Mechanism of alpha-lipoic acid in attenuating kanamycin-induced ototoxicity

In view of the theory that alpha-lipoic acid effectively prevents cochlear cells from injury caused by various factors such as cisplatin and noise, this study examined whether alpha-lipoic acid can prevent kanamycin-induced ototoxicity. To this end, healthy BALB/c mice were injected subcutaneously with alpha-lipoic acid and kanamycin for 14 days. Auditory brainstem response test showed that increased auditory brainstem response threshold shifts caused by kanamycin were significantly inhibited. Immunohistochemical staining and western blot analysis showed that the expression of phosphorylated p38 mitogen-activated protein kinase and phosphorylated c-Jun N-terminal kinase in mouse cochlea was significantly decreased. The experimental findings suggest that phosphorylated p38 and phosphorylated c-Jun N-terminal kinase mediated kanamycin-induced ototoxic injury in BALB/c mice. AIpha-lipoic acid effectively attenuated kanamycin ototoxicity by inhibiting the kanamycin-induced high expression of phosphorylated p38 and phosphorylated c-Jun N-terminal kinase.

Symptomatic and pathogenetic treatment of diabetic neuropathy Role of alpha-lipoic acid

Diabetic neuropathy, the most common form of peripheral neuropathy, presents as different forms of focal or diffuse neuropathy, including the disabling, or potentially life-threatening clinical entities of painful diabetic neuropathy, autonomic neuropathy, and diabetic foot. The pathogenesis of diabetic neuropathy results from the concurrent action of various intersecting factors of nerve damage, such as oxidative stress and mitochondrial dysfunction, inflammation, microangiopathy and ischemia, triggered by hyperglycemia and related biochemical changes. Symptomatic treatment of diabetic neuropathy mainly concerns therapies for neuropathic pain, interventions targeted at the organ systems involved in autonomic neuropathy, and management of diabetic foot. Therapeutic approaches to the pathogenesis of diabetic neuropathy have focused on the different components of the causes of nerve damage, particularly oxidative stress, which has been demonstrated to play a central role. Alpha-lipoic acid, a potent lipophilic free radical scavenger, has been used in treatment of patients with diabetic neuropathy, displaying efficacy on the chief symptoms, including neuropathic pain, and showing that neuropathic deficits may be improved by treatment. Current evidence suggests a possible efficacy of alpha-lipoic acid not only for neuropathic symptoms, but also for reducing the risk factors for diabetic neuropathy.

Storage Stability of Alpha-Lipoic Acid-loaded Lipid Nanoparticles

Alpha-lipoic acid-loaded lipid nanoparticles(ALA-LNs) were prepared by high pressure homogenization method.The influences of storage conditions such as time and temperature on the physical and chemical storage stability of ALA-LNs were studied in details.The stability was evaluated by particle size and polydispersity index,morphology of ALA-LNs,and capacity of ALA loading.The dilution and pH stability of ALA-LNs suspensions were also studied.After three months storage,the mean size of ALA-LNs at 4 and 40 ℃ was increased by 2.68% and 3.62% compared with the original size,respectively.ALA-LNs stored at 40 ℃ had ellipsoid shape and the mean size was about 152 nm(SD=23.6).The loading capacity of ALA at 40 ℃ was much higher than those stored at other two temperatures.The good dilution and pH stability were also demonstrated.The sample had good fluidity even at 4 ℃.

Determination of Alpha-Lipoic Acid in a Nutritional Supplement Using High Performance Liquid Chromatography

Alpha lipoic acid has the ability to react and neutralize reactive oxygen species (ROS) such as superoxide radicals, simple oxygen, hydroxyl radicals, hypochlorous acid and peroxyl radicals. A rapid high-performance liquid chromatographic method for determination of lipoic acid in a nutritional supplement was developed. The method involved sample preparation and the mobile phase comprised of 50 mM disodium hydrogen phosphate buffer (pH 2.5 adjusted with 1 M H3PO4): acetonitrile in the ratio of 50:50. The separation was done using a C18 column (150 mm) and detection was carried out using UV detection at 201 nm. The assay was found to be linear in the range of 1.56 - 50 μg/mL with the correlation coefficient of 0.9997. Method precision was determined while LOD was 0.05 μg/mL and LOQ 0.15 μg/mL. The chromatographic peak LA retention time was 6 min.

Alpha-lipoic Acid:Effects on the Beat-to-Beat Vectorcardiographic Parameters in Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy

Objective:Relevance of cardiac autonomic neuropathy has not been fully recognized and there is no standardized treatment protocol.Aim:To evaluate the effects of alpha-lipoic acid on the beat-to-beat vectorcardiographic parameters,namely spatial QRS-T angle,QT dispersion(QTd)and corrected QT interval(QTc)in type 2 diabetes mellitus persons with cardiac autonomic neuropathy.Research designs and methods:Our study involved 33 persons with definite stage of cardiac autonomic neuropathy and diabetes mellitus type 2,which were assigned to each of two groups:one took standard antihyperglycaemic treatment(n=15,control group)and the other(n=18)in addition to standard therapy-600 mg of alpha-lipoic acid daily for three months.The analysis of vectorcardiographic parameters was performed.Results:It was found out that alpha-lipoic acid contributed to decrease of the vectorcardiographic parameters,namely QRS-T angle,QTd and QTc.Conclusions:The positive influences of alpha-lipoic acid suggest the usefulness of its prescription to type 2 diabetes mellitus persons with definite stage of cardiac autonomic neuropathy.The efficacy of alpha-lipoic acid is the result of its direct effect on the parameters of vectorcardiography.

Effect of alpha-lipoic acid supplementation on blood pressure, renal oxidant-antioxidant status and renal damage in spontaneously hypertensive rats

Objective:To investigate the effect of alpha-lipoic acid(ALA)supplementation on systolic blood pressure(SBP),renal oxidant-antioxidant status and renal damage in spontaneously hypertensive rats(SHR)and SHR administered with Nω-nitro-L-arginine methyl ester(L-NAME).Methods:Male rats were divided into four groups(SHR,SHR+ALA,SHR+L-NAME,SHR+ALA+L-NAME).The respective group of rats was administered with ALA(100 mg/kg/day)from age 4 weeks to 28 weeks and L-NAME(25 mg/kg/day)from age 16 weeks to 28 weeks.SBP was measured every two weeks and twenty four hour urine was collected at 4 weeks,16 weeks and 28 weeks for estimation of protein,creatinine and N-acetyl-e end of 28 weeks,rats were sacrificed and blood and kidneys colα-Dglucosaminidase.At thlected for assessment of blood creatinine,kidney thiobarbituric acid reactive substances,protein carbonyls,superoxide dismutase,catalase,glutathione peroxidase,glutathione reductase,glutathione S-transferase,glutathione disulfide,glutathione,total antioxidant status and nitric oxide as well as histopathological examination.Results:ALA supplementation significantly reduced SBP of SHR and SHR+L-NAME rats when compared to their respective non-supplemented groups.Renal oxidant status markers including thiobarbituric acid reactive substances and protein carbonyls were significantly reduced on SHR and SHR+L-NAME rats supplemented with ALA at 28 weeks as well as ALA supplementation significantly increased renal antioxidants including superoxide dismutase,catalase,glutathione peroxidase,glutathione S-transferase,glutathione and glutathione/glutathione disulfide ratio at 28 weeks.No significant change in nitric oxide levels was observed between the ALA supplemented and non-supplemented groups.Renal dysfunction was ameliorated on ALA supplementation as evidenced by significant reduction in urine protein levels,N-acetyl-α-D-glucosaminidase activity and significant increase of creatinine clearance in SHR and SHR+L-NAME at 28 weeks.Renal histopathological examination showed that ALA supplementation prevented vascular damage in SHR and ameliorated glomerular damage in SHR+L-NAME at 28 weeks.Conclusions:ALA has hypotensive and renoprotective effects on both SHR and SHR+LNAME,which could be due to its ability to ameliorate oxidative stress in the kidneys.

Attenuation of myocardial apoptosis by alpha-lipoic acid through suppression of mitochondrial oxidative stress to reduce diabetic cardiomyopathy

Background Cardiac failure is a leading cause of the mortality of diabetic patients. In part this is due to a specific cardiomyopathy, referred to as diabetic cardiomyopathy. Oxidative stress is widely considered to be one of the major factors underlying the pathogenesis of the disease. This study aimed to test whether the antioxidant α-lipoic acid （α-LA） could attenuate mitochondrion-dependent myocardial apoptosis through suppression of mitochondrial oxidative stress to reduce diabetic cardiomyopathy. Methods A rat model of diabetes was induced by a single tail intravenous injection of streptozotocin （STZ） 45 mg/kg. Experimental animals were randomly assigned to 3 groups： normal control （NC）, diabetes （DM） and DM treated with α-LA （α-LA）. The latter group was administered with a-LA （100 mg/kg ip per day）, the remainder received the same volume vehicle. At weeks 4, 8, and 12 after the onset of diabetes, cardiac apoptosis was examined by TUNEL assay. Cardiomyopathy was evaluated by assessment of cardiac structure and function. Oxidative damage was evaluated by the content of malondialdehyde （MDA）, reduced glutathione （GSH） and the activity of manganese superoxide diamutase （Mn-SOD） in the myocardial mitochondria. Expression of caspase-9 and caspase-3 proteins was determined by immunohistochemistry and mitochondrial cytochrome c release was detected by Western blotting Results At 4, 8, and 12 weeks after the onset of diabetes, significant reductions in TUNEL-positive cells, caspase-9,-3 expression, and mitochondrial cytochrome c release were observed in the α-LA group compared to the DM group. In the DM group, the content of MDA in the myocardial mitochondria was significantly increased, and there was a decrease in both the mitochondrial GSH content and the activities of Mn-SOD. They were significantly improved by α-LA treatment. HE staining displayed structural abnormalities in diabetic hearts, while α-LA reversed this structural derangement. The index of cardiac function （±dp/dtmax） in the diabetes group was aggravated progressively from 4 weeks to 12 weeks, but α-LA delayed deterioration of cardiac function （P 〈0.05）. Conclusions Our findings indicate that the antioxidant α-LA can effectively attenuate mitochondria-dependent cardiac apoptosis and exert a protective role against the development of diabetic cardiomyopathy. The ability of α-LA to suppress mitochondrial oxidative damage is concomitant with an enhancement of Mn-SOD activity and an increase in the GSH content of myocardial mitochondria.

Decoding the nexus:branched-chain amino acids and their connection with sleep,circadian rhythms,and cardiometabolic health

The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and,either directly or indirectly,overall body health,encompassing metabolic and cardiovascular well-being.Given the heightened metabolic activity of the brain,there exists a considerable demand for nutrients in comparison to other organs.Among these,the branched-chain amino acids,comprising leucine,isoleucine,and valine,display distinctive significance,from their contribution to protein structure to their involvement in overall metabolism,especially in cerebral processes.Among the first amino acids that are released into circulation post-food intake,branched-chain amino acids assume a pivotal role in the regulation of protein synthesis,modulating insulin secretion and the amino acid sensing pathway of target of rapamycin.Branched-chain amino acids are key players in influencing the brain's uptake of monoamine precursors,competing for a shared transporter.Beyond their involvement in protein synthesis,these amino acids contribute to the metabolic cycles ofγ-aminobutyric acid and glutamate,as well as energy metabolism.Notably,they impact GABAergic neurons and the excitation/inhibition balance.The rhythmicity of branchedchain amino acids in plasma concentrations,observed over a 24-hour cycle and conserved in rodent models,is under circadian clock control.The mechanisms underlying those rhythms and the physiological consequences of their disruption are not fully understood.Disturbed sleep,obesity,diabetes,and cardiovascular diseases can elevate branched-chain amino acid concentrations or modify their oscillatory dynamics.The mechanisms driving these effects are currently the focal point of ongoing research efforts,since normalizing branched-chain amino acid levels has the ability to alleviate the severity of these pathologies.In this context,the Drosophila model,though underutilized,holds promise in shedding new light on these mechanisms.Initial findings indicate its potential to introduce novel concepts,particularly in elucidating the intricate connections between the circadian clock,sleep/wake,and metabolism.Consequently,the use and transport of branched-chain amino acids emerge as critical components and orchestrators in the web of interactions across multiple organs throughout the sleep/wake cycle.They could represent one of the so far elusive mechanisms connecting sleep patterns to metabolic and cardiovascular health,paving the way for potential therapeutic interventions.

Increased excitatory amino acid transporter 2 levels in basolateral amygdala astrocytes mediate chronic stress–induced anxiety-like behavior

The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with emotions.Specifically, astrocytes in the basolateral amygdala have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which basolateral amygdala astrocytes regulate chronic stress–induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal mice.After knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was obviously mitigated. Additionally, administration of an excitatory amino acid transporter 2 inhibitor in the basolateral amygdala yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that basolateral amygdala astrocytic excitatory amino acid transporter 2 plays a role in in the regulation of unpredictable chronic mild stress-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting excitatory amino acid transporter 2 in the basolateral amygdala holds therapeutic promise for addressing anxiety disorders.

Targeting harmful effects of non-excitatory amino acids as an alternative therapeutic strategy to reduce ischemic damage

The involvement of the excitatory amino acids glutamate and aspartate in ce rebral ischemia and excitotoxicity is well-documented.Nevertheless,the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied.The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra.Our findings indicated that the reversible loss of field excitato ry postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids(L-alanine,glycine,L-glutamine,and L-serine)at their plasma concentrations.These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia,along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors.Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia.It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels,leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation.Thus,previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury.Understanding these pathways co uld highlight new therapeutic targets to mitigate brain injury.

Additive neurorestorative effects of exercise and docosahexaenoic acid intake in a mouse model of Parkinson’s disease

There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids,such as docosahexaenoic acid,and exercise in Parkinson’s disease,we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway.First,mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation.Four weeks after lesion,animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks.During this period,the animals had access to a running wheel,which they could use or not.Docosahexaenoic acid treatment,voluntary exercise,or the combination of both had no effect on(i)distance traveled in the open field test,(ii)the percentage of contraversive rotations in the apomorphine-induction test or(iii)the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta.However,the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum.Compared to docosahexaenoic acid treatment or exercise alone,the combination of docosahexaenoic acid and exercise(i)improved forelimb balance in the stepping test,(ii)decreased the striatal DOPAC/dopamine ratio and(iii)led to increased dopamine transporter levels in the lesioned striatum.The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.

Maintaining moderate levels of hypochlorous acid promotes neural stem cell proliferation and differentiation in the recovery phase of stroke

It has been shown clinically that continuous removal of ischemia/reperfusion-induced reactive oxygen species is not conducive to the recovery of late stroke.Indeed,previous studies have shown that excessive increases in hypochlorous acid after stroke can cause severe damage to brain tissue.Our previous studies have found that a small amount of hypochlorous acid still exists in the later stage of stroke,but its specific role and mechanism are currently unclear.To simulate stroke in vivo,a middle cerebral artery occlusion rat model was established,with an oxygen-glucose deprivation/reoxygenation model established in vitro to mimic stroke.We found that in the early stage(within 24 hours)of ischemic stroke,neutrophils produced a large amount of hypochlorous acid,while in the recovery phase(10 days after stroke),microglia were activated and produced a small amount of hypochlorous acid.Further,in acute stroke in rats,hypochlorous acid production was prevented using a hypochlorous acid scavenger,taurine,or myeloperoxidase inhibitor,4-aminobenzoic acid hydrazide.Our results showed that high levels of hypochlorous acid(200μM)induced neuronal apoptosis after oxygen/glucose deprivation/reoxygenation.However,in the recovery phase of the middle cerebral artery occlusion model,a moderate level of hypochlorous acid promoted the proliferation and differentiation of neural stem cells into neurons and astrocytes.This suggests that hypochlorous acid plays different roles at different phases of cerebral ischemia/reperfusion injury.Lower levels of hypochlorous acid(5 and 100μM)promoted nuclear translocation ofβ-catenin.By transfection of single-site mutation plasmids,we found that hypochlorous acid induced chlorination of theβ-catenin tyrosine 30 residue,which promoted nuclear translocation.Altogether,our study indicates that maintaining low levels of hypochlorous acid plays a key role in the recovery of neurological function.

Enhanced autophagic clearance of amyloid-βvia histone deacetylase 6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo

Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.

Activation of adult endogenous neurogenesis by a hyaluronic acid collagen gel containing basic fibroblast growth factor promotes remodeling and functional recovery of the injured cerebral cortex

The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.

Recovery of Li, Ni, Co and Mn from spent lithium-ion batteries assisted by organic acids: Process optimization and leaching mechanism

The proper recycling of spent lithium-ion batteries(LIBs)can promote the recovery and utilization of valuable resources,while also negative environmental effects resulting from the presence of toxic and hazardous substances.In this study,a new environmentally friendly hydro-metallurgical process was proposed for leaching lithium(Li),nickel(Ni),cobalt(Co),and manganese(Mn)from spent LIBs using sulfuric acid with citric acid as a reductant.The effects of the concentration of sulfuric acid,the leaching temperature,the leaching time,the solid-liquid ratio,and the reducing agent dosage on the leaching behavior of the above elements were investigated.Key parameters were optimized using response surface methodology(RSM)to maximize the recovery of metals from spent LIBs.The maxim-um recovery efficiencies of Li,Ni,Co,and Mn can reach 99.08%,98.76%,98.33%,and 97.63%.under the optimized conditions(the sulfuric acid concentration was 1.16 mol/L,the citric acid dosage was 15wt%,the solid-liquid ratio was 40 g/L,and the temperature was 83℃ for 120 min),respectively.It was found that in the collaborative leaching process of sulfuric acid and citric acid,the citric acid initially provided strong reducing CO_(2)^(-),and the transition metal ions in the high state underwent a reduction reaction to produce transition metal ions in the low state.Additionally,citric acid can also act as a proton donor and chelate with lower-priced transition metal ions,thus speeding up the dissolution process.

Selective leaching of lithium from spent lithium-ion batteries using sulfuric acid and oxalic acid

Traditional hydrometallurgical methods for recovering spent lithium-ion batteries(LIBs)involve acid leaching to simultaneously extract all valuable metals into the leachate.These methods usually are followed by a series of separation steps such as precipitation,extraction,and stripping to separate the individual valuable metals.In this study,we present a process for selectively leaching lithium through the synergistic effect of sulfuric and oxalic acids.Under optimal leaching conditions(leaching time of 1.5 h,leaching temperature of 70°C,liquid-solid ratio of 4 mL/g,oxalic acid ratio of 1.3,and sulfuric acid ratio of 1.3),the lithium leaching efficiency reached89.6%,and the leaching efficiencies of Ni,Co,and Mn were 12.8%,6.5%,and 21.7%.X-ray diffraction(XRD)and inductively coupled plasma optical emission spectrometer(ICP-OES)analyses showed that most of the Ni,Co,and Mn in the raw material remained as solid residue oxides and oxalates.This study offers a new approach to enriching the relevant theory for selectively recovering lithium from spent LIBs.

Bile acids inhibit ferroptosis sensitivity through activating farnesoid X receptor in gastric cancer cells

BACKGROUND Gastric cancer(GC)is associated with high mortality rates.Bile acids(BAs)reflux is a well-known risk factor for GC,but the specific mechanism remains unclear.During GC development in both humans and animals,BAs serve as signaling molecules that induce metabolic reprogramming.This confers additional cancer phenotypes,including ferroptosis sensitivity.Ferroptosis is a novel mode of cell death characterized by lipid peroxidation that contributes universally to malignant progression.However,it is not fully defined if BAs can influence GC progression by modulating ferroptosis.AIM To reveal the mechanism of BAs regulation in ferroptosis of GC cells.METHODS In this study,we treated GC cells with various stimuli and evaluated the effect of BAs on the sensitivity to ferroptosis.We used gain and loss of function assays to examine the impacts of farnesoid X receptor(FXR)and BTB and CNC homology 1(BACH1)overexpression and knockdown to obtain further insights into the molecular mechanism involved.RESULTS Our data suggested that BAs could reverse erastin-induced ferroptosis in GC cells.This effect correlated with increased glutathione(GSH)concentrations,a reduced GSH to oxidized GSH ratio,and higher GSH peroxidase 4(GPX4)expression levels.Subsequently,we confirmed that BAs exerted these effects by activating FXR,which markedly increased the expression of GSH synthetase and GPX4.Notably,BACH1 was detected as an essential intermediate molecule in the promotion of GSH synthesis by BAs and FXR.Finally,our results suggested that FXR could significantly promote GC cell proliferation,which may be closely related to its anti-ferroptosis effect.CONCLUSION This study revealed for the first time that BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSHGPX4 axis in GC cells.This work provided new insights into the mechanism associated with BA-mediated promotion of GC and may help identify potential therapeutic targets for GC patients with BAs reflux.

Enabling heterogeneous catalysis to achieve carbon neutrality: Directional catalytic conversion of CO_(2) into carboxylic acids

The increase in anthropogenic carbon dioxide(CO_(2))emissions has exacerbated the deterioration of the global environment,which should be controlled to achieve carbon neutrality.Central to the core goal of achieving carbon neutrality is the utilization of CO_(2) under economic and sustainable conditions.Recently,the strong need for carbon neutrality has led to a proliferation of studies on the direct conversion of CO_(2) into carboxylic acids,which can effectively alleviate CO_(2) emissions and create high-value chemicals.The purpose of this review is to present the application prospects of carboxylic acids and the basic principles of CO_(2) conversion into carboxylic acids through photo-,electric-,and thermal catalysis.Special attention is focused on the regulation strategy of the activity of abundant catalysts at the molecular level,inspiring the preparation of high-performance catalysts.In addition,theoretical calculations,advanced technologies,and numerous typical examples are introduced to elaborate on the corresponding process and influencing factors of catalytic activity.Finally,challenges and prospects are provided for the future development of this field.It is hoped that this review will contribute to a deeper understanding of the conversion of CO_(2) into carboxylic acids and inspire more innovative breakthroughs.

Endogenous biosynthesis of docosahexaenoic acid(DHA)regulates fish oocyte maturation by promoting pregnenolone production

Omega-3 polyunsaturated fatty acids(n-3 PUFAs),particularly docosahexaenoic acid(22:6n-3,DHA),play crucial roles in the reproductive health of vertebrates,including humans.Nevertheless,the underlying mechanism related to this phenomenon remains largely unknown.In this study,we employed two zebrafish genetic models,i.e.,elovl2^(-/-)mutant as an endogenous DHAdeficient model and fat1(omega-3 desaturase encoding gene)transgenic zebrafish as an endogenous DHA-rich model,to investigate the effects of DHA on oocyte maturation and quality.Results show that the elovl2^(-/-)mutants had much lower fecundity and poorer oocyte quality than the wild-type controls,while the fat1 zebrafish had higher fecundity and better oocyte quality than wildtype controls.DHA deficiency in elovl2^(-/-)embryos led to defects in egg activation,poor microtubule stability,and reduced pregnenolone levels.Further study revealed that DHA promoted pregnenolone synthesis by enhancing transcription of cyp11a1,which encodes the cholesterol side-chain cleavage enzyme,thereby stabilizing microtubule assembly during oogenesis.In turn,the hypothalamic-pituitary-gonadal axis was enhanced by DHA.In conclusion,using two unique genetic models,our findings demonstrate that endogenously synthesized DHA promotes oocyte maturation and quality by promoting pregnenolone production via transcriptional regulation of cyp11a1.

A comparison study on structure-function relationship of polysaccharides obtained from sea buckthorn berries using different methods:antioxidant and bile acid-binding capacity

In this study,the structural characters,antioxidant activities and bile acid-binding ability of sea buckthorn polysaccharides(HRPs)obtained by the commonly used hot water(HRP-W),pressurized hot water(HRP-H),ultrasonic(HRP-U),acid(HRP-C)and alkali(HRP-A)assisted extraction methods were investigated.The results demonstrated that extraction methods had significant effects on extraction yield,monosaccharide composition,molecular weight,particle size,triple-helical structure,and surface morphology of HRPs except for the major linkage bands.Thermogravimetric analysis showed that HRP-U with filamentous reticular microstructure exhibited better thermal stability.The HRP-A with the lowest molecular weight and highest arabinose content possessed the best antioxidant activities.Moreover,the rheological analysis indicated that HRPs with higher galacturonic acid content and molecular weight showed higher viscosity and stronger crosslinking network(HRP-C,HRP-W and HRP-U),which exhibited stronger bile acid binding capacity.The present findings provide scientific evidence in the preparation technology of sea buckthorn polysaccharides with good antioxidant and bile acid binding capacity which are related to the structure affected by the extraction methods.