Krüppel-like factor 2 is an endoprotective transcription factor in diabetic kidney disease.

Diabetic kidney disease (DKD) is a microvascular complication of diabetes, and glomerular endothelial cell (GEC) dysfunction is a key driver of DKD pathogenesis. Krüppel-like factor 2 (KLF2), a shear stress-induced transcription factor, is among the highly regulated genes in early DKD. In the kidney, KLF2 expression is mostly restricted to endothelial cells, but its expression is also found in immune cell subsets. KLF2 expression is upregulated in response to increased shear stress by the activation of mechanosensory receptors but suppressed by inflammatory cytokines, both of which characterize the early diabetic kidney milieu. KLF2 expression is reduced in progressive DKD and hypertensive nephropathy in humans and mice, likely due to high glucose and inflammatory cytokines such as TNF-α. However, KLF2 expression is increased in glomerular hyperfiltration-induced shear stress without metabolic dysregulation, such as in settings of unilateral nephrectomy. Lower KLF2 expression is associated with CKD progression in patients with unilateral nephrectomy, consistent with its endoprotective role. KLF2 confers endoprotection by inhibition of inflammation, thrombotic activation, and angiogenesis, and thus KLF2 is considered a protective factor for cardiovascular disease (CVD). Based on similar mechanisms, KLF2 also exhibits renoprotection, and its reduced expression in endothelial cells worsens glomerular injury and albuminuria in settings of diabetes or unilateral nephrectomy. Thus KLF2 confers endoprotective effects in both CVD and DKD, and its activators could potentially be developed as a novel class of drugs for cardiorenal protection in diabetic patients.

Chronic kidney disease in a murine model of non-alcoholic steatohepatitis (NASH).

Clinical studies suggest that non-alcoholic steatohepatitis (NASH) is an independent risk factor for chronic kidney disease (CKD), but causality and mechanisms linking these two major diseases are lacking. To assess whether NASH can induce CKD, we have characterized kidney function, histological features, transcriptomic and lipidomic profiles in a well-validated murine NASH model. Mice with NASH progressively developed significant podocyte foot process effacement, proteinuria, glomerulosclerosis, tubular epithelial cell injury, lipid accumulation, and interstitial fibrosis. The progression of kidney fibrosis paralleled the severity of the histologic NASH-activity score. Significantly, we confirmed the causal link between NASH and CKD by orthotopic liver transplantation, which attenuated proteinuria, kidney dysfunction, and fibrosis compared with control sham operated mice. Transcriptomic analysis of mouse kidney cortices revealed differentially expressed genes that were highly enriched in mitochondrial dysfunction, lipid metabolic process, and insulin signaling pathways in NASH-induced CKD. Lipidomic analysis of kidney cortices further revealed that phospholipids and sphingolipids were the most significantly changed lipid species. Notably, we found similar kidney histological changes in human NASH and CKD. Thus, our results confirm a causative role of NASH in the development of CKD, reveal potential pathophysiologic mechanisms of NASH-induced kidney injury, and established a valuable model to study the pathogenesis of NASH-associated CKD. This is an important feature of fatty liver disease that has been largely overlooked but has clinical and prognostic importance.

Podocyte-derived soluble RARRES1 drives kidney disease progression through direct podocyte and proximal tubular injury.

Retinoic acid receptor responder protein-1 (RARRES1) is a podocyte-enriched transmembrane protein whose increased expression correlates with human glomerular disease progression. RARRES1 promotes podocytopenia and glomerulosclerosis via p53-mediated podocyte apoptosis. Importantly, the cytopathic actions of RARRES1 are entirely dependent on its proteolytic cleavage into a soluble protein (sRARRES1) and subsequent podocyte uptake by endocytosis, as a cleavage mutant RARRES1 exerted no effects in vitro or in vivo. As RARRES1 expression is upregulated in human glomerular diseases, here we investigated the functional consequence of podocyte-specific overexpression of RARRES1 in mice in the experimental focal segmental glomerulosclerosis and diabetic kidney disease. We also examined the effects of long-term RARRES1 overexpression on slowly developing aging-induced kidney injury. As anticipated, the induction of podocyte overexpression of RARRES1 (Pod-RARRES1WT) significantly worsened glomerular injuries and worsened kidney function in all three models, while overexpression of RARRES1 cleavage mutant (Pod-RARRES1MT) did not. Remarkably, direct uptake of sRARRES1 was also seen in proximal tubules of injured Pod-RARRES1WT mice and associated with exacerbated tubular injuries, vacuolation, and lipid accumulation. Single-cell RNA sequence analysis of mouse kidneys demonstrated RARRES1 led to a marked deregulation of lipid metabolism in proximal tubule subsets. We further identified matrix metalloproteinase 23 (MMP23) as a highly podocyte-specific metalloproteinase and responsible for RARRES1 cleavage in disease settings, as adeno-associated virus 9-mediated knockdown of MMP23 abrogated sRARRES1 uptake in tubular cells in vivo. Thus, our study delineates a previously unrecognized mechanism by which a podocyte-derived protein directly facilitates podocyte and tubular injury in glomerular diseases and suggests that podocyte-specific functions of RARRES1 and MMP23 may be targeted to ameliorate glomerular disease progression in vivo.

Supercritical CO2 and Subcritical H2O Analysis Instrument: Automated Lipid Analysis for In Situ Planetary Life Detection.

The search for extraterrestrial extant or extinct life in our Solar System will require highly capable instrumentation and methods for detecting low concentrations of biosignatures. This paper introduces the Supercritical CO2 and Subcritical H2O Analysis (SCHAN) instrument, a portable and automated system that integrates supercritical fluid extraction (SFE), supercritical fluid chromatography (SFC), and subcritical water extraction coupled with liquid chromatography. The instrument is compact and weighs 6.3 kg, making it suitable for spaceflight missions to planetary bodies. Traditional techniques, such as gas chromatography-mass spectrometry (MS), face challenges with involatile and thermally labile analytes, necessitating derivatization. The SCHAN instrument, however, eliminates the need for derivatization and cosolvents by utilizing neat supercritical CO2 with water as an additive. This SFE-SFC-MS method gives efficient lipid biosignature separations with median detection limits of 10 pg/g (ppt) for fatty acids and 50 pg/g (ppt) for sterols. Several free fatty acids and cholesterol were among the detected peaks in biologically lean samples from the Atacama Desert, demonstrating the instrument's potential for in situ life detection missions. The SCHAN instrument addresses the challenges of conventional systems, offering a compact, portable, and spaceflight-compatible tool for the analysis of organics for future astrobiology-focused missions.

Model-based precision dosing and remedial dosing recommendations for delayed or missed doses of isoniazid in Chinese patients with tuberculosis.

AIMS: Isoniazid (INH) has been used as a first-line drug to treat tuberculosis (TB) for more than 50 years. However, large interindividual variability was found in its pharmacokinetics, and effects of nonadherence to INH treatment and corresponding remedy regime remain unclear. This study aimed to develop a population pharmacokinetic (PPK) model of INH in Chinese patients with TB to provide model-informed precision dosing and explore appropriate remedial dosing regimens for nonadherent patients. METHODS: In total, 1012 INH observations from 736 TB patients were included. A nonlinear mixed-effects modelling was used to analyse the PPK of INH. Using Monte Carlo simulations to determine optimal dosage regimens and design remedial dosing regimens. RESULTS: A 2-compartmental model, including first-order absorption and elimination with allometric scaling, was found to best describe the PK characteristics of INH. A mixture model was used to characterize dual rates of INH elimination. Estimates of apparent clearance in fast and slow eliminators were 28.0 and 11.2 L/h, respectively. The proportion of fast eliminators in the population was estimated to be 40.5%. Monte Carlo simulations determined optimal dosage regimens for slow and fast eliminators with different body weight. For remedial dosing regimens, the missed dose should be taken as soon as possible when the delay does not exceed 12 h, and an additional dose is not needed. delay for an INH dose exceeds 12 h, the patient only needs to take the next single dose normally. CONCLUSION: PPK modelling and simulation provide valid evidence on the precision dosing and remedial dosing regimen of INH.

Ergone Derivatives from the Deep-Sea-Derived Fungus Aspergillus terreus YPGA10 and 25,28-Dihydroxyergone-Induced Apoptosis in Human Colon Cancer SW620 Cells.

Ten new ergone derivatives (1-10) and five known analogues (11-15) were isolated from the deep-sea-derived fungus Aspergillus terreus YPGA10. The structures including the absolute configurations were established by detailed analysis of the NMR spectroscopic data, HRESIMS, ECD calculation, and coupling constant calculation. All the structures are characterized by a highly conjugated 25-hydroxyergosta-4,6,8(14),22-tetraen-3-one nucleus. Structurally, compound 2 bearing a 15-carbonyl group and compounds 5-7 possessing a 15ß-OH/OCH3 group are rarely encountered in ergone derivatives. Bioassay results showed that compounds 1 and 11 demonstrated cytotoxic effects on human colon cancer SW620 cells with IC50 values of 8.4 and 3.1 µM, respectively. Notably, both compounds exhibited negligible cytotoxicity on the human normal lung epithelial cell BEAS-2B. Compound 11 was selected for preliminary mechanistic study and was found to inhibit cell proliferation and induce apoptosis in human colon cancer SW620 cells. In addition, compound 1 displayed cytotoxic activity against five human leukemia cell lines with IC50 values ranging from 5.7 to 8.9 µM. Our study demonstrated that compound 11 may serve as a potential candidate for the development of anticolorectal cancer agents.

Preparation of hyaluronic acid-loaded liquid-core hydrogel beads with acceptable mechanical properties and thermal stability.

BACKGROUND: Hyaluronic acid liquid-core hydrogel beads (HA-LHB) is a good way for oral intake of HA. However, HA may affect the reaction-diffusion of sodium alginate (SA) and Ca2+ leading to poor mechanical properties, since HA is a polyanionic electrolyte having electrostatic effect and a certain spatial site-blocking effect. RESULTS: The mechanical properties of HA-LHB were modified from bathing solution, core solution and secondary calcium bath time. The mechanical properties varied with the SA structure and concentration in bathing solution, where SA with high G (guluronic acid) segment compounded with SA with high M (mannuronic acid) segment at a mass ratio of 7:3 with a 11 g kg-1 concentration showed the best mechanical properties. The secondary calcium bath can greatly improve the mechanical properties due to the tight network formed by bidirectional crosslinking, and 15 min reaction reached the plateau if Ca2+ is sufficient. And the mechanical properties were positively correlated with calcium lactate concentration only at <70 g kg-1 in core solution, but the diffusion of Ca2+ was hindered by the tight gel network at higher concentrations. Moreover, the mechanical properties can be maintained during heat treatment, due to the rearrangement of alginate network structure. CONCLUSION: Our results suggested that the problem of poor mechanical properties of LHB in the presence of high HA concentration can be avoided by process control, which may broaden the development of HA and popping boba market. © 2024 Society of Chemical Industry.

Causal role of immune cells in prostate cancer: a bidirectional Mendelian-randomization analyses.

BACKGROUND: Immune cell signatures have been implicated in cancer progression and response to treatment. However, the causal relationship between immune cell signatures and prostate cancer (PCa) is still unclear. This study aimed to investigate the potential causal associations between immune cell signatures and PCa using Mendelian randomization (MR). METHOD: This study utilized genome-wide association studies (GWAS) summary statistics for PCa and immune cell signatures from publicly available datasets. MR analyses, including IVW, MR-Egger, and weighted median methods, were performed to evaluate the causal associations between immune cell signatures and PCa. Multiple sensitivity analysis methods have been adopted to test the robustness of our results. RESULTS: After FDR correction, our findings suggested that specific immune cell signatures, such as HLA DR on CD33+ HLA DR+ CD14dim (odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.12-1.92, p = 0.006), HLA DR on CD33+ HLA DR+ CD14- (OR = 1.32, 95% CI = 1.05-1.67, p = 0.018), and HLA DR on monocyte (OR = 1.23, 95% CI = 1.03-1.47, p = 0.021), were significantly associated with PCa. PCa had no statistically significant effect on immunophenotypes. These results remained robust in sensitivity analyses, supporting the validity of the causal associations. CONCLUSIONS: This study provides evidence of a potential causal relationship between certain immune cell signatures and PCa. We observed that immune cell signatures involving HLA DR expression on specific cell types are associated with an increased risk of PCa.

Synergistic effect of combining umami substances enhances perceived saltiness.

Umami substances have the potential to enhance the perception of saltiness and thus reduce sodium intake. Two sensory evaluation experiments were conducted, involving participants tasting salt solutions, and solutions with added umami substances at equal sodium concentrations. Umami substances included sodium glutamate (MSG), disodium inosinate (IMP), and the combination of them which has a synergistic effect and is a closer match to commonly-consumed foods. In Experiment 1, using the two-alternative forced-choice (2-AFC) method by 330 consumers, paired comparisons were conducted at three different sodium concentrations. The combination of MSG and IMP enhanced the perception of saltiness (p < .001 in the difference test), whereas presenting either umami substance in isolation failed to do so (p > .05 in the similarity test). Significant order effects occurred in paired comparisons. In Experiment 2, a two-sip time-intensity (TI) analysis with trained panellists verified these results and found that tasting MSG and IMP either simultaneously or successively enhanced saltiness perception at equal sodium concentrations. These findings indicate that the synergistic effect of umami substances may be the cause of saltiness enhancement, and represents a potential strategy for sodium reduction while satisfying the consumer demand for saltiness perception. Considering the application in food processing and in food pairing, umami substances can potentially be used to help to reduce salt intake in food consumption.

Enzymatic debittering of cheese flavoring and bitterness characterization of peptide mixture using sensory and peptidomics approach.

Peptides in cheese flavoring produced through proteolysis plus fermentation generated bitterness. Bitterness of individual peptide can be quantified using quantitative structure-activity relationship, where molecular mass (M), hydrophobicity, residues, C-terminal hydrophobic amino acids (C-HAAs), and N-terminal basic ones (N-BAAs) are crucial. However, their accumulative influence on the overall bitterness of peptide mixture remains unknown. This study delved into extensive proteolysis to debitter and to correlate the multi-influencing factors of peptides and the collective bitterness. As hydrolysis increased from 7.5 % to 28.0 %, bitterness reduced from 5.0 to 0.3-2.7 scores, contingent on proteases used, in which FU was optimal. The overall bitterness cannot be predicted through the summation of individual peptide bitterness, which depended on M (0.5-3 kDa) and 5-23 residues, followed by N-BAAs and C-HAAs. Analysis of enzymatic cleavage sites and substrate characteristics revealed, to more effectively debitter bovine milk protein hydrolysates, proteases specifically cleaving Pro, Leu, Phe, and Val were desired.

Influence of Long-Chain Amylopectin on Physicochemical and External Digestion Properties of Glutinous Rice in Zongzi.

Zongzi, made from glutinous rice, is usually thought to stay in the stomach for a long time, causing many people to shy away. In our research, Zongzi was prepared from three indica glutinous rice samples, and three japonica glutinous rice samples were digested in vitro in a human gastric simulator (HGS). It was found that digestion performance in HGS (gastric emptying) was mainly related to the hardness and stickiness of texture properties, and surprisingly, the hardness and stickiness of Zongzi were positively correlated, which contradicts past perception. Through the extraction and analysis of the coated layer on the surface of glutinous rice grains in Zongzi, the main source of its stickiness was the entanglement between the long chains of leached amylopectin molecules. The hardness was also mainly due to the high proportion of long chains in its glutinous rice starch, which made it difficult to gelatinize. Studies suggested that stickiness gradually disappeared during digestion, while hardness had a longer impact on digestive performance. The indica glutinous rice Zongzi with a higher long-chain level showed a higher resistant-starch (RS) level and slow hydrolysis in the intestinal digestion stage. Therefore, the texture and digestibility of Zongzi can be adjusted by changing the molecular structure of glutinous rice starch.

Prognostic value of left ventricular structure and strain in chronic kidney disease patients by cardiovascular magnetic resonance imaging: a retrospective study.

Background: Individuals suffering from chronic kidney disease (CKD) frequently face a heightened likelihood of experiencing cardiovascular complications, including heart failure and cardiac mortality. Cardiovascular magnetic resonance feature tracking (CMR-FT) is utilized to assess the micro-contraction function of the myocardium. The objective of this research is to explore the relationship between the left ventricular anatomy, myocardial strain, and the clinical outcomes in patients with CKD. Methods: A total of 77 patients with late-stage CKD were enrolled in this retrospective study. They underwent cardiac magnetic resonance imaging and were followed up, with no history of significant cardiac diseases. The patients were divided into two groups: those with a left ventricular global longitudinal strain (LVGLS) ≥ -15.2% (n = 49) and those with LVGLS < -15.2% (n = 28). The clinical endpoints were defined as hospitalization for heart failure or all-cause mortality. Results: Over an average observation period of 22 ± 9 months, 11 (14%) patients passed away and 30 (39%) were admitted to the hospital for heart failure, with eight encountering both incidents. Those with LVGLS ≥ -15.2% had markedly lower rates of event-free survival concerning heart failure admissions and overall mortality than their counterparts (log-rank P = 0.014). Cox multivariable analysis indicated that reduced LVGLS consistently predicted a higher likelihood of combined outcomes of heart failure admissions and total mortality (HR: 3.40, 95% CI [1.35-8.56], P = 0.009), even when factoring in age, diabetes, left atrial diameter, and left ventricular mass index (LVMI). However, the LVMI showed no significant correlation with the risk of heart failure admissions or overall mortality. Conclusion: Compared to patients with LVGLS < -15.2%, CKD patients with LVGLS ≥ -15.2% have an increased risk of heart failure hospitalization and all-cause mortality. The prognostic role of LVMI in assessing CKD patients among the Asian population requires further investigation.

Respiration-Triggered Release of Cinnamaldehyde from a Biomolecular Schiff Base Composite for Preservation of Perishable Food.

One-third of the food produced worldwide is wasted annually and never consumed, of which ≈ 40-50% are perishable vegetables and fruits (VFs). Although various methods are proposed to reduce this loss, high manufacturing costs and food safety concerns pose significant challenges for the preservation of VFs. Herein, a respiration-triggered, self-saving strategy for the preservation of perishable products based on a biomolecular Schiff base composite fabricated by imidization of chitosan and cinnamaldehyde (CS-Cin) is reported. Ripening of VFs produces acid moisture and triggers a Schiff base reaction in CS-Cin, permitting the release of volatile Cin into the storage space. This enables versatile preservation by placing CS-Cin on the side without the need to touch the food, like the desiccant packet in a food packaging bag, while the rotting of VFs is retarded in a self-saving manner. As a result, the lifetimes of broccoli and strawberries are extended from 2 to 8 days. Furthermore, CS-Cin with restored preservative properties can be repeatedly recycled from used CS via imidization with Cin. Compared with conventional techniques, the preservatives are easy to use, versatile, and cost-effective, and the respiration-responsive release of Cin empowers a self-saving approach toward the smart preservation of perishable food.

Molecular investigation of soybean protein for improving the stability of quinoa (Chenopodium quinoa willd.) milk substitute.

Soybean could greatly improve stability of quinoa milk substitute. However, the key compound and underlying mechanisms remained unclear. Here we showed that soybean protein was the key component for improving quinoa milk substitute stability but not oil or okara. Supplementary level of soybean protein at 0%, 2%, 4%, and 8% of quinoa (w/w) was optimized. Median level at 4% could effectively enhance physical stability, reduce particle size, narrow down particle size distribution, and decrease apparent viscosity of quinoa milk substitute. Microscopic observation further confirmed that soybean protein could prevent phase separation. Besides, soybean protein showed increased surface hydrophobicity. Molecular docking simulated that soybean protein but not quinoa protein, could provide over 10 anchoring points for the most abundant quinoa vanillic acid, through hydrogen bond and Van-der-Waals. These results contribute to improve stability of quinoa based milk substitute, and provide theoretical basis for the interaction of quinoa phenolics and soybean protein.

A comparative study to determine the key aroma components of yogurt aroma types based on Sensomics and Flavoromics.

This study used Sensomics to examine four previously obtained yogurt aroma type profiles. 14 key aroma-active compounds were identified as significant contributors (p ≤ 0.05) in the four aroma types using gas chromatography-mass spectrometry-olfactometry (GC-MS/O), aroma extract dilution analysis (AEDA), odor activity values (OAV), and aroma recombination and omission experiments. The Sensomics and previous Flavoromics results were compared, showing that Flavoromics identified 10 indicator compounds for distinguishing aroma types. Eight were the same as the key aroma-active compounds identified via Sensomics, namely acetic acid, pentanoic acid, decanoic acid, 3-hydroxy-2-butanone, 2,3-pentanedione, acetaldehyde, δ-decalactone, and dimethyl sulfone. Sensomics revealed a prominent similarity between the categories of key aroma-active compounds of the four aroma types, with a higher sensory contribution. Flavoromics showed less overlapping between the indicator compounds, mainly related to the distinction between the four aroma types. Sensomics and Flavoromics serve distinct research objectives and should be selected according to the study subject.

[Variation Characteristics and Source Analysis of Atmospheric Ozone Pollution in Guanzhong Region].

Guanzhong urban agglomeration has a good development foundation and great development potential, and it has a unique strategic position in the national all-round opening up pattern. In recent years, the problem of near-surface ozone （O3） in the Guanzhong Region has become increasingly prominent, which has become a bottleneck affecting the continuous improvement of air quality. In order to effectively prevent and control O3 pollution, this study analyzed the characteristics of annual, monthly, and daily changes in O3 concentration in the Guanzhong Region based on the environmental monitoring data from 2018 to 2021. A geo-detector was used to study the driving factors of the spatial differentiation of O3 concentration, and the sources of O3 were analyzed using a backward trajectory model and emission inventory construction. The results showed that the daily and monthly variation in O3 concentration in the Guanzhong Region were unimodal. The daily maximum value appeared at 15：00, the minimum value appeared at 07：00, the peak value of the monthly average appeared in June, and the valley value appeared in December. The O3 concentration was highest in summer, followed by that in spring, and the lowest in winter. The days of O3 exceeding the standard showed mainly mild pollution, and moderate and above pollution showed a trend of decreasing first and then increasing. The O3 concentration in the Guanzhong Region was mainly closely related to precursors and meteorological factors, and the explanatory power of the interaction of each factor was significantly greater than that of any single factor. The regional transport of O3 concentration in the Guanzhong Region was mainly affected by easterly airflow, followed by the northwest direction, with the potential source areas located mainly in Henan Province and Hubei Province. The main local sources of volatile organic compounds （VOCs） were solvent use sources, process sources, and mobile sources, and the main emission sources of nitrogen oxides （NOx） were mobile sources and industrial production combustion sources. The research results have a guiding significance for O3 joint prevention and control in the Guanzhong Region.

FABP3 Induces Mitochondrial Autophagy to Promote Neuronal Cell Apoptosis in Brain Ischemia-Reperfusion Injury.

This study elucidates the molecular mechanisms by which FABP3 regulates neuronal apoptosis via mitochondrial autophagy in the context of cerebral ischemia-reperfusion (I/R). Employing a transient mouse model of middle cerebral artery occlusion (MCAO) established using the filament method, brain tissue samples were procured from I/R mice. High-throughput transcriptome sequencing on the Illumina CN500 platform was performed to identify differentially expressed mRNAs. Critical genes were selected by intersecting I/R-related genes from the GeneCards database with the differentially expressed mRNAs. The in vivo mechanism was explored by infecting I/R mice with lentivirus. Brain tissue injury, infarct volume ratio in the ischemic penumbra, neurologic deficits, behavioral abilities, neuronal apoptosis, apoptotic factors, inflammatory factors, and lipid peroxidation markers were assessed using H&E staining, TTC staining, Longa scoring, rotation experiments, immunofluorescence staining, and Western blot. For in vitro validation, an OGD/R model was established using primary neuron cells. Cell viability, apoptosis rate, mitochondrial oxidative stress, morphology, autophagosome formation, membrane potential, LC3 protein levels, and colocalization of autophagosomes and mitochondria were evaluated using MTT assay, LDH release assay, flow cytometry, ROS/MDA/GSH-Px measurement, transmission electron microscopy, MitoTracker staining, JC-1 method, Western blot, and immunofluorescence staining. FABP3 was identified as a critical gene in I/R through integrated transcriptome sequencing and bioinformatics analysis. In vivo experiments revealed that FABP3 silencing mitigated brain tissue damage, reduced infarct volume ratio, improved neurologic deficits, restored behavioral abilities, and attenuated neuronal apoptosis, inflammation, and mitochondrial oxidative stress in I/R mice. In vitro experiments demonstrated that FABP3 silencing restored OGD/R cell viability, reduced neuronal apoptosis, and decreased mitochondrial oxidative stress. Moreover, FABP3 induced mitochondrial autophagy through ROS, which was inhibited by the free radical scavenger NAC. Blocking mitochondrial autophagy with sh-ATG5 lentivirus confirmed that FABP3 induces mitochondrial dysfunction and neuronal apoptosis by activating mitochondrial autophagy. In conclusion, FABP3 activates mitochondrial autophagy through ROS, leading to mitochondrial dysfunction and neuronal apoptosis, thereby promoting cerebral ischemia-reperfusion injury.

Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances.

Spinocerebellar ataxia is a phenotypically and genetically heterogeneous group of autosomal dominant-inherited degenerative disorders. The gene mutation spectrum includes dynamic expansions, point mutations, duplications, insertions, and deletions of varying lengths. Dynamic expansion is the most common form of mutation. Mutations often result in indistinguishable clinical phenotypes, thus requiring validation using multiple genetic testing techniques. Depending on the type of mutation, the pathogenesis may involve proteotoxicity, RNA toxicity, or protein loss-of-function. All of which may disrupt a range of cellular processes, such as impaired protein quality control pathways, ion channel dysfunction, mitochondrial dysfunction, transcriptional dysregulation, DNA damage, loss of nuclear integrity, and ultimately, impairment of neuronal function and integrity which causes diseases. Many disease-modifying therapies, such as gene editing technology, RNA interference, antisense oligonucleotides, stem cell technology, and pharmacological therapies are currently under clinical trials. However, the development of curative approaches for genetic diseases remains a global challenge, beset by technical, ethical, and other challenges. Therefore, the study of the pathogenesis of spinocerebellar ataxia is of great importance for the sustained development of disease-modifying molecular therapies.

A Novel Necroptosis-Related Signature Can Predict Prognosis and Chemotherapy Sensitivity in Multiple Myeloma.

BACKGROUND: Necroptosis is an inflammatory cell death mode, and its association with multiple myeloma (MM) remains unclear. METHODS: This prospective study first analyzed the association between necroptosis-related signature as well as prognosis and chemotherapy sensitivity in MM using the necroptosis score. Consensus clustering was used to identify necroptosis-related molecular clusters. Least absolute shrinkage and selection operator analysis and multivariate Cox regression analysis were performed to establish the prognostic model of necroptosis-related genes (NRGs). RESULTS: A high necroptosis score was associated with poor prognosis and abundant immune infiltration. Two molecular clusters (clusters A and B) significantly differed in terms of prognosis and tumor microenvironment. Cluster B had a worse prognosis and higher tumor marker pathway activity than cluster A. The risk score model based on four NRGs can accurately predict the prognosis of patients with MM, which was validated in two validation cohorts. Receiver operating characteristic curve analysis showed that the area under the curves of the risk score in predicting the 1-, 3-, and 5-year survival rates were 0.710, 0.758, and 0.834, respectively. Further, the activity of pathways related to proliferation and genetic regulation in the high-risk group significantly increased. The drug prediction results showed that the low-risk score group was more sensitive to bortezomib, cytarabine, and doxorubicin than the high-risk score group. Meanwhile, the high-risk score group was more sensitive to lenalidomide and vinblastine than the low-risk score group. Finally, the upregulation of model genes CHMP1A, FAS, JAK3, and HSP90AA1 in clinical samples collected from patients with MM was validated via real-time polymerase chain reaction. CONCLUSION: A systematic analysis of NRGs can help identify potential necroptosis-related mechanisms and provide novel biomarkers for MM prognosis prediction, tumor microenvironment evaluation, and personalized treatment planning.

Valorization of barley (Hordeum vulgare L.) brans from the sustainable perspective: A comprehensive review of bioactive compounds and health benefits with emphasis on their potential applications.

Barley is an important source of sustainable diets for humans, while its brans is commonly disposed as wastes. The recycling of barley brans has become a key for facilitating the valorization of barley as a whole to achieve its sustainable development. This review summarized the value of barley brans as an excellent source of multiple functional components (phenolic compounds, ß-glucan, and arabinoxylan), which conferred extensive health benefits to barley brans mainly including antioxidant, anti-obesity and lipid-lowering, anti-diabetic, and hepatoprotective properties. The utilization of barley brans reflected a great potential for sustainable development. Exploiting of food products and edible films containing barley brans or their bioactive compounds and non-food applications (preparation of bioactive substances, laccase enzymes, and biosorbents) have been attempted for supporting the zero-waste concept and circular economy. Considering their diverse applications, effective extraction techniques of bioactive compounds from barley brans and their safety are the priority of future research.