Elevated Lipid Research Articles

#1389 Identification of serum lipidomic profile in nephrotic syndrome patients

Abstract Background and Aims Nephrotic syndrome describes a collection of symptoms, mainly heavy proteinuria leading to kidney function loss, that can be caused by different underlying kidney diseases. Common primary causes of nephrotic syndrome include focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD) and membranous nephropathy (MN). Nephrotic syndrome is often characterized by plasma lipid abnormalities with elevations in cholesterol, triglycerides and lipoproteins. Here we set out to generate a detailed lipidomic analysis of FSGS, MCD and MN patient's plasma to find lipid changes common to nephrotic syndrome or specific for the underlying disease. Method For this lipidomic study, we included patients with primary FSGS (2 cohorts with n = 5), genetic FSGS (n = 5), MCD (n = 5) and MN (n = 5) in whom serum had been collected at the time they presented at our center with active nephrotic syndrome. We compared the serum lipidome of nephrotic syndrome patients with age matched healthy controls (n = 5), and with age matched patients with familial hypercholesterolemia (n = 5) who, like patients with nephrotic syndrome, have significantly elevated lipid values. Serum was analyzed using the Shotgun Lipidomics platform by Lipotype GmbH (Dresden, Germany), as previously described [1]. Results The lipidomic profile of patients with nephrotic syndrome was markedly different compared to control groups (Fig. 1A). In particular, lower levels of lyso-phophatidylcholine (LPC) and higher concentrations of phosphatidylethanolamine (PE) and lyso-PE (LPE) compared to control groups were most prominent (Fig. 1B). Subspecies analysis identified LPC 16:0;0 to be highly downregulated in patients with nephrotic syndrome (Fig. 2A), whereas LPE 18:0;0 and nearly all PE subspecies were increased compared to control groups (Fig. 2B and C). The lipidomic profile was largely comparable between different underlying diseases and we could not identify lipid classes specifically different for certain diseases. Conclusion Our lipidomic data show that patients with nephrotic syndrome have a distinct lipid profile compared to healthy controls or other disease controls. We identified LPCs, PEs and LPEs to be changed in nephrotic syndrome. We could not identify lipids specific for certain diseases underlying nephrotic syndrome, but rather identified a general nephrotic syndrome lipid profile. This suggests that lipid changes are rather a consequence of disease manifestation in these patients with various underlying causes. Further research should focus on confirming this lipid profile in larger cohorts and unraveling the mechanisms leading to the observed lipid changes.

Effect of three oral pathogens on the TMA-TMAO metabolic pathway.

Trimethylamine-N-oxide (TMAO) is produced by hepatic flavin-containing monooxygenase 3 (FMO3) from trimethylamine (TMA). High TMAO level is a biomarker of cardiovascular diseases and metabolic disorders, and it also affects periodontitis through interactions with the gastrointestinal microbiome. While recent findings indicate that periodontitis may alter systemic TMAO levels, the specific mechanisms linking these changes and particular oral pathogens require further clarification. In this study, we established a C57BL/6J male mouse model by orally administering Porphyromonas gingivalis (P. gingivalis, Pg), Fusobacterium nucleatum (F. nucleatum, Fn), Streptococcus mutans (S. mutans, Sm) and PBS was used as a control. We conducted LC-MS/MS analysis to quantify the concentrations of TMAO and its precursors in the plasma and cecal contents of mice. The diversity and composition of the gut microbiome were analyzed using 16S rRNA sequencing. TMAO-related lipid metabolism and enzymes in the intestines and liver were assessed by qPCR and ELISA methods. We further explored the effect of Pg on FMO3 expression and lipid molecules in HepG2 cells by stimulating the cells with Pg-LPS in vitro. The three oral pathogenic bacteria were orally administered to the mice for 5 weeks. The Pg group showed a marked increase in plasma TMAO, betaine, and creatinine levels, whereas no significant differences were observed in the gut TMAO level among the four groups. Further analysis showed similar diversity and composition in the gut microbiomes of both the Pg and Fn groups, which were different from the Sm and control groups. The profiles of TMA-TMAO pathway-related genera and gut enzymes were not significantly different among all groups. The Pg group showed significantly higher liver FMO3 levels and elevated lipid factors (IL-6, TG, TC, and NEFA) in contrast to the other groups. In vitro experiments confirmed that stimulation of HepG2 cells with Pg-LPS upregulated the expression of FMO3 and increased the lipid factors TC, TG, and IL-6. This study conclusively demonstrates that Pg, compared to Fn and Sm, plays a critical role in elevating plasma TMAO levels and significantly influences the TMA-TMAO pathway, primarily by modulating the expression of hepatic FMO3 and directly impacting hepatic lipid metabolism.

Management of Pregnancy in a Patient with Familial Hypercholesterolemia and Previous Myocardial Infarction—Treatment with LDL Apheresis: A Case Report

Familial hypercholesterolemia, a genetic disorder marked by elevated low-density lipoprotein cholesterol (LDL-C), poses significant risks for premature atherosclerosis and cardiovascular diseases, particularly during pregnancy. One of the safe methods of treating this condition in pregnancy is with the use of LDL apheresis. We present a 38-year-old primigravida with homozygous Familial Hypercholesterolemia (HoFH), ischemic cardiomyopathy, and angina pectoris. Two years before conception, extremely elevated lipid levels prompted statin therapy and lifestyle changes. Stent placements followed acute myocardial infarction. When planning pregnancy, statins were discontinued, but lipid levels elevated. LDL apheresis was initiated, achieving a 60% reduction. Throughout pregnancy, 16 LDL apheresis sessions were performed every 14 days, maintaining optimal lipid profiles. A cesarean section was performed in the 38th week of gestation, delivering a healthy infant. The patient resumed statin therapy after 8 months of breastfeeding. The patient maintained cardiovascular health, demonstrating the feasibility of controlled HoFH pregnancies. This case highlights the successful management of HoFH during pregnancy using LDL apheresis, ensuring maternal and fetal well-being. Future research on novel treatments and their safety during pregnancy is essential for refining therapeutic approaches in similar cases.

Time-course of oral toxicity to contaminated groundwater in male Sprague Dawley rats

Assessing toxicity of complex mixtures of contaminants from industrial sites with historic and ongoing contamination remains a challenge for risk assessors. Groundwater from a pesticide packaging site in Canada containing a complex mixture of known and unknown contaminants was examined in male rats to determine the target organ toxicity. This study determined the time-course of toxicity (7, 14, 28, and 60 days) following ad libitum oral exposure to 0.05% v/v contaminated groundwater compared to tap water (control) in male Sprague Dawley rats (n=5 /group/time). Exposure to groundwater resulted in inflammation, indicated by a statistically significant increase in plasma lymphocyte and neutrophil counts on days 7 and 60, respectively, but a reduction in the plasma alpha 2 macroglobulin levels by day 60. Gonadotoxicity was indicated by a reduced Johnsen score (grading spermatogenesis) in all exposed groups at all time points, while seminiferous epithelial height was reduced on days 7, 14, and 28 compared to controls. Plasma testosterone was reduced in exposed groups on days 7 and 28, accompanied by elevated testicular lipid peroxidation at all time points compared to control. In contrast, lipid peroxidation in the lungs from exposed rats was elevated on days 7, 14, and 28. Plasma symmetric dimethylarginine was elevated on day 14 in the exposed group indicating renal impairment. Taken together, these results indicate that testes, kidney, immune and lung are target organs for the contaminated groundwater from this industrial site. The current study highlights the challenge in hazard assessment for complex mixtures and highlights the need for effects-directed analysis and the continued, albeit limited, use of animal models in toxicity testing.

Prolonged exposure to mercuric chloride induces oxidative stress-mediated nephrotoxicity in freshwater food fish Channa punctatus.

Mercury (Hg) is regarded as a serious hazard to aquatic life and is particularly prevalent in aquatic ecosystems. However, there is little evidence available regarding the toxicity of mercury chloride (HgCl2) in vital organs of fish. This study was conducted to assess the effects of HgCl2 (0.039mg/L and 0.078mg/L) on oxidative stress-mediated genotoxicity, poikilocytosis, apoptosis, and renal fibrosis after 15, 30, and 45days of the exposure period. According to the findings, HgCl2 intoxication in fish resulted in a significantly (P < 0.05) elevated lipid peroxidation (LPO), protein carbonyls (PC), lactate dehydrogenase (LDH) activity levels in kidney tissues and significantly (P < 0.05) increased reactive oxygen species (ROS), poikilocytosis, DNA tail length, and the frequency of apoptotic cells (AC%) in blood cells. Kidney's ultra-structure and histopathology revealed its fibrosis, which was evident by mRNA expression of targeted genes KIM1, NOX4, TGFβ, and NFϏβ. Different indicators of oxidative stress, apoptosis, and genotoxicity were altered in a dose and time-dependent manner, according to a two-way ANOVA analysis. There was a considerable positive link between oxidative stress and kidney fibrosis in the fish Channa punctatus, and it is evident from regression correlation and PCA data analysis. The kidney's ultra-structure evaluation and histopathology both revealed a noticeable fibrosis state. Additionally, a significant (P < 0.05) downregulation in PPARδ reveals that fish body was unable to combat diseases such as kidney fibrosis induced by HgCl2. This study shed fresh light on the mechanisms underlying nephrotoxicity caused by HgCl2 exposure.

Iron accumulation in ovarian microenvironment damages the local redox balance and oocyte quality in aging mice

Accumulating oxidative damage is a primary driver of ovarian reserve decline along with aging. However, the mechanism behind the imbalance in reactive oxygen species (ROS) is not yet fully understood. Here we investigated changes in iron metabolism and its relationship with ROS disorder in aging ovaries of mice. We found increased iron content in aging ovaries and oocytes, along with abnormal expression of iron metabolic proteins, including heme oxygenase 1 (HO-1), ferritin heavy chain (FTH), ferritin light chain (FTL), mitochondrial ferritin (FTMT), divalent metal transporter 1 (DMT1), ferroportin1(FPN1), iron regulatory proteins (IRP1 and IRP2) and transferrin receptor 1 (TFR1). Notably, aging oocytes exhibited enhanced ferritinophagy and mitophagy, and consistently, there was an increase in cytosolic Fe2+, elevated lipid peroxidation, mitochondrial dysfunction, and augmented lysosome activity. Additionally, the ovarian expression of p53, p21, p16 and microtubule-associated protein tau (Tau) were also found to be upregulated. These alterations could be phenocopied with in vitro Fe2+ administration in oocytes from 2-month-old mice but were alleviated by deferoxamine (DFO). In vivo application of DFO improved ovarian iron metabolism and redox status in 12-month-old mice, and corrected the alterations in cytosolic Fe2+, ferritinophagy and mitophagy, as well as related degenerative changes in oocytes. Thereby in the whole, DFO delayed the decline in ovarian reserve and significantly increased the number of superovulated oocytes with reduced fragmentation and aneuploidy. Together, our findings suggest that aging-related disturbance in ovarian iron homeostasis contributes to excessive ROS production and that iron chelation may improve ovarian redox status, and efficiently delay the decline in ovarian reserve and oocyte quality in aging mice. These data propose a novel intervention strategy for preserving the ovarian reserve function in elderly women.

Captopril's influence on Danio rerio embryonic development: Unveiling significant toxic outcomes at environmentally relevant concentrations

Anticipating a global increase in cardiovascular diseases, there is an expected surge in the use of angiotensin-converting enzyme inhibitors, notably captopril (CAP). This heightened usage raises significant environmental apprehensions, mainly due to limited knowledge regarding CAP's toxic effects on aquatic species. In response to these concerns, the current study aimed to tackle this knowledge gap by evaluating the potential influence of nominal concentrations of CAP (0.2–2000 μg/L) on the embryonic development of Danio rerio. The findings revealed that CAP at all concentrations, even at concentrations considered environmentally significant (0.2 and 2 μg/L), induced various malformations in the embryos, ultimately leading to their mortality. Main malformations included pericardial edema, craniofacial malformation, scoliosis, tail deformation, and yolk sac deformation. In addition, CAP significantly altered the antioxidant activity of superoxide dismutase and catalase across all concentrations. Simultaneously, it elevated lipid peroxidation levels, hydroperoxides, and carbonylic proteins in the embryos, eliciting a substantial oxidative stress response. Likewise, CAP, at all concentrations, exerted significant modulatory effects on the expression of genes associated with apoptosis (bax, bcl2, p53, and casp3), organogenesis (tbx2a, tbx2b, and irx3b), and ion exchange (slc12a1 and kcnj1) in Danio rerio embryos. Both augmentation and reduction in the expression levels of these genes characterized this modulation. The Pearson correlation analysis indicated a close association between oxidative damage biomarkers and the expression patterns of all examined genes with the elevated incidence of malformations and mortality in the embryos. In summary, it can be deduced that CAP poses a threat to aquatic species. Nevertheless, further research is imperative to enhance our understanding of the environmental implications of this pharmaceutical compound.

Patients with Steroid Sensitive Nephrotic Syndrome: A Case Series

Nephrotic syndrome (NS) is one of the most common kidney diseases found in childhood. The prevalence of nephrotic syndrome worldwide is approximately 16 cases per 100,000 children with an incidence of two to seven per 100,000 children. Nephrotic syndrome may affect adults and children of both genders and any race. Nephrotic syndrome in children can be classified into three groups; secondary, congenital, infantile, and idiopathic. In first case, a 3-year-old male patient was presented with complaints of fever, cough for 6 days and swelling all over the body, decreased urine output, oral intake for 2 days, edema of face, body and tiredness for 3 days. Laboratory investigations showed elevated ESR, ferritin and lipid profile. Urine routine examination showed elevated urine albumin levels (+++). USG abdomen and pelvis conveyed right basal pleural effusion. In second case, a 4-year-old male patient was presented with complaints of facial puffiness, fever, breathing difficulty, abdominal distension and pain but no edema. He had history of right inguinal hernia and atrial septal defect. Cholesterol level was found to be elevated. Urine routine examination showed elevated urine albumin levels (+++). USG abdomen and pelvis showed mild ascites and right pleural effusion. Presenting third case, a 12-year-old female patient was presented with complaints of edema and decreased urine output. Patient had history of recurrent episodes of edema and decreased urine output for 11 months. Laboratory investigations showed elevated total cholesterol, declined LFT test and RFT test was found to be normal. Urine routine examination showed elevated urine albumin levels (+++), pus cells, RBC, granular cast and bacteria present. USG abdomen and pelvis indicate acute glomerulo nephritis and acute to moderate ascites. Here case series with 3 cases showed the sequence of nephrotic syndrome which is treated with corticosteroid with its side effects and cumulative dose of steroid in children. Keywords: Nephrotic syndrome, Hypocholesteremia, Hypoproteinuria, Hyponatremia, pediatric

Doenjang Ameliorates Diet-Induced Hyperlipidemia and Hepatic Oxidative Damage by Improving Lipid Metabolism, Oxidative Stress, and Inflammation in ICR Mice.

Hyperlipidemia, characterized by elevated cholesterol, lipids, and triglycerides in the bloodstream, is linked to hepatic oxidative damage. Doenjang, a traditional Korean condiment made from fermented soybeans, is known for its health benefits, yet its anti-hyperlipidemic effects remain understudied. Our study aimed to assess the hypolipidemic and hepatic protective effects of Doenjang on male ICR mice fed a high-fat cholesterol diet for 8 weeks. Mice were divided into three groups: the normal diet (ND), the high-fat cholesterol diet (HD), and the Doenjang-supplemented HD diet (DS) group. Doenjang supplementation significantly regulated total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol levels compared to the HD group. It also downregulated lipogenic genes, including PPARγ, FAS, and ACC, and positively influenced the cholesterol metabolism-related genes HMGCR and LXR. Moreover, Doenjang intake increased serum glutathione levels, activated oxidative stress defense genes (NRF2, SOD, GPx1, and CAT), positively modulated inflammation genes (NF-kB and IL6) in hepatic tissue, and reduced malondialdehyde levels. Our findings highlight the effectiveness of traditional Doenjang in preventing diet-induced hyperlipidemia and protecting against hepatic oxidative damage.

Diagnosis and treatment of dyslipidemia in children and adolescents

Background: Atherosclerotic cardiovascular disease is a major cause of morbidity and mortality worldwide, including in South Korea. Dyslipidemia is an independent risk factor for the development of atherosclerotic cardiovascular diseases. There is strong evidence that atherosclerosis begins early in life and that elevated lipid levels in childhood predict elevated lipid levels into adulthood.Current Concepts: A universal approach for cholesterol screening in all children is recommended. Lipid profiles should be studied for all children aged 9 to 11 years and then for those aged 17 to 21 years, as cholesterol levels may vary after puberty. The non-fasting lipid profile can be as useful in detecting severe genetic dyslipidemias as the fasting lipid profile and thus can be used as a first-line screening in children. The initial treatment for dyslipidemia in a child always begins with a 6-month trial of lifestyle modifications, such as improvements in dietary and physical activity patterns. Statins are as effective in children as in adults and can lower low-density lipoprotein cholesterol levels by up to 50%. Therefore, they are considered first-line therapy for children who meet the criteria for pharmacological therapy.Discussion and Conclusion: Statins and non-statin lipid-lowering agents can lower cholesterol levels with minimal adverse effects in children and adolescents with hypercholesterolemia. However, limited data is currently available on the long-term safety and efficacy of lipid-lowering agents in the pediatric population. Furthermore, non-statin lipid-lowering agents are used far less frequently in children. Therefore, further long-term safety and efficacy studies on lipid-lowering agents in pediatric populations and clinical trials with non-statin lipid-lowering agents are required.

An Analysis on Link of Maternal Lipid Profile and Gestational Diabetes Mellitus: A Case Control Study of 120 Women

BACKGROUND: Gestational diabetes mellitus GDM is a clinical condition, or disease, wherein, a marked reduction in the sensitivity of insulin, during pregnancy, is attributed to the metabolic disturbance that occurs widespread. Although, information on the association among dyslipidaemia and GDM remains uncertain till date. The main objective of the present investigation is to detect any correlation between lipid profile of GDM subjects and healthy control women,using biochemical indicators. METHODS: A careful clinical case study was performed, involving a total of 120 subjects, comprising two distinct groups. Group I includes 60 pregnant women, those were recently detected as GDM cases. Group ll covers healthy control subjects collected from Open Patients unit and Registry of Diabetic Unit of Dhanalakshmi Srinivasan Institute Medical science and Hospital, Perambalur, Tamil Nadu. Both groups' subjects were bifurcated, based on their age groups, and found to be 25 to 45 years. Estimation of glycemic condition, in prior and post fasting was performed, using an analyzer appropriately. Similarly, maternal lipid profile for both groups was also determined. Moreover, HbAl c, an important biochemical indicator was also detected for both groups of subjects with respect to their age, using HPLC technique. Received data were pooled and a statistical analysis was performed, using Student t test to identify the significance difference or association between GDM group and healthy subjects, in specific, on the maternal lipid profile. FINDING: Analysis showed that there is a significant difference observed in the maternal lipid profile of GDM group, when compared with healthy subjects. The P value of Very Low Lipid protein VLDL, low density lipoprotein LDL, High density lipoprotein HDL was found to be 0.01, 0.028, and 0.038 respectively. Whereas, p value for HbAl c was recorded as 0.02, and found significant difference at 0.01 percent level. Interestingly, no difference was observed in the limit of FG, and Triglycerides limit, and were reported as p _0.28, and p- 0.316 respectively. A marked difference was also detected among the 30 to 35 yrs age group. INTERPRETATION: Present investigation elucidated that there is a strong correlation between GDM subjects and dyslipidemia. Further, this study strengthened and promised that elevated maternal lipid profile is highly linked with GDM condition.

Pervasive influence of heavy metals on metabolic pathways is potentially relieved by hesperidin to enhance the phytoremediation efficiency of Bassia scoparia.

Hesperidin (HSP), a flavonoid, is a potent antioxidant, metal chelator, mediator of signaling pathways, and regulator of metal uptake in plants. The study examined the ameliorative effects of HSP (100 μM) on Bassia scoparia grown under excessive levels of heavy metals (zinc (500 mg kg-1), copper (400 mg kg-1), cadmium (100 mg kg-1), and chromium (100 mg kg-1)). The study clarifies the underlying mechanisms by which HSP lessens metabolic mayhem to enhance metal stress tolerance and phytoremediation efficiency of Bassia scoparia. Plants manifested diminished growth because of a drop in chlorophyll content and nutrient acquisition, along with exacerbated deterioration of cellular membranes reflected in elevated reactive oxygen species (ROS) production, lipid peroxidation, and relative membrane permeability. Besides the colossal production of cytotoxic methylglyoxal, the activity of lipoxygenase was also higher in plants under metal toxicity. Conversely, hesperidin suppressed the production of cytotoxic ROS and methylglyoxal. Hesperidin improved oxidative defense that protected membrane integrity. Hesperidin caused a more significant accumulation of osmolytes, non-protein thiols, and phytochelatins, thereby rendering metal ions non-toxic. Hydrogen sulfide and nitric oxide endogenous levels were intricately maintained higher in plants treated with HSP. Hesperidin increased metal accumulation in Bassia scoparia and thereby had the potential to promote the reclamation of metal-contaminated soils.

Chemical diversity and antimelanoma potential of rosemary essential oils: Unveiling mechanistic insights through quantitative proteomics

Rosemary essential oil (REO) is widely recognized as a popular natural product because of its antioxidant, antibacterial, and anti-inflammatory properties, but its role in cancer treatment remains relatively understudied. In light of melanoma’s status as one of the most hazardous tumors, this study employed GCMS to analyze three REOs, focusing on their antiproliferative effects and the underlying mechanisms in melanoma cells. Through multivariate analysis, active components associated with cytotoxicity were identified, with the ‘Dutch Mill’ REO showing the strongest antiproliferative effect and selected for further investigation. The impacts on the cell cycle and death mechanisms were explored in B16-F10 cells, and quantitative proteomics revealed 165 differentially regulated proteins, some of which were significantly associated with ferroptosis. REO notably increased reactive oxygen species levels, decreased mitochondrial membrane potential, and elevated lipid peroxidation in B16-F10 cells. The qRTPCR results confirmed significant alterations in the ferroptosis pathway. Furthermore, the antiproliferative and ROS-promoting effects of REO were reversed by ferroptosis inhibitors. These findings highlight the promising potential of REO in health care and pharmaceuticals.

Abstract 1122: Endothelial Cd36 Mediates Lipid-induced Stiffening Of Aortic Endothelium And Western Diet-induced Barrier Disruption

Introduction: Western diet (WD) associates with elevations in blood lipids. Endothelial cells (EC) uptake lipids through scavenger receptors such as CD36. In our studies we demonstrated that exposure to lipids induces a stiffening response in ECs, with in vivo studies showing that this stiffening is abrogated in mice with a global CD36 knockout. Hypothesis: WD associates with aortic barrier disruption. in vitro studies have demonstrated that EC stiffening correlates with barrier disruption. It is our hypothesis that EC stiffening mediates WD-induced aortic barrier disruption in an endothelial CD36-dependent manner. Methods: To generate a model of endothelial-specific CD36 deficiency, we crossed tamoxifen-inducible Cre mice with an EC-promoter with CD36 fl/fl mice. Cre only mice are employed as controls. At the end of the study window, aortas are excised for assessment of EC stiffening via atomic force microscopy. Separate cohorts are assessed for barrier disruption via quantification of Evans blue dye (EBD) leakage or VE-cadherin junctional thickness. Inhibition of CD36 in vitro was accomplished with SSO. For cell experiments we employed long-chain fatty acids (LCFAs), lipid ligands for CD36. Results: WD induced significant stiffening of the aortic endothelium [p&lt;0.05]. This phenomenon was only observed in male (n=5-6) and not female (n=3-10) mice. EC stiffening associated with aortic barrier disruption as indicated by increased EBD permeation (n=3-8) and increased VE-cadherin thickness (n=3-4) [p&lt;0.05]. Use of an endothelial-specific CD36 deficiency significantly abrogated stiffening and barrier disruption [p&lt;0.05]. Controls demonstrated no effects by tamoxifen (n=2-3). Exposure to 5 μM of palmitic and stearic acids (saturated LCFAs) results in stiffening while exposure to oleic acid (unsaturated LCFA) does not (n=5-12) [p&lt;0.05]. Palmitic acid-induced EC stiffening was shown to be dependent on CD36 (n=5-6) and activation of RhoA protein kinase (n=3-8) [p&lt;0.05]. Conclusions: Our results demonstrate that endothelial CD36 is required for WD-induced EC stiffening and subsequent disruption of the aortic barrier. Furthermore, our results suggest that CD36 mediates EC stiffening through its role as scavenger receptor to saturated LCFAs.

Fluorescent rotor: Labeling lysosomes, mitochondria and lipid droplets through polarity and viscosity assessment

The viscosity and polarity of cells are inherent physical parameters, and changes to these attributes are frequently linked to malfunctioning conditions or different diseases. Cancer cells often harbor elevated nonpolar lipid droplets (LDs), acting as energy reserves. The rise in lipid droplets (LDs) and viscosity, distinctive traits of cancer cells, has motivated us to develop a fluorescent probe based on naphthalimide. The fluorescent marker LD-VP exhibits fluorescence signals at 520 nm in nonpolar dioxane and 600 nm in highly viscous glycerol. This implies that probe LD-VP can furnish details regarding cellular microviscosity and lipid droplets within live cells by providing dual-channel images. The probe LD-VP is chemically inert and harmless, enabling its safe utilization in live cell imaging. We conducted fluorescence imaging based on viscosity using probe LD-VP in the red channel, which is found to be co-localized in both mitochondria and lysosomes. Moreover, the probe effectively marks lipid droplets in the green channel. The probe LD-VP represents a distinctive fluorescent tool capable of monitoring both viscosity and lipid droplet expression in live cells. This tool holds the potential for visualizing physiological abnormalities or pathological conditions.

Milk thistle protects against non-alcoholic fatty liver disease induced by dietary thermally oxidized tallow

Non-alcoholic fatty liver disease (NAFLD) is a chronic condition caused by several factors including thermally oxidized tallow. Various strategies have been considered to ameliorate NAFLD. However, the role of milk thistle (MT) in ameliorating NAFLD caused by thermally oxidized tallow has not been reported. The purpose of this study was to evaluate the ability of milk thistle to protect rabbits from the toxicity of oxidized tallow (OT). The rabbits were given OT and an extract of MT. The composition of MT was analyzed using HPLC-DAD, and tallow samples were studied using GC-MS. The study also examined liver histology, antioxidant levels, liver-related inflammatory markers, and serum lipid profile. The results showed that the major components of the MT extract were silybin B, formononetin-glucuronic acid, proanthocyanidin B1, silychristin B, silydianin, and isosilybin A. The group given OT showed elevated lipid profiles, lower antioxidant status, higher levels of hepatic inflammatory markers, and lower levels of anti-inflammatory markers. This group also had higher fat storage in the liver compared to the control or treatment groups. However, when MT was supplemented, the pro-inflammatory cytokines (IL-1, IL-4, IL-6, and TNF-α) and antioxidant status (CAT, SOD, GSH-Px, GSH, and TBARS) of the liver returned to normal. This suggests that MT extract is an excellent source of hepatoprotective compounds. It protects the liver by increasing antioxidant enzymes, decreasing pro-inflammatory cytokines, and increasing anti-inflammatory markers.

Arctigenin induces activated HSCs quiescence via AMPK-PPARγ pathway to ameliorate liver fibrosis in mice

Arctigenin (ATG), a traditional Chinese herbal medicine, is a natural lignan compound extracted from the seeds of burdock (Arctium lappa L, Asteraceae). As a natural product with multiple biological activities, the effect and mechanism of ATG against liver fibrosis are not fully elucidated yet. In current work, we first discovered that ATG could improve CCl4-induced liver injury reflected by lower plasma ALT and AST levels, liver coefficient and pathological scoring of ballooning. Furthermore, it also could reduce the positive areas of Masson, Sirius red and α-SMA staining, inhibit the expression of fibrosis-related genes (Col1a1, Col3a1, Acta2), and decrease the content of hydroxyproline, indicated ATG treatment had benefits in alleviating CCl4-induced liver fibrosis. In vitro, we observed that ATG can inhibit collagen production stimulated by TGF-β1 in LX2 cells. By analysis of the information obtained from SymMap and GeneCards databases and in vitro validation experiments, ATG was proven to be an indirect PPARγ agonist and its effect on collagen production was dependent on PPARγ. Subsequently, we confirmed that ATG activating AMPK was the contributor of its effect on PPARγ and collagen production. Finally, the transformation of activated hepatic stellate cells was determined after treated with ATG, in which ATG treatment could return activated LX2 cells to quiescence because of the elevated quiescent markers and lipid droplets. Our work has highlighted the potential of ATG in the treatment of liver fibrosis and clarified that ATG can activate AMPK/PPARγ pathway to restore the activated hepatic stellate cell to quiescence thereby improving liver fibrosis.

Traditional and non-traditional lipid parameters as risk factors for sudden sensorineural hearing loss

ObjectiveThe purpose was to explore the effects of traditional and non-traditional lipid parameters on Sudden Sensorineural Hearing Loss (SSNHL). MethodsThe study included 452 patients diagnosed with SSNHL, among whom 206 patients had a level of hearing improvement ≥10 dB after one month of follow-up. A propensity score-matched (2:1) control group was used. Conditional and unconditional logistic regression were used to analyze the risk factors for SSNHL. ResultsPatients with SSNHL had a higher risk of concomitant hypertension and elevated atherosclerogenic lipid levels, with apolipoprotein B and apolipoprotein E identified as independent risk factors for the onset of SSNHL. Additionally, the Lipid Comprehensive Index (LCI) was an independent risk factor for the degree of hearing loss. A positive linear correlation was revealed between triglyceride, non-high-density lipoprotein cholesterol, atherogenic index, Castelli risk index, atherogenic index of plasma, LCI and hearing loss. However, no linear relationship was observed between hearing gain and any lipid parameters. When Total Cholesterol (TC) was in the range of borderline high, the treatment effect was the best. However, the statistical significance disappeared upon adjusting for confounding factors. ConclusionPatients with SSNHL exhibited markedly dysregulated lipid metabolism. Elevated serum lipid levels may be a causative factor in auditory impairment and can influence the extent of hearing loss. Promptly improving cochlear microcirculation may benefit patients with borderline elevated TC. Level of evidence4.

Preventative treatment of tuberous sclerosis complex with sirolimus: Phase I safety and efficacy results

AbstractObjectiveTuberous sclerosis complex (TSC) results from overactivity of the mechanistic target of rapamycin (mTOR). Sirolimus and everolimus are mTOR inhibitors that treat most facets of TSC but are understudied in infants. We sought to understand the safety and potential efficacy of preventative sirolimus in infants with TSC.MethodsWe conducted a phase 1 clinical trial of sirolimus, treating five patients until 12 months of age. Enrolled infants had to be younger than 6 months of age with no history of seizures and no clinical indication for sirolimus treatment. Adverse events (AEs), tolerability, and blood concentrations of sirolimus measured by tandem mass spectrometry were tracked through 12 months of age, and clinical outcomes (seizure characteristics and developmental profiles) were tracked through 24 months of age.ResultsThere were 92 AEs, with 34 possibly, probably, or definitely related to treatment. Of those, only two were grade 3 (both elevated lipids) and all AEs were resolved by the age of 24 months. During the trial, 94% of blood sirolimus trough levels were in the target range (5–15 ng/mL). Treatment was well tolerated, with less than 8% of doses held because of an AE (241 of 2941). Of the five patients, three developed seizures (but were well controlled on medications) at 24 months of age. Of the five patients, four had normal cognitive development for age. One was diagnosed with possible autism spectrum disorder.InterpretationThese results suggest that sirolimus is both safe and well tolerated by infants with TSC in the first year of life. Additionally, the preliminary work suggests a favorable efficacy profile compared with previous TSC cohorts not exposed to early sirolimus treatment. Results support sirolimus being studied as preventive treatment in TSC, which is now underway in a prospective phase 2 clinical trial (TSC‐STEPS).

Mechanical regulation of lipid and sugar absorption by Piezo1 in enterocytes

Obesity is primarily caused by excessive intake as well as absorption of sugar and lipid. Postprandial surge in distention pressure and intestinal motility accelerates the absorption of nutrients. The response of intestinal epithelial cells to mechanical stimulation is not fully understood. Piezo1, a mechanosensitive ion channel, is widely expressed throughout the digestive tract. However, its function in intestinal nutrient absorption is not yet clear. In our study, excessive lipid deposition was observed in the duodenum of obese patients, while duodenal Piezo1–CaMKK2–AMPKα was decreased when compared to normal-weight individuals. Under high-fat diet condition, the Piezo1iKO mice exhibited abnormally elevated sugar and lipid absorption as well as severe lipid deposition in the duodenum and liver. These phenotypes were mainly caused by the inhibition of duodenal CaMKK2–AMPKα and the upregulation of SGLT1 and DGAT2. In contrast, Yoda1, a Piezo1 agonist, was found to reduce intestinal lipid absorption in diet induced obese mice. Overexpression of Piezo1, stretch and Yoda1 inhibited lipid accumulation and the expression of DGAT2 and SGLT1, whereas knockdown of Piezo1 stimulated lipid accumulation and DGAT2 in Caco-2 cells. Our study reveals a previously unexplored mechanical regulation of nutrient absorption in intestinal epithelial cells, which may shed new light on the therapy of obesity.