BTLA deficiency promotes HSC activation and protects against hepatic ischemia-reperfusion injury.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion injury (IRI) is unavoidable even despite the development of more effective surgical approaches. During hepatic IRI, activated HSC (aHSC) are involved in liver injury and recovery. APPROACH AND RESULT: A proportion of aHSC increased significantly both in the mouse liver tissues with IRI and in the primary mouse HSCs and LX-2 cells during hypoxia-reoxygenation. "Loss-of-function" experiments revealed that depleting aHSC with gliotoxin exacerbated liver damage in IRI mice. Subsequently, we found that the transcription of mRNA and the expression of B and T lymphocyte attenuator (BTLA) protein were lower in aHSC compared with quiescent HSCs. Interestingly, overexpression or knockdown of BTLA resulted in opposite changes in the activation of specific markers for HSCs such as collagen type I alpha 1, α-smooth muscle actin, and Vimentin. Moreover, the upregulation of these markers was also observed in the liver tissues of global BLTA-deficient (BTLA-/-) mice and was higher after hepatic IRI. Compared with wild-type mice, aHSC were higher, and liver injury was lower in BTLA-/- mice following IRI. However, the depletion of aHSC reversed these effects. In addition, the depletion of aHSC significantly exacerbated liver damage in BTLA-/- mice with hepatic IRI. Furthermore, the TGF-ß1 signaling pathway was identified as a potential mechanism for BTLA to negatively regulate the activation of HSCs in vivo and in vitro. CONCLUSIONS: These novel findings revealed a critical role of BTLA. Particularly, the receptor inhibits HSC-activated signaling in acute IRI, implying that it is a potential immunotherapeutic target for decreasing the IRI risk.

Study on Soil Selenium-Induced Copper Deficiency in Yudong Black Goats.

Due to the degradation of pasture and strict restrictions on grazing ranges in recent years, copper (Cu) deficiency in Yudong black goats has been occurring, mainly manifested as emaciation, anemia, loss of appetite and lack of spirit. To explore the main causes of Cu deficiency in Yudong black goats, 40 black goats (1 year old, 25.11 ± 0.52 kg) were selected for this experiment; among them, 20 Yudong black goats with Cu deficiency from the experimental pasture were used as the experimental group, and 20 healthy Yudong black goats from the control pasture were used as the control group. In the pre-experiment, the mineral contents of the soil, forage, blood, and liver of black goats in both groups were determined, and in formal experiments, blood hematological, biochemical, antioxidant, and hemorheological parameters were analyzed. An experiment on the treatment of Cu deficiency in black goats was also conducted. This study showed that selenium (Se) levels in the soil, forage, blood, and liver from the experimental group were significantly lower than those from the control group (p < 0.01). The content of sulfur (S) in the forage was considerably higher than that of the control group (p < 0.01). The contents of Cu in the blood and liver from the experimental group were significantly lower than that from the control group (p < 0.01), and the content of S was considerably higher than that from the control group (p < 0.01). The blood hematology of the experimental group was affected, as evidenced by a decrease in hemoglobin, hematocrit value, mean corpuscular volume and mean corpuscular hemoglobin. The immunity and antioxidant capacity of black goats in the experiment group were impaired to varying degrees, with significant decreases in ceruloplasmin, immunoglobulin M, immunoglobulin G, glutathione peroxidase, and superoxide dismutase, and substantial increases in malondialdehyde. In addition, the experimental group showed a decrease in blood viscosity as evidenced by the rise in high shear viscosity, low shear viscosity, erythrocyte rigidity index, erythrocyte aggregation index, and erythrocyte deformation index, and a decrease in plasma viscosity. In the treatment experiment, oral administration of copper sulfate solution was carried out on 10 black goats with Cu deficiency. All the Cu deficiency goats were cured, and the Cu content in their bodies rebounded. In summary, low Se soil caused an increase in S content in the forage, and Yudong black goats feeding on high S forage resulted in a decrease in Cu absorption, which led to a secondary Cu deficiency.

Studies of a Naturally Occurring Selenium-Induced Microcytic Anemia in the Przewalski's Gazelle.

Due to the fencing of the Przewalski's gazelle (Procapra przewalskii), the microcytic anemia incidence rate continues to increase. The primary pathological symptoms include emaciation, anemia, pica, inappetence, and dyskinesia. To investigate the cause of microcytic anemia ailment in the Przewalski's gazelle, the Upper Buha River Area with an excessive incidence was chosen as the experimental pasture, and the Bird Island Area without microcytic anemia disease was chosen as the control field. Then, the mineral contents in the soil, forage, blood, and liver, as well as the blood routine parameters and biochemical indexes were measured. The findings showed that the experimental pasture had much lower Se content in the soil and forage than the control field (p < 0.01), while the impacted pasture had significantly higher S content in the forage. The damaged gazelles had considerably lower Se and Cu contents and higher S content in the blood and liver than the healthy gazelles (p < 0.01). The presences of Hb, HCT, MCV, and MCH were significantly decreased compared to those in healthy gazelles (p < 0.01). The experimental group had a significantly lower level of GSH-Px activity in their serums compared to the control group (p < 0.01). In the treatment experiment, ten gazelles from the affected pasture were orally administered CuSO4, 6 g/animal once every 10 days for two consecutive times, and all gazelles were successfully cured. Therefore, it is possible that low Se content in the soil induced an increase in the absorption of S content by forage, leading to the deficiency of secondary Cu in the Przewalski's gazelles, resulting in microcytic anemia.

Glycyrrhiza Extract and Curcumin Alleviates the Toxicity of Cadmium via Improving the Antioxidant and Immune Functions of Black Goats.

To investigate the mitigative effects of glycyrrhiza extract (GE) and curcumin (CUR) on the antioxidant and immune functions of the Guizhou black goat exposed to cadmium (Cd), 50 healthy Guizhou black goats (11.08 ± 0.22 kg, male, six months old) were used in a 60-day trial and were randomly assigned to five groups with 10 replicates per group, one goat per replicate. All goats were fed a basal diet, with drinking water and additives varying slightly between groups. Control group: tap water (0.56 µg·L-1 Cd); Cd group: drinking water containing Cd (20 mg Cd·kg-1·body weight, CdCl2·2.5H2O); GE group: drinking water containing Cd, at days 31 to 60, the basic diet had added 500 mg·kg-1 GE; CUR group: drinking water containing Cd, at days 31 to 60, the basic diet had added 500 mg·kg-1 CUR; combined group: drinking water containing Cd, at days 31 to 60, the basic diet had added 500 mg·kg-1 GE and CUR. Compared with the Cd group, GE and CUR significantly increased the levels of hemoglobin and red blood cell count in the blood, and the activities of serum antioxidant enzyme activity and immune function in the Guizhou black goat (p < 0.05). The treatment effect in the combined group was better than that in the GE and CUR groups. The results showed that GE and CUR improved the antioxidant and immune functions of the serum and livers of the Guizhou black goat and alleviated the toxicity damage of Cd contamination. This research has positive implications for both livestock management and human health.

Identification of exosome protein panels as predictive biomarkers for non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related deaths worldwide, primarily due to its propensity for metastasis. Patients diagnosed with localized primary cancer have higher survival rates than those with metastasis. Thus, it is imperative to discover biomarkers for the early detection of NSCLC and the timely prediction of tumor metastasis to improve patient outcomes. METHODS: Here, we utilized an integrated approach to isolate and characterize plasma exosomes from NSCLC patients as well as healthy individuals. We then conducted proteomics analysis and parallel reaction monitoring to identify and validate the top-ranked proteins of plasma exosomes. RESULTS: Our study revealed that the proteome in exosomes from NSCLC patients with metastasis was distinctly different from that from healthy individuals. The former had larger diameters and lower concentrations of exosomes than the latter. Furthermore, among the 1220 identified exosomal proteins, we identified two distinct panels of biomarkers. The first panel of biomarkers (FGB, FGG, and VWF) showed potential for early NSCLC diagnosis and demonstrated a direct correlation with the survival duration of NSCLC patients. The second panel of biomarkers (CFHR5, C9, and MBL2) emerged as potential biomarkers for assessing NSCLC metastasis, of which CFHR5 alone was significantly associated with the overall survival of NSCLC patients. CONCLUSIONS: These findings underscore the potential of plasma exosomal biomarkers for early NSCLC diagnosis and metastasis prediction. Notably, CFHR5 stands out as a promising prognostic indicator for NSCLC patients. The clinical utility of exosomal biomarkers offers the potential to enhance the management of NSCLC.

Characterization of Spray-Dried Microcapsules of Paprika Oleoresin Induced by Ultrasound and High-Pressure Homogenization: Physicochemical Properties and Storage Stability.

As an indispensable process in the microencapsulation of active substances, emulsion preparation has a significant impact on microencapsulated products. In this study, five primary emulsions of paprika oleoresin (PO, the natural colourant extracted from the fruit peel of Capsicum annuum L.) with different particle sizes (255-901.7 nm) were prepared using three industrialized pulverization-inducing techniques (stirring, ultrasound induction, and high-pressure homogenization). Subsequently, the PO emulsion was microencapsulated via spray drying. The effects of the different induction methods on the physicochemical properties, digestive behaviour, antioxidant activity, and storage stability of PO microencapsulated powder were investigated. The results showed that ultrasound and high-pressure homogenization induction could improve the encapsulation efficiency, solubility, and rehydration capacity of the microcapsules. In vitro digestion studies showed that ultrasound and high-pressure homogenization induction significantly increased the apparent solubility and dissolution of the microcapsules. High-pressure homogenization induction significantly improved the antioxidant capacity of the microcapsules, while high-intensity ultrasound (600 W) induction slowed down the degradation of the microcapsule fats and oils under short-term UV and long-term natural light exposure. Our study showed that ultrasound and high-pressure homogenization equipment could successfully be used to prepare emulsions containing nanoscale capsicum oil resin particles, improve their functional properties, and enhance the oral bioavailability of this bioactive product.

Cadmium Exposure Affects Serum Metabolites and Proteins in the Male Guizhou Black Goat.

Food safety and environmental pollution are the hotspots of general concern globally. Notably, long-term accumulation of trace toxic heavy metals, such as cadmium (Cd), in animals may endanger human health via the food chain. The mechanism of Cd toxicity in the goat, a popular farmed animal, has not been extensively investigated to date. Therefore, in this study, ten male goats (Nubian black goat × native black goat) were exposed to Cd via drinking water containing CdCl2 (20 mg Cd·kg-1·BW) for 30 days (five male goats per group). In this study, we used an integrated approach combining proteomics and metabolomics to profile proteins and metabolites in the serum of Cd-exposed goats. It was found that Cd exposure impacted the levels of 30 serum metabolites and 108 proteins. The combined proteomic and metabolomic analysis revealed that Cd exposure affected arginine and proline metabolism, beta-alanine metabolism, and glutathione metabolism. Further, antioxidant capacity in the serum of goats exposed to Cd was reduced. We identified CKM and spermidine as potential protein and metabolic markers, respectively, of early Cd toxicity in the goat. This study details approaches for the early diagnosis and prevention of Cd-poisoned goats.

Abnormal Phenylalanine Metabolism of Procapra przewalskii in Chronic Selenosis in Selenium-Enriched Habitats.

Selenium (Se)-enriched habitats have led to chronic selenosis, seriously affecting the health and survival of Procapra przewalskii (P. przewalskii). Our targets were to explore the molecular mechanisms of chronic selenosis and to look for a new way to protect endangered species. The mineral contents of soils, grass, blood, and muscle were analyzed. The biochemical indices, antioxidant capability, and immune function were also investigated. The analyses of proteomics and metabolomics were also carried out. The results showed that the Se contents in the muscle and blood of P. przewalskii, and the soil and grass in the Se-enriched habitats were significantly higher than those in healthy pastures. The P. przewalskii in the Se-enriched habitats showed symptoms of anemia, decreased antioxidant capability, and low immune function. A total of 44 differential proteins and 36 differential metabolites were screened by analyzing their proteomics and metabolomics. These differential proteins and metabolites were involved in glycolysis pathway, amino acid biosynthesis, carbon metabolism, phenylalanine metabolism, and energy metabolism. In particular, phenylalanine metabolism was the common pathway of proteomics and metabolomics, which was an important finding in studying the mechanism of chronic selenosis in animals. This study will help us to further understand the mechanism of chronic selenosis in P. przewalskii, and it provides a scientific basis for the protection of endangered species in Se-enriched habitats.

Analysing transcriptomic signatures and identifying potential genes for the protective effect of inactivated COVID-19 vaccines.

Inactivated vaccines are one of the most effective strategies for controlling the coronavirus disease 2019 (COVID-19) pandemic. However, the response genes for the protective effect of inactivated vaccines are still unclear. Herein, we analysed the neutralization antibody responses elicited by vaccine serum and carried out transcriptome sequencing of RNAs isolated from the PBMCs of 29 medical staff receiving two doses of the CoronaVac vaccine. The results showed that SARS-CoV-2 neutralization antibody titers varied considerably among individuals, and revealed that many innate immune pathways were activated after vaccination. Furthermore, the blue module revealed that NRAS, YWHAB, SMARCA5, PPP1CC and CDC5L may be correlated with the protective effect of the inactivated vaccine. Additionally, MAPK1, CDC42, PPP2CA, EP300, YWHAZ and NRAS were demonstrated as the hub genes having a significant association with vaccines. These findings provide a basis for understanding the molecular mechanism of the host immune response induced by inactivated vaccines.

Effects of Cadmium on Liver Function and Its Metabolomics Profile in the Guizhou Black Goat.

Cadmium (Cd) is a toxic heavy metal, which will lead to ecosystem contamination, threatening the life of grazing animals. Goats are an important grazing animal biomarker to evaluate Cd toxicity, but the effect of short-term and high-concentration Cd toxicity on goat liver function and its latent mechanism is still unclear. A total of ten male Guizhou black goats were randomly divided into two groups: CON group, sterilized tap water (no CdCl2), and Cd group (20 mg Cd·kg-1·BW, CdCl2⋅2.5H2O). The test lasted for 30 days. In this study, we found that Cd poisoning in drinking water affected significantly the distribution of Cd in the goat offal and tissues, and damaged the goat's immune function of the liver. With a metabolomics approach, 59 metabolites were identified. Metabolomics analysis suggested that Cd affected lipid and amino acid metabolism of the goat liver. Collectively, our results confirmed the effect of Cd on liver function and liver metabolism, and provided insights on the molecular basis for early warnings of Cd poisoning in goats.

Molybdenum fertilizer improved antioxidant capacity of Chinese Merino sheep under compound contamination.

To investigate the response of different levels of molybdenum (Mo) fertilizer to Chinese Merino sheep (Junken Type) grazing on natural heavy metal-contaminated meadows, this study was carried out in the Bayanbulak Grassland lying in the northwest of Xinjiang Uygur Autonomous Region, China. A total of 24-hm2 polluted meadows were fenced and were randomly divided into four groups (3 replication/group and 2 hm2/replication) applied 0-kg Mo, 1-kg Mo, 2-kg Mo, and 3-kg Mo (ammonium molybdate tetrahydrate) per hectare for the CON group, group I, group II, and group III, respectively. Seventy-two healthy 1-year-old Chinese Merino sheep (45.56 ± 2.35 kg) were randomly assigned to the tested pastures for 90 days. Compared with the CON group, the Mo content from fertilized groups and the Se content from group II and group III in serums and livers were significantly increased (P < 0.05), and the Cu content from fertilized groups in serums and livers was significantly decreased (P < 0.05). The levels of blood Hb and RBC, and the activities of serum SOD, CAT, GSH-Px, and Cp in group III, were significantly higher (P < 0.05) than those in the CON group, group I, and group II. Serum MDA content in group III was significantly lower (P < 0.05) than that in the other three groups. In summary, Mo fertilization improved the antioxidant capacity of grazing sheep and also reduced the toxic damage to Chinese Merino sheep grazing on natural grasslands contaminated by heavy metals, but Mo poisoning caused by excessive fertilization should be prevented.

Effects of Nano-Cu2O on the Productivity in the Cu-Stripped Chinese Merino Sheep.

This research is to study the effects of nano-Cu2O on blood parameters, growth performance, and wool yield in the Cu-stripped ranches, and provide reference for further study on prevention and treatment in Cu-deficient Chinese Merino sheep. We selected twenty Chinese Merino sheep from Cu-deficient and normal ranch, respectively. The results have shown that the Cu content in the soils, forages, blood, and wool from Cu-deficient ranches was significantly lower than those from normal ranches (P < 0.01). There were no significant differences in the contents of other elements. Treatment experiments of nano-Cu2O were carried out for 50 days. We found that the Cu content in the blood was increased continuously in the sheep after adding nano-Cu2O, and reached the highest level at 40 days. The levels of Hb, RBC, PCV, MCV, and MCH in the nano-Cu2O-fed animals were remarkably higher than those in the control animals (P < 0.01). The daily gain and wool yield in the nano-Cu2O-fed animals were also significantly higher than those in the control sheep (P < 0.01). Therefore, adding nano-Cu2O not only remarkably increases the Cu content in the blood, but also greatly improves the daily gain and wool yield in Cu-deficient animals.

Effects of Molybdenosis on Antioxidant Capacity in Endangered Przewalski's Gazelles in the Qinghai Lake National Nature Reserve in the Northwestern China.

The purpose of this study is to investigate the effects of molybdenosis on antioxidant capacity in endangered Przewalski's gazelles (Procapra przewalskii) in the animal rescue center in the Qinghai Lake National Nature Reserve in Northwestern China. Ten P. przewalskii in molybdenosis were selected and treated orally with copper sulfate (CuSO4) at a dose of 20 g/animal/5 days for 20 days. Ten healthy P. przewalskii were also selected and allocated to healthy pastures for 20 days. Samples of soil, forage, and animal tissue were collected. The values of mineral and hematological parameters were measured. Results showed levels of molybdenum (Mo) in soil and forage were significantly higher than those in healthy ranches (P < 0.01). The Mo content of blood and hair in gazelles from the rescue center was also significantly higher than those in the healthy ranches animals (P < 0.01). The copper (Cu) contents in blood and hair from the rescue center were significantly lower than those from the healthy pasture (P < 0.01). Hemoglobin (Hb) and red cell volume (PCV) in the gazelles from the animal rescue center were significantly lower than those from animals in healthy ranches (P < 0.01). Aspartate aminotransferase (AST), lactate dehydrogenase (LDH), phosphocreatine kinase (CPK), and alkaline phosphatase (ALP) were significantly higher than those from gazelles in healthy ranches (P < 0.01). The antioxidant capacity in gazelles from the animal rescue center was significantly lower than that of gazelles in healthy ranches. Supplementing CuSO4 significantly decreased the Mo content of blood and cured molybdenosis in gazelles. In summary, the Mo content of soil and forage was very excessive for gazelles in the animal rescue center. The antioxidant capacity of P. przewalskii has been seriously affected by molybdenosis.

Effect of Mulberry Leaf TMR on Growth Performance, Meat Quality and Expression of Meat Quality Master Genes (ADSL, H-FABP) in Crossbred Black Goats.

This study was conducted to examine the effect of a mulberry leaf total mixed ration (TMR) diet on growth performance, apparent digestibility, meat quality and the expression of related meat-quality genes (ADSL, H-FABP) in crossbred black goats. Forty-four Guizhou crossbred black goats (Nubian black goat ♂ × Guizhou black goat ♀), weighing 33.43 ± 0.55 kg, were chosen. The goats were randomly divided into four groups, with 11 test replicates in each group. Group I was the control group and fed with the traditional feeding method of roughage and concentrate supplement without adding mulberry leaf. Group II was fed with a 40% mulberry leaf pellet TMR diet. Group III was fed with a freshly processed 40% mulberry leaf TMR diet. Group IV was fed with a 40% mulberry leaf fermented total mixed rations (FTMR) diet. The results showed that the average daily gain (ADG) of group II was significantly higher than that of group I and III (p < 0.05). The apparent digestibility of group II of ether extract (EE) and neutral detergent fiber (NDF) was significantly higher than that of group I (p < 0.05), and the apparent digestibility of dry matter (DM) and crude protein (CP) was significantly higher than that of group I (p < 0.01). Compared with group I, meat in group II had lower meat color lightness (L*) and yellowness (b*) values (p < 0.01) in the Longissimus thoracis et lumborum. The shear force of group II was significantly lower than that of group I (p < 0.05). The total fatty acids (TFA) of group II was significantly higher than that of groups I and III (p < 0.05), but the total saturated fatty acids (SFA) of group II was significantly lower that than of group I (p < 0.01). Subsequently, the Unsaturated fatty acids (USFA), Monounsaturated fatty acids (MUFA), and Polyunsaturated fatty acids (PUFA) of group II were significantly higher than those in group I (p < 0.01). The contents of total amino acids (TAA), total essential amino acids (EAA), total non-essential amino acids (NEAA) and total of major fresh-tasting amino acids (DAA) of groups II, III and IV were significantly higher than those of group I (p < 0.05), as well as the contents of IMP (p < 0.01). The expression of the H-FABP gene in the arm triceps of group II was significantly higher than that of groups I, III and IV (p < 0.05). The expression of the ADSL gene in the Longissimus thoracis et lumborum and biceps femoris of group II was significantly higher than that of group I (p < 0.05). Collectively, the results of the current study indicated that the mulberry leaf TMR diet improved the growth performance, apparent digestibility and expression of related meat-quality master genes (ADSL, H-FABP) in crossbred black goats, which promoted the deposition of intramuscular fat (IMF) and inosinic acid (IMP) and improved the composition of fatty acids and amino acids in the muscles.

The impact of CoronaVac on the neutralization breadth and magnitude of the antibody response to SARS-CoV-2 viruses.

Although immune response enhancement has been reported after primary and booster vaccines of CoronaVac, neutralization breadth of SARS-CoV-2 variants is still unclear. In the present study, we examined the neutralization magnitude and breadth of SARS-CoV-2 variants including Beta (B.1.351), Delta (B.1.617.2) and Omicron (B.1.1.529) in 33 convalescent COVID-19 patients and a cohort of 55 medical staff receiving primary CoronaVac vaccines and an additional homologous booster dose. Results showed that, as compared with the two-dose primary vaccination, the homologous booster dose achieved 2.24-, 3.98-, 4.58- and 2.90-fold increase in neutralization titer against wild-type, Beta, Delta, and Omicron, respectively. After booster dose, neutralization titer reduction for variants was less than that after the primary vaccine or that for convalescents. The proportion of recipients able to neutralize 2 or more variants increased from 36.36% post the primary vaccination to 87.27% after the booster. Significant increase in neutralization breadth of 1.24 (95% confidence interval (CI), 0.89-1.59) variants was associated with a log10 increase in neutralization titer against the wild-type. In addition, anti-RBD IgG level was identified as an excellent surrogate for positive neutralization of SARS-CoV-2 and neutralization breadth of variants. These findings highlight the value of an additional homologous CoronaVac dose in broadening the cross-neutralization against SARS-CoV-2 variants, and are critical for informing the booster dose vaccination efforts.

Concomitant viral and bacterial pneumonia among patients in ICU with mechanical respiratory support.

INTRODUCTION: The use of mechanical ventilators in the intensive care unit (ICU) is often associated with higher risk of respiratory tract infections, including ventilator-associated pneumonia (VAP). Concomitant bacterial-viral infection was reported to worsen patient's clinical condition. This study evaluated the rate of concomitant bacterial-viral infections in patients with VAP and analyzed their clinical outcomes. METHODOLOGY: In this retrospective observational study 107 patients diagnosed with VAP and admitted in ICU with mechanical ventilator support between April 2018 and May 2019 in the Department of Respiratory Medicine, Dachang Hospital, Shanghai, China were included. 27 most commonly involved lower respiratory tract infection (LRTI) pathogens (bacteria and virus) and seven genetic markers of antibiotic resistance were detected and analyzed using Biofire® FilmArray® Pneumonia Panel plus (bioMérieux SA, Paris, France). RESULTS: Of the 107 patients, 45 (42.1%) patients had bacterial infection alone (bacterial group), 26 (24.3%) had virus infection alone (viral group) and 24 (22.4%) patients had concomitant bacterial-viral infection (mixed group). Sixty-nine (64.5%) and 50 (46.7%) patient samples were positive for bacterial (bacterial and mixed groups) and viral (viral and mixed groups) detection, respectively. Streptococcus pneumonia (11.2%) and Influenza A (17, 15.9%), were the predominantly identified bacterial and viral species. The blaCTX-M (21.5%) was the predominant resistance gene detected. Twenty-four (22.4%) patients were positive for concomitant bacterial-viral infection; Staphylococcus aureus and Influenza A were the most common bacterial-viral combination identified. CONCLUSIONS: Concomitant bacterial-viral infection was higher compared to previously published studies and the increased duration of mechanical ventilation was associated with increased disease severity.

Efficacy and Safety of the Ketogenic Diet for Mitochondrial Disease With Epilepsy: A Prospective, Open-labeled, Controlled Study.

Background: The ketogenic diet (KD) is increasingly used to treat drug-resistant epilepsy because of its favorable effect on seizure reduction. Patients with mitochondrial diseases tend to experience seizures. Therefore, this study aimed to test the efficacy of the KD on participants with mitochondrial diseases in a controlled trial. Methods: Participants from fourteen clinical centers who were diagnosed with mitochondrial disease were semi-randomized to either the intervention (KD) or control group. The KD group followed a 3-month KD intervention, while the control group received a 1-month normal diet initially and then a 3-month KD intervention. The primary outcome measure was seizure reduction. Biomarker changes, cognitive impairments, and side effects were also recorded, if available. Result: A total of 33 participants were assigned to the KD (n = 22) and control groups (n = 11). In the KD group, 31.8% (7/22) of participants achieved ≥50% seizure reduction after 1 month of diet intervention, which increased to 40.9% (9/22) at 3 months. In the control group, only 18.2% (2/11) of the participants had ≥50% seizure reduction during the normal diet period. After the control group was transferred to the KD, 63.6% (7/11) of participants had >50% seizure reduction, and this rate increased to 72.7% (8/11) at 3 months. The KD also showed high efficacy in participants with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) or pathogenic variants in mitochondrial DNA (mtDNA) (90% and 93.3% response rates, respectively). The most frequent side effects reported at the 3-month review were vomiting, cold, hyperlipidemia, and bloating. Conclusion: The KD is a safe and effective therapy for seizure control in mitochondrial diseases, especially MELAS and pathogenic variants of mtDNA. KD intervention can be considered in the management of these patients.

Gasdermin D-mediated pyroptosis suppresses liver regeneration after 70% partial hepatectomy.

Pyroptosis is a kind of programmed cell death primarily mediated by gasdermin D (GSDMD) and shown to regulate multiple diseases. However, its contribution to liver regeneration, a fine-tuned tissue repair process mediated primarily by hepatocytes after mass loss, remains unclear. Herein, we found that caspase-11/GSDMD-mediated pyroptosis was activated in regenerating liver after 70% partial hepatectomy. Impeding pyroptosis by deleting GSDMD significantly reduced liver injury and accelerated liver regeneration. Mechanistically, GSDMD deficiency up-regulates the activation of hepatocyte growth factor/c-Met and epidermal growth factor receptor mitogenic pathways at the initiation phase. Moreover, activin A and glypican 3 (GPC3), two terminators of liver regeneration, were inhibited when GSDMD was absent. In vitro study suggested the expressions of activin A and GPC3 were induced by interleukin (IL)-1ß and IL-18, whose maturations were regulated by GSDMD-mediated pyroptosis. Similarly, pharmacologically inhibiting GSDMD recapitulates these phenomena. Conclusion: This study characterizes the role of GSDMD-mediated pyroptosis in liver regeneration and lays the foundation for enhancing liver restoration by targeting GSDMD in liver patients with impaired regenerative capacity.

The Invasive Potential of Hepatoma Cells Induced by Radiotherapy is Related to the Activation of Hepatic Stellate Cells and Could be Inhibited by EGCG Through the TLR4 Signaling Pathway.

Post-radiotherapy recurrence and metastasis of liver cancer were thought to arise from the invasion and metastasis of residual hepatocellular carcinoma cells, but it has now been shown to be closely related to the increased metastatic potential of residual liver cancer cells mediated by radiotherapy. The changes of liver microenvironment after radiotherapy also provide a favorable condition for promoting the metastatic potential of hepatocellular carcinoma. Studies have shown that radiation-induced activation of hepatic stellate cells (HSCs) is one of the main changes in the microenvironment of hepatocellular carcinoma. Therefore, we hypothesized that activated HSCs are involved in regulating the metastatic capacity of residual cancer cells after radiotherapy. The present study observed that 48 h co-culture of three human hepatoma cell lines (MHCC97-L, Hep-3B, LM3) with a irradiated human HSC line (LX-2) in a transwell chamber could significantly improve the invasion of the human hepatoma cells; and the culture supernatant of activated HSCs could also enhance the invasion of the hepatoma cells. In contrast, co-culture with irradiated hepatoma cells enhanced the invasion of LX-2 cells. In vitro, irradiation enhanced the activation phenotype and the toll like receptor 4 (TLR4) signaling pathway of LX-2 cells or primary mouse HSCs, which upregulated intercellular cell adhesion molecule-1 (ICAM1), laminin receptor (67 LR), Interleukin- 6 (IL-6), and CX3C chemokine ligand 1 (CX3CL1) and downregulated toll-interacting proteins. The compound (-)-epigallocatechin-3-gallate (EGCG) inhibited signal transduction of activated TLR4 and radiation-induced invasion of LX-2 cells by binding to 67 LR. These observations indicated that the enhancement of the metastatic potential of hepatoma cells after irradiation was relevant to the activation of HSCs, and the activation of TLR4 signaling pathway was involved in this process, which was inhibited by EGCG. Our results will help enhance the therapeutic efficacy of liver cancer stereotactic body radiation therapy to prevent and decrease the risks of post-radiotherapy recurrence and metastasis.