.

Kupffer cells (KCs) are key regulators of liver immunity composing the principal part of hepatic macrophages even body tissue macrophages. They reside in liver sinusoids towards portal vein. The micro-environment shapes KCs unique immunosuppressive features and functions. KCs express specific surface markers that distinguish from other liver macrophages. By engulfing gut-derived foreign products and apoptotic cells without triggering excessive inflammation, KCs maintain homeostasis of liver and body. Heterogeneity of KCs has been identified in different studies. In terms of the origin, adult KCs are derived from progenitors of both embryo and adult bone marrow. Embryo-derived KCs compose the majority of KCs in healthy and maintain by self-renewal. Bone marrow monocytes replenish massively when embryo-derived KC proliferation are impaired. The phenotype of KCs is also beyond the traditional dogma of M1-M2. Functionally, KCs play central roles in pathogenesis of acute and chronic liver injury. They contribute to each pathological stage of liver disease. By initiating inflammation, regulating fibrosis, cirrhosis and tumor cell proliferation, KCs contribute to the resolution of liver injury and restoration of tissue architecture. The underlying mechanism varied by damage factors and pathology. Understanding the characteristics and functions of KCs may provide opportunities for the therapy of liver injury. Herein, we attempt to afford insights on heterogeneity and functions of KCs in liver injury using the existing findings.

Gut Microbiota Alteration Influences Colorectal Cancer Metastasis to the Liver by Remodeling the Liver Immune Microenvironment

Background/AimsThis study aimed to explore the effect of gut microbiota-regulated Kupffer cells (KCs) on colorectal cancer (CRC) liver metastasis.MethodsA series of in vivo and in vitro researches were showed to demonstrate the gut microbiota and its possible mechanism in CRC liver metastasis.ResultsFewer liver metastases were identified in the ampicillin-streptomycin-colistin and colistin groups. Increased proportions of Parabacteroides goldsteinii, Bacteroides vulgatus, Bacteroides thetaiotaomicron, and Bacteroides uniformis were observed in the colistin group. The significant expansion of KCs was identified in the ampicillin-streptomycin-colistin and colistin groups. B. vulgatus levels were positively correlated with KC levels. More liver metastases were observed in the vancomycin group. An increased abundance of Parabacteroides distasonis and Proteus mirabilis and an obvious reduction of KCs were noted in the vancomycin group. P. mirabilis levels were negatively related to KC levels. The number of liver metastatic nodules was increased in the P. mirabilis group and decreased in the B. vulgatus group. The number of KCs decreased in the P. mirabilis group and increased in the B. vulgatus group. In vitro, as P. mirabilis or B. vulgatus doses increased, there was an opposite effect on KC proliferation in dose- and time-dependent manners. P. mirabilis induced CT26 cell migration by controlling KC proliferation, whereas B. vulgatus prevented this migration.ConclusionsAn increased abundance of P. mirabilis and decreased amount of B. vulgatus play key roles in CRC liver metastasis, which might be related to KC reductions in the liver.

Problems of formation of the toxic hepatopathy forming in the conditions of chronic fluoride intoxication of the body

Introduction. Aluminium production is characterized by the accumulation of impurities of various toxic and chemical compositions in the air of working areas, the predominant among which are fluoride compounds. The accumulation of fluorides in the body causes the development of osteoarticular and associated systemic pathology. The aim of the study was to evaluate the hygienic and medico-biological features of toxic liver damage in the conditions of chronic fluoride intoxication of the body. Material and methods. The hygienic working conditions of the workers of the primary professions in aluminium production were evaluated. The analysis of hepatobiliary dysfunction based on clinical and instrumental methods was carried out in 263 subjects with fluoride intoxication and a comparison group of 116 persons. Experimental studies of the morpho-functional liver state in modelling chronic fluoride intoxication were carried out based on toxicological, biochemical, pathomorphological methods with histological analysis of tissues. The toxic properties of sodium fluoride were studied in 117 white laboratory male rats with its peroral route intake into the body. Results. The qualitative composition of the air in the working areas in the electrolysis building was analyzed. The prevalence of pathological disorders of the biliary tract in metallurgists engaged in aluminium production was assessed. Clinical studies revealed a significant prevalence of toxic fluoride hepatopathy, fatty hepatosis, cholecystitis and other disorders in the group of patients with chronic fluoride intoxication. The harmful effect of sodium fluoride on hepatocytes, vessels of the portal tract was shown in an experiment. Hyperfunction of the reticuloendothelial system, Kupffer cell proliferation, irreversible destruction of hepatocytes, necrosis against the background of severe dystrophy, and decreased synthetic activity of the liver were determined. Conclusion. The structure of occupational diseases in the workers engaged in the aluminium production is dominated by hepatobiliary pathology caused by toxic liver damage with fluoride confirmed by experimental data on destructive violations of its morphostructure.

Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners.

Kupffer cells (KCs), which are liver-resident macrophages, originate from the fetal yolk sac and represent one of the largest macrophage populations in the body. However, the current data on the origin of the cells that restore macrophages during liver injury and regeneration remain controversial. Here, we address the question of whether liver macrophage restoration results from circulating monocyte infiltration or local KC proliferation in regenerating livers after partial hepatectomy (PHx) and uncover the underlying mechanisms. By using several strains of genetically modified mice and performing immunohistochemical analyses, we demonstrated that local KC proliferation mainly contributed to the restoration of liver macrophages after PHx. Peak KC proliferation was impaired in Il6-knockout (KO) mice and restored after the administration of IL-6 protein, whereas KC proliferation was not affected in Il4-KO or Csf2-KO mice. The source of IL-6 was identified using hepatocyte- and myeloid-specific Il6-KO mice and the results revealed that both hepatocytes and myeloid cells contribute to IL-6 production after PHx. Moreover, peak KC proliferation was also impaired in myeloid-specific Il6 receptor-KO mice after PHx, suggesting that IL-6 signaling directly promotes KC proliferation. Studies using several inhibitors to block the IL-6 signaling pathway revealed that sirtuin 1 (SIRT1) contributed to IL-6-mediated KC proliferation in vitro. Genetic deletion of the Sirt1 gene in myeloid cells, including KCs, impaired KC proliferation after PHx. In conclusion, our data suggest that KC repopulation after PHx is mainly driven by local KC proliferation, which is dependent on IL-6 and SIRT1 activation in KCs.

Alleviation of cisplatin-induced hepatotoxicity by gliclazide: Involvement of oxidative stress and caspase-3 activity.

AimsCisplatin (CP), as an effective alkylating agent, is widely used in cancer treatment, while hepatotoxicity is one of its side effects. Gliclazide (GLZ), as an oral hypoglycemic drug, has antioxidant and anti‐inflammatory properties. This study was designed to investigate the protective effect of GLZ against CP‐induced hepatotoxicity in mice.MethodsIn this experimental study, 64 adult male mice randomly were allocated into eight groups (8 mice/group). Control, GLZ (5, 10, and 25 mg/kg, orally), CP (10 mg/kg, single dose, intraperitoneally), and CP+GLZ (in three doses). GLZ was administrated for 10 consecutive days. CP was injected on the 7th day of the study. At the end of the experiment, hepatotoxicity was evaluated by serum and tissue biochemical, histopathological, and immunohistochemical assessments.ResultsThe data were revealed that CP increased oxidative stress (increased MDA and reduced GSH), liver damage enzymes (ALT, AST, and ALP), and immunoreactivity of caspase‐3 in liver tissue of CP‐injected mice. Also, CP induced histopathological changes such as eosinophilic of hepatocytes, dilatation of sinusoids, congestion, and proliferation of Kupffer cells. GLZ administration significantly ameliorated serum functional enzyme and hepatic oxidative stress markers in CP‐injected mice. In addition, the histological and immunohistochemical alterations were ameliorated in GLZ‐treated mice. Of the three doses, 10 and 25 mg/kg were more effective.ConclusionsIn conclusion, GLZ with its antioxidant, anti‐inflammatory, and anti‐apoptotic activities, can be suggested as a promising drug in the treatment of CP‐induced hepatotoxicity.

The Preventive Effects and Mode of Actions of Ulva Fasciata Synthesized Silver Nanoparticles in Doxorubicin-Induced Hepatotoxicity in Wistar Rats

Background: Hepatotoxicity was one of the major side effects associated with doxorubicin treatment in cancer chemotherapy. The synthesized silver nanoparticles (AgNPs) from natural products such as algae especially green algae is one of the favorable means to minimize the deleterious effects of the chemotherapy. Thus, this study aimed to evaluate the preventive role of AgNPs synthesized by Ulva fasciata (U. fasciata) against doxorubicin-induced hepatotoxicity and oxidative stress in the liver of male Wistar rats. &#x0D; Materials and Methods: In the present study, the green macroalga U. fasciata ethanolic extract was used as reducing agents to reduce Ag ions to Ag0. Doxorubicin-injected male Wistar rats were concomitantly treated with U. fasciata ethanolic extract and AgNPs synthesized by U. fasciata extract (AgNPs/U. fasciata) 3 times/week by oral gavage for 6 weeks.&#x0D; Results: The results showed that male Wistar rats injected with doxorubicin showed a significant increase in ALT, ALP and GGT activities and total bilirubin level as well as a reduction in the serum albumin level. The concurrent treatments of doxorubicin-injected rats with U. fasciata ethanolic extract and AgNPs/U. fasciata significantly abrogate these alterations. The altered levels of tumor biomarkers CA19.9 and AFP as well as pro-inflammatory cytokine, TNF-α, and anti-inflammatory cytokine, IL-4, in doxorubicin-injected animals were significantly ameliorated by concurrent treatment with U. fasciata and AgNPs/U. fasciata. Moreover, the elevated mRNA expression of p53 significantly decreased by treatment. In association, the doxorubicin-induced deleterious histological changes represented by severe hydropic degenerative changes, steatosis, inflammatory cell infiltration, Kupffer cell proliferation and apoptosis were remarkably improved by concurrent treatment with U. fasciata extract and AgNPs/U. fasciata which was more potent.&#x0D; Conclusion: Based on results of this study, it can be concluded that U. fasciata extract and AgNPs/U. fasciata counteracts doxorubicin-induced toxicity by suppression of inflammation, oxidative stress and apoptosis. AgNPs/U. fasciata was the most potent in improving hepatocyte integrity and liver histological architecture. &#x0D; Graphical Abstract&#x0D; &#x0D;

Systemic consequences and clinical aspects of SARS-CoV-2 infection

HintergrundCOVID-19 wird als systemische Erkrankung eingestuft. Ein schwerer Verlauf mit tödlichem Ausgang ist möglich und unvorhersehbar.FragestellungWelche Organsysteme sind primär betroffen? Welche Organveränderungen prädisponieren für einen ungünstigen Verlauf? Welche Organschädigungen finden sich bei letalem Ausgang?Material und MethodeDaten aus publizierten Obduktionsstudien (davon 28 eigene publizierte Fälle) in Hinblick auf Organschädigung und mögliche Todesursachen.ErgebnisseDie schwersten Veränderungen finden sich in den Lungen in Form eines diffusen Alveolarschadens als akutes Atemnotsyndrom des Erwachsenen (ARDS), zum Teil bereits mit Fibrose. Thrombosen in kleinen bis mittelgroßen Pulmonalarterien sind mit Lungeninfarkten vergesellschaftet. Häufige Komplikationen sind bakterielle Bronchopneumonien, seltener Pilzpneumonien. Pulmonale Thromboembolien finden sich in 20–30 % der tödlichen Verläufe, auch bei Fehlen einer tiefen Beinvenenthrombose. Eine intestinale Beteiligung von COVID-19 kann mit ischämischer Schädigung des Darmes einhergehen, in erster Linie bedingt durch Schock oder lokale Thrombose. Die Nieren zeigen eine akute Tubulusschädigung als Ausdruck eines akuten Nierenversagens, Lymphknoten und Milz einen Schwund der Lymphozyten, die Nebennierenrinde eine Hyperplasie. In der Leber finden sich häufig eine Steatose, Leberzellnekrosen, ein portales Entzündungsinfiltrat und eine Proliferation der Kupffer-Zellen. Häufige Grunderkrankungen sind in den Autopsiekollektiven arterieller Hypertonus mit hypertensiver und ischämischer Kardiomyopathie und Diabetes mellitus. In großen bevölkerungsbasierten Studien ergibt sich aber für Hypertoniker im Gegensatz zu Diabetikern kein erhöhtes Mortalitätsrisiko.SchlussfolgerungenPulmonale Kreislaufstörungen mit arteriellen Thrombosen, Infarkten und Pneumonien sind wesentliche und oft letale Komplikationen des ARDS bei COVID-19. Die Erkenntnisse aus Obduktionsstudien haben Therapie und Prophylaxe beeinflusst.

Haematococcus pluvialis Carotenoids Enrich Fractions Ameliorate Liver Fibrosis Induced by Thioacetamide in Rats: Modulation of Metalloproteinase and Its Inhibitor.

Hepatic fibrosis is a consequence of chronic liver diseases. Metalloproteinase and its inhibitor have crucial roles in the resolution of liver fibrosis. The current relevant study is aimed to evaluate the therapeutic effect of Haematococcus pluvialis (H. pluvialis) extract, astaxanthin-rich fraction, astaxanthin ester-rich fraction, and β-carotene-rich fraction as well as their mechanisms of action in curing hepatic fibrosis induced by thioacetamide (TAA). Liver fibrosis was induced using TAA (intraperitoneal injection, two times a week for 6 weeks), in a rat model and H. pluvialis extract (200 mg/kg), and other fractions (30 mg/kg) were orally administered daily for 4 weeks after the last TAA injection. Based on HPLC analysis, H. pluvialis extract contains β-carotene (12.95 mg/g, extract) and free astaxanthin (10.85 mg/g, extract), while HPLC/ESI-MS analysis revealed that H. pluvialis extract contains 28 carotenoid compounds including three isomers of free astaxanthin, α or β-carotene, lutein, 14 astaxanthin mono-esters, 5 astaxanthin di-esters, and other carotenoids. H. pluvialis and its fractions reduced liver enzymes, nitric oxide, collagen 1, alpha-smooth muscle actin, and transforming growth factor-beta as well as elevated catalase antioxidant activity compared to the TAA group. Also, H. pluvialis extract and its fractions exceedingly controlled the balance between metalloproteinase and its inhibitor, activated Kupffer cells proliferation, and suppressed liver apoptosis, necrobiosis, and fibrosis. These findings conclude that H. pluvialis extract and its fractions have an antifibrotic effect against TAA-induced liver fibrosis by regulating the oxidative stress and proinflammatory mediators, suppressing multiple profibrogenic factors, and modulating the metalloproteinase and its inhibitor pathway, recommending H. pluvialis extract and its fractions for the development of new effective medicine for treating hepatic fibrosis disorders.