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Background The characteristics, outcomes, and risk factors for in-hospital death of critically ill intensive care unit (ICU) patients with coronavirus disease-2019 (COVID-19) have been described in patients from Europe, North America and China, but there are few data from COVID-19 patients in Middle Eastern countries. The aim of this study was to investigate the characteristics, outcomes, and risk factors for in-hospital death of critically ill patients with COVID-19 pneumonia admitted to the ICUs of a University Hospital in Egypt. Methods Retrospective analysis of patients with COVID-19 pneumonia admitted between April 28 and July 29, 2020 to two ICUs dedicated to the isolation and treatment of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Cairo University Hospitals. Diagnosis was confirmed in all patients using real-time reverse transcription polymerase chain reaction on respiratory samples and radiologic evidence of pneumonia. Results Of the 177 patients admitted to the ICUs during the study period, 160 patients had COVID-19 pneumonia and were included in the analysis (mean age: 60 ± 14 years, 67.5% males); 23% of patients had no known comorbidities. The overall ICU and hospital mortality rates were both 24.4%. The ICU and hospital lengths of stay were 7 (25–75% interquartile range: 4–10) and 10 (25–75% interquartile range: 7–14) days, respectively. In a multivariable analysis with in-hospital death as the dependent variable, ischemic heart disease, history of smoking, and secondary bacterial pneumonia were independently associated with a higher risk of in-hospital death, whereas greater PaO2/FiO2 ratio on admission to the ICU was associated with a lower risk. Conclusion In this cohort of critically ill patients with COVID-19 pneumonia, ischemic heart disease, history of smoking, and secondary bacterial pneumonia were independently associated with a higher risk of in-hospital death.

Highlights • A low-cost manufacturing process for a neonatal rotavirus vaccine was developed. • The formulation process developed resulted in a stable liquid vaccine at 2–8 °C. • No pretreatment of vaccinees with antacid needed before oral administration. • Tech. transfer package includes manufacturing, formulation, assays and COGs model., Despite solid evidence of the success of rotavirus vaccines in saving children from fatal gastroenteritis, more than 82 million infants worldwide still lack access to a rotavirus vaccine. The main barriers to global rotavirus vaccine coverage include cost, manufacturing capacity and suboptimal efficacy in low- and lower-middle income countries. One vaccine candidate with the potential to address the latter is based on the novel, naturally attenuated RV3 strain of rotavirus, RV3-BB vaccine administered in a birth dose strategy had a vaccine efficacy against severe rotavirus gastroenteritis of 94% at 12 months of age in infants in Indonesia. To further develop this vaccine candidate, a well-documented and low-cost manufacturing process is required. A target fully loaded cost of goods (COGs) of ≤$3.50 per course of three doses was set based on predicted market requirements. COGs modelling was leveraged to develop a process using Vero cells in cell factories reaching high titers, reducing or replacing expensive reagents and shortening process time to maximise output. Stable candidate liquid formulations were developed allowing two-year storage at 2–8 °C. In addition, the formulation potentially renders needless the pretreatment of vaccinees with antacid to ensure adequate gastric acid neutralization for routine oral vaccination. As a result, the formulation allows small volume dosing and reduction of supply chain costs. A dose ranging study is currently underway in Malawi that will inform the final clinical dose required. At a clinical dose of ≤6.3 log10 FFU, the COGs target of ≤$3.50 per three dose course was met. At a clinical dose of 6.5 log10 FFU, the final manufacturing process resulted in a COGs that is substantially lower than the current average market price, 2.44 USD per dose. The manufacturing and formulation processes were transferred to BioFarma in Indonesia to enable future RV3-BB vaccine production.

Typhoid vaccines based on protein-conjugated capsular Vi polysaccharide (TCVs) prevent typhoid in infants and young children. Analysis of the serum anti-Vi IgG response following immunisation against typhoid confirms the immunogenicity of TCVs and forms an important part of the pathway to licensing. Comparative studies could expedite the licencing process, and the availability of a standardised ELISA method alongside the 1st International Standard (IS) 16/138 for anti-typhoid capsular Vi polysaccharide IgG (human) will facilitate this process. To this end, a non-commercial ELISA based on a coat of Vi and poly-l-lysine (Vi-PLL ELISA) was evaluated by 10 laboratories. Eight serum samples, including IS 16/138, were tested in the standardised Vi-PLL ELISA (n = 10), a commercial Vi ELISA (n = 3) and a biotinylated Vi ELISA (n = 1). Valid estimates of potencies relative to IS 16/138 were obtained for all samples in the Vi-PLL ELISA and the commercial ELISA, with good repeatability and reproducibility evident from the study results and concordant estimates obtained by the two ELISA methods. The study demonstrates that the Vi-PLL ELISA can be used in clinical trial studies to determine the immunogenicity of TCVs.

Graphical abstract, Highlights • Murraya koenigii induced higher cytotoxicity in Dalton’s lymphoma through apoptotic cell death as compared to other plants under study. • The plant extract mediated apoptotic cell death is mediated by ROS generation and caspases activation. • The study support the ethnomedicinal uses of these plants extracts and suggests further validation in other human cancer cell lines. • Conservation organization would eventually need to document this indigenous traditional knowledge (TK)., Annonareticulate (Mart.), Lablab purpureus (L.) Sweet, Murrayakoenigii (L.) Spreng, Moringaoleifera (Lam.), Hibiscussabdariffa (L.) and Euphorbiahirta (L.) are most commonly used medicinal plants by the traditional healers of Karbi Anglong district of Assam, India against different human ailments including cancer suspected cases. The proposed study includes field survey related to ethnomedicinal aspects of medicinal plants, phytochemical analysis, and evaluation of their cytostatic potential with the possible mode of action against Dalton's lymphoma (DL) cell line. The phytochemical analysis of all the plant's extract was studied using standard protocol. The cytotoxicity of the methanol extracts was determined by MTT reduction assay. The effect of the same extract was also tested for development of apoptosis features in DL cells using a fluorescence microscope and flowcytometry. The underlying mechanism closely associated with apoptotic cell death was also studied by measuring reactive oxygen species (ROS), mitochondrial membrane potential, and expression level of apoptosis inducing proteins. Murraya koenigii induced more apoptotic features in DL cells, followed by Annona reticulate. The decrease in mitochondrial membrane potential, release of cytochrome- c, increase in ROS level and higher expression of caspases (3 and 9) after plant extracts treatment may cause involvement of mitochondria in the process of apoptosis. From this study, it can be concluded that the plant species mainly Murraya koenigi and Annona reticulate significantly induced cytotoxicity in DL cells through apoptosis by utilizing mitochondrial pathway.

Introduction One of the relatively rare hemostatic disorders is coagulation factors' deficiency, where a single factor or multiple factors can be deficient. All hereditary coagulation factors' deficiencies are autosomal recessive, so they can manifest in both genders, but Hemophilia A and B are X-linked disorders. Therefore, females can rarely be affected. This paper reports the first case of simultaneous coagulation factors’ deficiencies of FVIII and FXI in a female. Case presentation A 17-year-old female came to the office due to prolonged epistaxis, with a history of severe menstrual bleeding and frequent episodes of epistaxis. In her familial history, a brother complained of epistaxis episodes. Bleeding time and prothrombin time were normal but activated partial thromboplastin time was increased. Von Willebrand disease was excluded, and she was diagnosed with hemophilia A and C. Discussion Females can be affected with X-linked disorders such as hemophilia A and B in some rare cases: a carrier mother and affected father, skewed X chromosome inactivation, Turner syndrome, inhibiting antibodies (acquired hemophilia), or a sporadic mutation on the most activated X chromosome. On the other hand, Hemophilia C is an autosomal recessive disease. Treatment of such cases is a challenge, and the recombinant coagulation factors are the treat-of-choice. Conclusion Although Von Willebrand disease is the most common hereditary bleeding disorder in females, other rare diseases could be suspected such as Hemophilia. X-linked Hemophilia should be kept in mind as a differential diagnosis in any female patient suffering from hemorrhage., Highlights • This study is the first case of both Hemophilia A and C in a female. • Females can be affected with X-linked disorders such as hemophilia A in rare cases. • Treatment of combined Coagulation factors' deficiencies is a challenge.

Objectives: Systemic to pulmonary shunt (commonly known as Modified Blalock–Taussig shunt) is a palliative procedure in cyanotic heart diseases to overcome inadequate blood flow to the lungs. Based on the most recent risk stratification score, the mortality and morbidity of this procedure is still high especially in neonates and over-shunting patients. We developed and implemented protocol-based management in March 2013 to better standardize the management of these patients. The aim of this study is to evaluate the effects of applying this protocol-based management in our center. Methods: We conducted a retrospective cohort study through chart review analysis.We included all children who underwent MBTS from January 2000 till December 2015. We compared the early postoperative outcome of patients operated after the protocol-based management implementation (March 2013 till December 2015) (protocol group) with patients operated before implementing the MBTS protocoled management (control group). Results: 197 patients underwent MBTS from January 2000 till December 2015. Of the 197 patients, 25 patients were in the protocol group and 172 patients were in the control group. There was a significant improvement in the postoperative course and less morbidity after protocoled management implementation as reflected in ventilation time, reintubation rate, inotropic support duration, intensive care unit ICU stay and significantly lower postoperative complications in the protocol group. Mortality of the control group versus protocol group (19.3% VS 8%) with Standardized Mortality Ratio (SMR) dropped from 2.27 before protocoled management to 0.94 after protocoled management (protocol group). Conclusion: The study suggests that protocoled management of patients with MBTS can improve the postoperative course and early outcome. Keywords: Congenital heart disease, Post-operative, Pediatric, Cardiac surgery, Blalock–Taussig shunt

Background Systematic review and meta-analyses of observational studies on maternal vitamin D status and risk of respiratory allergic conditions indicated that mothers who had supplementation during pregnancy could decrease the risk of recurrent wheeze or asthma in their offspring. Objectives We conducted this meta-analysis of Randomized Controlled Trials with the primary intention of detecting the effect of prenatal vitamin D supplementation on the offspring's asthma. Secondary outcomes under respiratory health include eczema, lower respiratory tract infections, Immunoglobulin E positive test, upper respiratory tract infections, and allergic rhinitis. Methods A comprehensive search of PubMed, ScienceDirect, Google Scholar, and Cochrane Library databases was performed to retrieve randomized controlled trials. Risk Ratio with 95% confidence intervals was computed from dichotomous data using a random-effects model, with I2 >50% representing notable heterogeneity. Results Six clinical trials met the inclusion criteria, involving a total of 2898 subjects (1461 experimental group and 1437 control group). There was non-significant inverse relationship between vitamin D intake during pregnancy and the occurrence of asthma in offspring (pooled RR = 0.89, 95% CI = 0.69–1.15, I2 = 46% and Z-static = 0.90, P-value = 0.37). There is no significant difference in the risk of assessed childhood respiratory problems due to maternal supplementation of vitamin D during pregnancy. Conclusion and implications Currently, there is no fertile evidence to promote vitamin D supplementation in pregnancy for childhood respiratory health. Future clinical trials should emphasize early initiation of vitamin D supplementation, consider 6 weeks to 6 months postnatal critical window for vitamin D deficiency for offspring, lower risk dose of vitamin D, and identify different phenotypes of asthma and response to vitamin D supplementation.

Contains fulltext : 225474.pdf (Publisher’s version ) (Open Access) Coronavirus disease-2019 (COVID-19) is associated with severe inflammation in mainly the lung, and kidney. Reports suggest a beneficial effect of the use of heparin/low molecular weight heparin (LMWH) on mortality in COVID-19. In part, this beneficial effect could be explained by the anticoagulant properties of heparin/LMWH. Here, we summarise potential beneficial, non-anticoagulant mechanisms underlying treatment of COVID-19 patients with heparin/LMWH, which include: (i) Inhibition of heparanase activity, responsible for endothelial leakage; (ii) Neutralisation of chemokines, and cytokines; (iii) Interference with leukocyte trafficking; (iv) Reducing viral cellular entry, and (v) Neutralisation of extracellular cytotoxic histones. Considering the multiple inflammatory and pathogenic mechanisms targeted by heparin/LMWH, it is warranted to conduct clinical studies that evaluate therapeutic doses of heparin/LMWH in COVID-19 patients. In addition, identification of specific heparin-derived sequences that are functional in targeting non-anticoagulant mechanisms may have even higher therapeutic potential for COVID-19 patients, and patients suffering from other inflammatory diseases.

Mechanical loading-related strains trigger bone formation by osteoblasts while suppressing resorption by osteoclasts, uncoupling the processes of formation and resorption. Osteocytes may orchestrate this process in part by secreting sclerostin (SOST), which inhibits osteoblasts, and expressing receptor activator of nuclear factor-κB ligand (RANKL/TNFSF11) which recruits osteoclasts. Both SOST and RANKL are targets of the master osteoblastic transcription factor RUNX2. Subjecting human osteoblastic Saos-2 cells to strain by four point bending down-regulates their expression of SOST and RANKL without altering RUNX2 expression. RUNX2 knockdown increases basal SOST expression, but does not alter SOST down-regulation following strain. Conversely, RUNX2 knockdown does not alter basal RANKL expression, but prevents its down-regulation by strain. Chromatin immunoprecipitation revealed RUNX2 occupies a region of the RANKL promoter containing a consensus RUNX2 binding site and its occupancy of this site decreases following strain. The expression of epigenetic acetyl and methyl writers and readers was quantified by RT-qPCR to investigate potential epigenetic bases for this change. Strain and RUNX2 knockdown both down-regulate expression of the bromodomain acetyl reader BRD2. BRD2 and RUNX2 co-immunoprecipitate, suggesting interaction within regulatory complexes, and BRD2 was confirmed to interact with the RUNX2 promoter. BRD2 also occupies the RANKL promoter and its occupancy was reduced following exposure to strain. Thus, RUNX2 may contribute to bone remodeling by suppressing basal SOST expression, while facilitating the acute strain-induced down-regulation of RANKL through a mechanosensitive epigenetic loop involving BRD2., Highlights • Mechanical strain reduces SOST and RANKL expression. • RUNX2 knockdown increases SOST levels. • RUNX2 facilitates strain-mediated RANKL suppression. • BRD2 expression is modulated by strain and RUNX2. • Strain alters BRD2 and RUNX2 occupancy at the RANKL promoter.

Highlights • Opuntia f-i cladodes are used as unique carbon source for wild microorganisms growth. • A. pittii and K. marxianus had hydrolytic activity on cladode flour, CF. • K. marxianus was the microorganisms more adequate for hydrolysis and fermentation. • The CF degradation process will allow bioethanol production with competitive yield., In the present work the effect of three factors: pH, temperature and type of microorganism using a factorial design 32x2 was evaluated on: growth, total cellulases hydrolytic activity (FPases), endoglucanases hydrolytic activity (CMCases), free reducing sugars (FRS), glucose, sucrose, and alcohol production using a culture medium based on mineral salts added with cladodes flour of Opuntia ficus-indica at 20% as the unique carbon source. Two wild microorganisms were used, Acinetobacter pittii a bacteria isolated from decaying cladodes, and Kluyveromyces marxianus a yeast isolated from termite stomach. The maximum hydrolytic activities were obtained with Acinetobacter pittii at 37 °C and pH 6.5 for total cellulases (0.67 ± 0.02 IU/ml) and for endoglucanases (0.23 ± 0.02 IU/ml) at 24 and 4 h. The maximum production of alcohol was 12.98 ± 0.06 g/L obtained with Kluyveromyces marxianus at 4 h with conditions of 40 °C and pH 5.5.

Vitamin D deficiency is a pandemic problem. Non-animal source of vitamin D is obtained from edible mushrooms. Oyster mushroom (Pleurotus ostreatus) was sliced into the size of 1 cm3, 4 cm3 and 9 cm3, and treated with the sun as a natural resource of UVB under subtropical settings in Ethiopia. The content of vitamin D was measured by using high-performance liquid chromatography (HPLC). After sun treatment, there was a significant increment in the content of vitamin D2 from nil to 67.4 ± 28.0 µg/g dry weight (DW). Based on the results of the overall pairwise comparisons, 1 cm3 size of slice group had the highest content of vitamin D2. Duration of sun exposure, sizes of mushroom slices and moisture content were identified as determining factors for vitamin D2 synthesis. Exposing slices of oyster mushroom to the sunlight for

Graphical abstract Highlights ► We developed a transcutaneous vaccine formulation using a hydrogel patch. ► We performed clinical trial for vaccination against tetanus and diphtheria in human. ► The vaccine formulation did not induce local or systemic severe adverse events. ► Toxoid-specific serum antibody titers increased by application of the formulation. ► This formulation will enable mass treatment and increase of vaccination rates., Transcutaneous immunization (TCI) is a non-invasive and easy-to-use vaccination method. We demonstrated the efficacy and safety of a transcutaneous vaccine formulation using a hydrogel patch in animal experiments. In the present study, we performed a clinical study to apply our TCI formulation for vaccination against tetanus and diphtheria in human. The TCI device was a hydrogel patch (antigen-free) applied to the left brachial medial skin of 22 healthy volunteers for 48 h. Next, the hydrogel patch, containing 2 mg tetanus toxoid (TT) and 2 mg diphtheria toxoid (DT) as the TCI formulation, was applied to 27 healthy volunteers for 24 h and some volunteers were vaccinated again by TCI formulation. For safety assessment, the patch application site was observed to assess local adverse events, and systemic adverse events were determined by a blood test. The antigen-free hydrogel patch and TCI formulation containing TT and DT did not induce local or systemic severe adverse events. For vaccine efficacy estimation, toxoid-specific serum antibody titers were determined by ELISA and the toxin-neutralizing activity of the induced antibody was evaluated in a passive-challenge experiment. The anti-TT IgG titer and the anti-DT IgG titer increased, and a significant effect was detected by paired t-test. The antibody titers were maintained at higher level than that before vaccination for at least 1 year. Moreover, toxoid-specific antibodies were produced by the second vaccination in some subjects. Antibodies induced by application of the TCI formulation neutralized the toxin and prevented toxic death in mice. In addition, changes in the skin condition due to application of the TCI formulation were observed under in vivo confocal Raman spectroscopy. The amount of water and patch components in the stratum corneum increased after application of the TCI formulation, suggesting that the change in the skin condition was related to antigen penetration. These data indicate that this easy-to-use TCI system induces an immune response without severe adverse reactions in humans. This easy-to-use and safe TCI formulation enables mass treatment in an outbreak setting and increased vaccination rates in developing countries, and will greatly contribute to worldwide countermeasures against infectious diseases.

This study reports a new immunomagnetic bead-based microfluidic system for the rapid detection of influenza A virus infection by performing a simple two-step diagnostic process that includes a magnetic bead-based fluorescent immunoassay (FIA) and an end-point optical analysis. With the incorporation of monoclonal antibody (mAb)-conjugated immunomagnetic beads, target influenza A viral particles such as A/H1N1 and A/H3N2 can be specifically recognized and are bound onto the surface of the immunomagnetic beads from the specimen sample. This is followed by labeling the fluorescent signal onto the virus-bound magnetic complexes by specific developing mAb with R-phycoerythrin (PE). Finally, the optical intensity of the magnetic complexes can be analyzed immediately by the optical detection module. Significantly, the limit of detection (LOD) of this immunomagnetic bead-based microfluidic system for the detection of influenza A virus in a specimen sample is approximately 5 × 10−4 hemagglutin units (HAU), which is 1024 times better than compared to conventional bench-top systems using flow cytometry. More importantly, the entire diagnostic protocol, from the purification of target viral particles to optical detection of the magnetic complexes, can be automatically completed within 15 min in this immunomagnetic bead-based microfluidic system, which is only 8.5% of the time required when compared to a manual protocol. As a whole, this microfluidic system may provide a powerful platform for the rapid diagnosis of influenza A virus infection and may be extended for diagnosis of other types of infectious diseases with a high specificity and sensitivity.

Gas chromatography/mass spectrometry (GC/MS) is the preferred technique for the detection of urinary steroid androgens for drug testing in athletics. Excreted in either the glucuronide or sulfated conjugated form, steroids must first undergo deconjugation followed by derivatisation to render them suitable for GC analysis. Discussed herein are the deconjugation and the derivatisation preparative options. The analytical challenges surrounding these preparatory approaches, in particular the inability to cleave the sulfate moiety have led to a focus on testing protocols that reply on glucuronide conjugates. Other approaches which alleviate the need for deconjugation and derivatisation are also highlighted.

Vitamin D is a fat-soluble hormone that traditionally has been linked to bone health. Recently, its involvement has been extended to other (extra-skeletal) disease areas, such as cancer, CVD, energy metabolism and autoimmune diseases. Vitamin D deficiency is a worldwide problem, and several recommendation-setting bodies have published guidelines for adequate vitamin D intake and status. However, recommendations from, for example, the Health Council of the Netherlands do not provide advice on how to treat vitamin D deficiency, a condition that is often encountered in the clinic. In addition, these recommendations provide guidelines for the maintenance of ‘minimum levels’, and do not advise on ‘optimum levels’ of vitamin D intake/status to further improve health. The NutriProfiel project, a collaboration between the Gelderse Vallei Hospital (Ede, the Netherlands) and the Division of Human Nutrition of Wageningen University (Wageningen, the Netherlands), was initiated to formulate a protocol for the treatment of vitamin deficiency and for the maintenance of optimal vitamin D status. To discuss the controversies around treatment of deficiency and optimal vitamin D status and intakes, a workshop meeting was organised with clinicians, scientists and dietitians. In addition, a literature review was conducted to collect recent information on optimal intake of vitamins, their optimal circulating concentrations, and effective dosing regimens to treat deficiency. This information has been translated into the NutriProfiel advice, which is outlined in this article.

In three successive experiments, the immune functions of pigs persistently infected with the porcine reproductive and respiratory syndrome virus (PRRSV) have been evaluated. Non-specific immune responses were analyzed over a period of 12 weeks post-infection (PI). In addition, the capacity of PRRSV-infected pigs to develop an efficient immune response against pseudorabies virus (PRV) glycoproteins and to resist to a subsequent virulent challenge was investigated. Our results demonstrate that PRRSV produced minor effects on the immune system of pigs. The skin delayed type hypersensitivity (DTH) in response to phytohemagglutinine injection was slightly diminished one week after challenge, but was restored thereafter. However, three weeks after the infection, the total white blood cell count, and the number of CD2+, CD8+ and IgM+ cells were enhanced. The increase in numbers of CD8+ cells persisted for three consecutive weeks. Serum immunoglobulins in infected pigs also increased by week 3 PI and up to 8 weeks PI. These results show that PRRSV may have stimulating effects on the pig immune system during the phase of long-lasting infection. After immunization with PRV glycoproteins, the production of anti-PRV antibodies and skin DTH response against PRV glycoproteins were not affected. On the contrary, following a virulent PRV challenge, PRRSV-infected pigs developed a better secondary antibody response and their resistance to the infection was as effective as in control pigs. Taken together, our data do not support a systemic immunosuppressive effect of PRRSV, during the persistent phase of infection. Other mechanisms may therefore apply to explain the emergence of secondary infections in endemically infected herds.

The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD) upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake) reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD + BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR), inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA) in the HFD + BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte., Highlights • BCAA cause hepatic injury via complex mechanisms involving both adipocytes and hepatic cells. • In the adipocyte, BCAA activate AMPKα2 and stimulate lipolysis, increasing plasma free fatty acids (FFA), which in turn results in hepatic FFA accumulation. • In the liver, BCAA activate mTOR and inhibit FFA to TG conversion and autophagy, intensifying FFA lipotoxicity. High fat diet (HFD) induces systemic BCAA catabolic defects. Under HFD conditions, increased BCAA consumption further increases circulating BCAA abundance. BCAA-enhanced adipocyte lipolysis induces hyperlipidemia through activating AMPKα2. Elevated circulating FFA results in insulin resistance and hepatic lipotoxicity. Moreover, BCAA activate hepatic mTOR, inhibit lipogenesis and autophagy, therefore increasing hepatic susceptibility to FFA-mediated lipotoxicity. As BCAA are abundant in protein, our results call for caution regarding the ingestion of high protein diets in obesity and diabetic individuals, unless their BCAA metabolic pathways are determined normal.