Roles of cigar microbes in flavor formation during roasted-rice leachate fermentation.

Roasted-rice leachate fermentation, a distinctive local tobacco fermentation method in Sichuan, imparts a mellow flavor and glossy texture to tobacco leaves, along with a roasted rice aroma. In order to find out the impact of roasted-rice leachate on cigar tobacco leaves, the physicochemical properties, volatile flavor profile, and microbial community were investigated. The content of protein significantly decreased after fermentation. The volatile flavor compounds increased following roasted-rice leachate fermentation, including aldehydes, alcohols, acids, and esters. High-throughput sequencing identified Staphylococcus, Pseudomonas, Pantoea, Oceanobacillus, Delftia, Corynebacterium, Sphingomonas, Aspergillus, Weissella, and Debaryomyces as the primary genera. Network and correlation analysis showed Debaryomyces played a crucial role in roasted-rice leachate fermentation, due to its numerous connections with other microbes and positive relationships with linoelaidic acid, aromandendrene, and benzaldehyde. This study is useful for gaining insight into the relationship between flavor compounds and microorganisms and provides references regarding the effect of extra nutrients on traditional fermentation products. KEY POINTS: • Volatile flavor compounds increased following roasted-rice leachate fermentation • Staphylococcus was the primary genera in fermented cigar • Debaryomyces may improve the quality of tobacco leaves.

Lysosomal dysfunction in α-synuclein pathology: molecular mechanisms and therapeutic strategies.

In orchestrating cell signaling, facilitating plasma membrane repair, supervising protein secretion, managing waste elimination, and regulating energy consumption, lysosomes are indispensable guardians that play a crucial role in preserving intracellular homeostasis. Neurons are terminally differentiated post-mitotic cells. Neuronal function and waste elimination depend on normal lysosomal function. Converging data suggest that lysosomal dysfunction is a critical event in the etiology of Parkinson's disease (PD). Mutations in Glucosylceramidase Beta 1 (GBA1) and leucine-rich repeat kinase 2 (LRRK2) confer an increased risk for the development of parkinsonism. Furthermore, lysosomal dysfunction has been observed in the affected neurons of sporadic PD (sPD) patients. Given that lysosomal hydrolases actively contribute to the breakdown of impaired organelles and misfolded proteins, any compromise in lysosomal integrity could incite abnormal accumulation of proteins, including α-synuclein, the major component of Lewy bodies in PD. Clinical observations have shown that lysosomal protein levels in cerebrospinal fluid may serve as potential biomarkers for PD diagnosis and as signs of lysosomal dysfunction. In this review, we summarize the current evidence regarding lysosomal dysfunction in PD and discuss the intimate relationship between lysosomal dysfunction and pathological α-synuclein. In addition, we discuss therapeutic strategies that target lysosomes to treat PD.

Characteristics of a Novel Zearalenone Lactone Hydrolase ZHRnZ and Its Thermostability Modification.

Zearalenone (ZEN) is a toxic secondary metabolite produced by the Fusarium fungi, which widely contaminates grains, food, and feed, causing health hazards for humans and animals. Therefore, it is essential to find effective ZEN detoxification methods. Enzymatic degradation of ZEN is believed to be an eco-friendly detoxification strategy, specifically thermostable ZEN degradation enzymes are needed in the food and feed industry. In this study, a novel ZEN lactone hydrolase ZHRnZ from Rosellinia necatrix was discovered using bioinformatic and molecular docking technology. The recombinant ZHRnZ showed the best activity at pH 9.0 and 45 °C with more than 90% degradation for ZEN, α-zearalenol (α-ZOL), ß-zearalenol (ß-ZOL) and α-zearalanol (α-ZAL) after incubation for 15 min. We obtained 10 mutants with improved thermostability by single point mutation technology. Among them, mutants E122Q and E122R showed the best performance, which retained more than 30% of their initial activity at 50 °C for 2 min, and approximately 10% of their initial activity at 60 °C for 1 min. The enzymatic kinetic study showed that the catalytic efficiency of E122R was 1.3 times higher than that of the wild-type (WT). Comprehensive consideration suggests that mutant E122R is a promising hydrolase to detoxify ZEN in food and feed.

KRASG 12C-inhibitor-based combination therapies for pancreatic cancer: insights from drug screening.

Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto-oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRASG12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRASG12C-inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine-protein phosphatase non-receptor type 11 (PTPN11)/Src homology region 2 domain-containing phosphatase-2 (SHP2) inhibitors, and broad-spectrum multi-kinase inhibitors. Validation in a novel and unique KRASG12C-mutated patient-derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRASG12C-inhibitor efficacy, guiding clinical trial design and molecular tumor boards.

Alkali-Resistant Domestication of Bacillus pasteurii and Its Growth Kinetics in Sodium Carboxymethyl Cellulose Solid-Free Drilling Fluids.

Microbially induced calcium carbonate precipitation (MICP) provides a novel approach for use in addressing the instabilities of borehole walls comprising broken formations, but the highly alkaline environments of drilling fluids are unfavorable for microbial growth. Therefore, this study investigated the alkali-resistant domestication of Bacillus pasteurii commonly used in MICP. Using gradient domestication, B. pasteurii was domesticated under different pH conditions (pH 8.0, 9.0, 10.0, and 11.0) in sodium carboxymethyl cellulose solid-free drilling fluids. Its growth patterns and variations in urease activity were analyzed to assess the effectiveness of domestication. The Gompertz and logistic models were used to fit the growth patterns of B. pasteurii under different pH conditions, and growth kinetic models were constructed based on the mean square error, Akaike information criterion, and coefficient of determination. The bacterial concentration and urease activity of B. pasteurii were enhanced after alkali-resistant gradient domestication. The Gompertz model accurately described the growth patterns of B. pasteurii after gradient domestication at pH 8.0, 10.0, and 11.0, whereas the logistic model accurately described the growth pattern after gradient domestication at pH 9.0. This study provides scientific evidence and a theoretical basis for the use of B. pasteurii in maintaining the stabilities of borehole walls comprising broken formations.

Search flavor labels in beverages: An electrophysiological investigation of color-flavor congruency and association strength in visual search.

Individuals are apt to link various characteristics of an object or event through different sensory experiences. We conducted two electrophysiological experiments to investigate the effects of color-flavor congruency and association strength on visual search efficiency and the in-depth cognitive mechanisms underlying multisensory processes. Participants were prompted with a flavor label and asked to identify the primed flavor from four beverage bottle images. Experiment 1 focused on color-flavor congruency and noted faster searches for congruent targets than incongruent ones. EEG data exhibited smaller N2, larger P3 and LPC, and increased parietal-occipital midline (POM) alpha power for incongruent targets than congruent ones. Experiment 2 manipulated color-flavor association strength within each flavor. Behavioral findings showed that searches for targets with weak association strength took longer than those with strong association strength. Moreover, time-frequency analysis displayed that the former evoked greater frontal midline (FM) theta power and higher alpha power than the latter. Altogether, our research indicated that (1) color expectations based on prior experience can automatically guide people's attentional selection, (2) the color-flavor congruency and association strength impact the visual search efficiency via distinct pathways, and (3) theta and alpha activities make a pivotal role in unraveling multisensory information processing. These findings shed some light on the intricate cognitive processes involved in crossmodal visual search and the underlying neurocognitive dynamics.

Intestinal glucagon-like peptide-1: A new player associated with impaired counterregulatory responses to hypoglycaemia in type 1 diabetic mice.

BACKGROUND: Impaired hypoglycaemic counterregulation has emerged as a critical concern for diabetic patients who may be hesitant to medically lower their blood glucose levels due to the fear of potential hypoglycaemic reactions. However, the patho-genesis of hypoglycaemic counterregulation is still unclear. Glucagon-like peptide-1 (GLP-1) and its analogues have been used as adjunctive therapies for type 1 diabetes mellitus (T1DM). The role of GLP-1 in counterregulatory dys-function during hypoglycaemia in patients with T1DM has not been reported. AIM: To explore the impact of intestinal GLP-1 on impaired hypoglycaemic counterregulation in type 1 diabetic mice. METHODS: T1DM was induced in C57BL/6J mice using streptozotocin, followed by intraperitoneal insulin injections to create T1DM models with either a single episode of hypoglycaemia or recurrent episodes of hypoglycaemia (DH5). Immunofluorescence, Western blot, and enzyme-linked immunosorbent assay were employed to evaluate the influence of intestinal GLP-1 on the sympathetic-adrenal reflex and glucagon (GCG) secretion. The GLP-1 receptor agonist GLP-1(7-36) or the antagonist exendin (9-39) were infused into the terminal ileum or injected intraperitoneally to further investigate the role of intestinal GLP-1 in hypoglycaemic counterregulation in the model mice. RESULTS: The expression levels of intestinal GLP-1 and its receptor (GLP-1R) were significantly increased in DH5 mice. Consecutive instances of excess of intestinal GLP-1 weakens the sympathetic-adrenal reflex, leading to dysfunction of adrenal counterregulation during hypoglycaemia. DH5 mice showed increased pancreatic δ-cell mass, cAMP levels in δ cells, and plasma somatostatin concentrations, while cAMP levels in pancreatic α cells and plasma GCG levels decreased. Furthermore, GLP-1R expression in islet cells and plasma active GLP-1 levels were significantly increased in the DH5 group. Further experiments involving terminal ileal infusion and intraperitoneal injection in the model mice demonstrated that intestinal GLP-1 during recurrent hypoglycaemia hindered the secretion of the counterregulatory hormone GCG via the endocrine pathway. CONCLUSION: Excessive intestinal GLP-1 is strongly associated with impaired counterregulatory responses to hypoglycaemia, leading to reduced appetite and compromised secretion of adrenaline, noradrenaline, and GCG during hypo-glycaemia.

Fabrication of Single-Ion Conductors Based on Liquid Crystal Polymer Network for Quasi-Solid-State Lithium Ion Batteries.

Single-ion conductive polymer electrolytes can improve the safety of lithium ion batteries (LIBs) by increasing the lithium transference number (tLi+) and avoiding the growth of lithium dendrites. Meanwhile, the self-assembled ordered structure of liquid crystal polymer networks (LCNs) can provide specific channels for the ordered transport of Li ions. Herein, single-ion conductive nematic and cholesteric LCN electrolyte membranes (denoted as NLCN-Li and CLCN-Li) were successfully prepared. NLCN-Li was then coated on commercial Celgard 2325 while CLCN-Li was coated on poly(vinylidene fluoride-hexafluoropropylene) film, coupled with plasticizer, to make NLCN-Li/Cel and CLCN-Li/Pv quasi-solid-state electrolyte membranes, respectively. Their electrochemical properties were evaluated, and it was found that they possessed benign thermal stability and electrolyte/electrode compatibility, high tLi+ up to 0.98 and high electrochemical stability window up to 5.2 V. A small amount (0.5M) of extra Li salt added to the plasticizer could improve the ion conductivity from 1.79 × 10-5 to 5.04 × 10-4 S cm-1, while the tLi+ remained 0.85. The assembled LFP|Li batteries also exhibited excellent cycling and rate performances. The orderliness of the LCN layer played an important role in the distribution and movement of Li ions, thereby affecting the Li deposition and growth of Li dendrites. As the first report of nematic and cholesteric LCN single-ion conductors, this work sheds light on the design and fabrication of ordered quasi-solid-state electrolytes for high-performance and safe LIBs.

Hexavalent chromium reduces testosterone levels by impairing lipophagy and disrupting lipid metabolism homeostasis: Based on a metabolomic analysis.

Hexavalent chromium (Cr(VI)) causes testicular damage and reduces testosterone secretion. Testosterone synthesis relies on cholesterol as a raw material, and its availability can be affected by lipophagy. However, the role of lipophagy in Cr(VI)-induced testicular damage and reduced testosterone secretion remains unclear. In this study, we investigated the effect of Cr(VI) on lipid metabolism and lipophagy in the testes of ICR mice. Forty mice were randomly divided into four groups and exposed to different doses of Cr(VI) (0, 75, 100, 125 mg/kg) for thirty days. Cr(VI) increased the rate of sperm abnormalities, decreased testosterone level, and decreased the levels of testosterone synthesis-related proteins, namely steroidogenic acute regulatory (StAR) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) proteins. Through metabolomic analysis, Oil Red O staining, and biochemical indicator (triglyceride and total cholesterol) analysis, Cr(VI) was found to disrupt testicular lipid metabolism. Further investigation revealed that Cr(VI) inhibited the AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein 1 (SREBP1) pathway, elevated levels of the autophagy-related proteins microtubule-associated protein 1 light chain 3B (LC3B) and sequestosome 1 (SQSTM1)/P62 and lipophagy-related proteins Rab7 and Rab10, while increasing colocalization of LC3B and Perilipin2. These findings suggest that Cr(VI) exposure leads to abnormal lipid metabolism in the testes by suppressing the AMPK/SREBP1 pathway and disrupting lipophagy, ultimately reducing testosterone level and inducing testicular damage.

The aroma formation from fresh tea leaves of Longjing 43 to finished Enshi Yulu tea at an industrial scale.

BACKGROUND: Enshi Yulu tea (ESYL) is the most representative of steamed green tea in China, but its aroma formation in processing is unclear. Thus, the ESYL volatiles during the whole industrial processing were investigated using headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry. RESULTS: A total of 134 volatiles were identified. Among these, 31 differential volatiles [P < 0.05 and variable importance in projection (VIP) > 1] and 25 key volatiles [relative odor activity value (rOAV) and/or the ratio of each rOAV to the maximum rOAV (ROAV) > 1.0] were screened out, wherein ß-ionone and nonanal were the most key odorants. Besides, the sensory evaluation combined with multivariate statistical analysis of volatiles pinpointed spreading, fixation, first drying, and second drying as the key processing steps that have a pronounced influence on the aroma quality of ESYL. Furthermore, the oxidative degradation of unsaturated fatty acids, synthesis of monoterpenes, and degradation of carotenoids were the main metabolic pathway for the formation of key odorants. CONCLUSION: The study provides comprehensive insights into the volatile characteristics during the industrial processing of ESYL and promote our understanding of the aroma formation in steamed green teas. © 2024 Society of Chemical Industry.

Topography- and depth-dependent rhizosphere microbial community characteristics drive ecosystem multifunctionality in Juglans mandshurica forest.

Rhizosphere microbial community characteristics and ecosystem multifunctionality (EMF), both affected by topographic factors, are closely correlated. However, more targeted exploration is yet required to fully understand the variations of rhizosphere microbial communities along topographic gradients in different soil layers, as well as whether and how they regulate EMF under specific site conditions. Here, we conducted relevant research on Juglans mandshurica forests at six elevation gradients and two slope positions ranging from 310 to 750 m in Tianjin Baxian Mountain. Results demonstrated that rhizosphere soil physicochemical properties and enzyme activities of both layers (0-20 cm and 20-40 cm) varied significantly with elevation, while only at top layer did slope position have significant impacts on most indicators. Bacterial richness and diversity were higher in the top layer at slope bottom and middle-high elevation, the difference in fungi was not as noticeable. Both topographic factors and soil depth significantly impacted microbial community structure, with Candidatus_Udaeobacter of bacteria, Mortierella, Sebacina, and Hygrocybe of fungi mainly contributing to the dissimilarity between communities. EMF rose with increasing elevation, bacteria were more critical drivers of this process than fungi, and topographic factors could affect EMF by altering bacterial diversity and dominant taxa abundance. For evaluating EMF, the aggregate structure of sub layer and the carbon cycle-related indicators of top layer were of higher importance. Our results revealed the depth-dependent characteristics of the rhizosphere microbial community along topographic gradients in studied stands, as well as the pivotal regulatory role of bacteria on EMF, while also highlighting depth as an important variable for analyzing soil properties and EMF. This work helps us better understand the response of individuals and communities of J. mandshurica to changing environmental conditions, further providing a scientific reference for the management and protection of secondary forests locally and in North China.

Lindenane sesquiterpenoid dimers with NLRP3 inflammasome inhibitory activities from Chloranthus holostegius var. shimianensis.

Thirteen previously undescribed lindenane sesquiterpenoid dimers (LSDs), named chlorahololides G-S (1-13), were isolated from the whole plants of Chloranthus holostegius var. shimianensis, along with ten known analogues (14-23). The structures and absolute configurations of compounds 1-13 were elucidated through comprehensive spectroscopic analysis, NMR and electronic circular dichroism (ECD) calculations, and X-ray single-crystal diffraction. Chlorahololide G (1) represents the first instance of LSDs formed via a C-15-C-9' carbon-carbon single bond, whose plausible biosynthetic pathway was also proposed. Chlorahololides I and J (3 and 4) were deduced to be rare 8,9-seco and 9-deoxy LSDs with C-11-C-7' carbon-carbon bond, respectively. The inhibitory activity against NLRP3 inflammasome activation was evaluated for all isolates, with six compounds (5, 7, 8, 17, 22, and 23) exhibiting significant effects, and IC50 values ranging from 2.99 to 8.73 µM. Additionally, a preliminary structure-activity relationship analysis regarding their inhibition of NLRP3 inflammasome activation was summarized. Compound 17 exhibited dose-dependent inhibition of nigericin-induced pyroptosis in J774A.1 cells. Molecular docking studies suggested a strong interaction between compound 17 and NLRP3.

Alstomaphylines A-K, monoterpenoid bisindole alkaloids from Alstonia macrophylla with AChE inhibitory activity and cytotoxicity.

Eleven undescribed monoterpenoid bisindole alkaloids, alstomaphyines A-K (1-11), along with three known analogues were isolated from the leaves and stem bark of the Alstonia macrophylla. Compounds 1-3 were unprecedented dimerization alkaloids incorporating a macroline-type motif with an ajmaline-type motif via a C-C linkage. Their structures and absolute configurations were elucidated by extensive spectroscopic analysis, electronic circular dichroism (ECD) calculation, and CD exciton chirality method. Compounds 1-3 displayed potential inhibitory bioactivity against AChE with IC50 values of 4.44 ± 0.35, 3.59 ± 0.18, and 3.71 ± 0.23 µM, respectively. Enzyme kinetic study revealed compounds 1-3 as mixed competitive AChE inhibitors. Besides, compounds 8 and 12-14 exhibited better cytotoxicity against human cancer cell line HT-29 than cisplatin. Flow cytometry data revealed that compounds 8, 13, and 14 significantly induced the HT-29 cells arrest in G0/G1 phase in a concentration-dependent manner.

DNA Tetrahedron Delivering miR-21-5p Promotes Senescent Bone Defects Repair through Synergistic Regulation of Osteogenesis and Angiogenesis.

Compromised osteogenesis and angiogenesis is the character of stem cell senescence, which brought difficulties for bone defects repairing in senescent microenvironment. As the most abundant bone-related miRNA, miRNA-21-5p plays a crucial role in inducing osteogenic and angiogenic differentiation. However, highly efficient miR-21-5p delivery still confronts challenges including poor cellular uptake and easy degradation. Herein, TDN-miR-21-5p nanocomplex is constructed based on DNA tetrahedral (TDN) and has great potential in promoting osteogenesis and alleviating senescence of senescent bone marrow stem cells (O-BMSCs), simultaneously enhancing angiogenic capacity of senescent endothelial progenitor cells (O-EPCs). Of note, the activation of AKT and Erk signaling pathway may direct regulatory mechanism of TDN-miR-21-5p mediated osteogenesis and senescence of O-BMSCs. Also, TDN-miR-21-5p can indirectly mediate osteogenesis and senescence of O-BMSCs through pro-angiogenic growth factors secreted from O-EPCs. In addition, gelatin methacryloyl (GelMA) hydrogels are mixed with TDN and TDN-miR-21-5p to fabricate delivery scaffolds. TDN-miR-21-5p@GelMA scaffold exhibits greater bone repair with increased expression of osteogenic- and angiogenic-related markers in senescent critical-size cranial defects in vivo. Collectively, TDN-miR-21-5p can alleviate senescence and induce osteogenesis and angiogenesis in senescent microenvironment, which provides a novel candidate strategy for senescent bone repair and widen clinical application of TDNs-based gene therapy.

Serum levels of soluble receptor activator for nuclear factor kB ligand play a crucial role in the association of osteoprotegerin with coronary artery disease.

Osteoprotegerin (OPG) is a soluble decoy receptor for receptor activator of nuclear factor kB ligand (RANKL), and is implicated in the pathogenesis of atherosclerosis. The aim of the present study was to examine the hypothesis that serum OPG concentrations are increased in patients with stable coronary artery disease (CAD) at different serum levels of soluble RANKL (sRANKL). The study used a case-control design in which consecutively hospitalized individuals were recruited. Fasting blood samples were taken upon admission for serum testing. Participants with previously diagnosed CAD that was asymptomatic or had controlled symptoms constituted the stable CAD group, whereas patients with negative coronary computed tomography angiography results constituted the control non-CAD group. Exclusion criteria included recent acute coronary syndrome, severe heart failure, CAD-complicating autoimmune, blood or thyroid diseases, cancer, elevated temperature with or without infection, severe liver or kidney dysfunction, abnormal calcium metabolism, recent surgery and trauma history. A total of 118 individuals were included in the study. Smoothed plots generated using the recursive method and multivariate models showed that the incidence of stable CAD increased with serum OPG level up to the turning point of 18 pg/ml. This trend was observed at both high [odds ratio (OR), 1.61; 95% confidence interval (CI), 1.04-2.50; P=0.032) and low sRANKL concentrations (OR, 1.52; 95% CI, 1.06-2.17; P=0.022) after adjustment for cardiovascular risk factors. In conclusion, serum OPG levels ≤18 pg/ml are positively associated with stable CAD, regardless of sRANKL levels. In addition, at the same serum OPG level, higher sRANKL levels are associated with a greater incidence of stable CAD compared with lower sRANKL levels. This study identified the relationship between OPG, sRANKL, and stable CAD, and established the reference range for future clinical use.

Sensitive subcellular scale and real-time detection of hydrogen peroxide by a W-doped Pt microelectrode.

A W-doped Pt modified graphene oxide (Pt-W-GO) electrochemical microelectrode was developed to detect hydrogen peroxide (H2O2) in real time at a subcellular scale. Interestingly, results showed that the concentration of H2O2 in the nucleus of HeLa cells was 2.68 times and 0.51 times that in the extracellular membrane and cytoplasm, respectively.

The predictive value of albumin to alkaline phosphatase ratio for vertebral refractures in postmenopausal women.

INTRODUCTION: To investigate the clinical value of serum albumin to alkaline phosphatase ratio (AAPR) in predicting the risk of osteoporotic vertebral refractures group (OVRFs) after percutaneous vertebral augmentation (PVA) in postmenopausal women. MATERIALS AND METHODS: This is a retrospective case-control study including a series of postmenopausal women patients with osteoporotic vertebral fracture (OVF) and underwent PVA. Patients were divided into OVRFs and non-OVRFs. COX model was used to evaluate the correlation between preoperative AAPR and OVRFs after PVA. The receiver operating characteristic (ROC) curve and Kaplan-Meier method were used to analyze the predictive value of AAPR for the incidence of OVRFs. RESULTS: A total of 305 patients were included in the final study, and the incidence of postoperative OVRFs was 28.9%. Multivariate COX analysis showed that advanced age (HRs = 1.062, p = 0.002), low BMI (HRs = 0.923, p = 0.036), low AAPR (HRs = 0.019, p = 0.001), previous fall history (HRs = 3.503, p = 0.001), denosumab treatment (HRs = 0.409, p = 0.007), low L3 BMD (HRs = 0.977, p = 0.001) and low L3 paravertebral muscle density (PMD)value (HRs = 0.929, p = 0.001)) were closely related to the incidence of OVRFs. The area under the curve (AUC) of AAPR for predicting OVRFs was 0.740 (p < 0.001), and the optimal diagnostic cut-off value was 0.49. Kaplan-Meier curve analysis showed that low AAPR group (< 0.49) was significantly associated with lower OVRFs-free survival (p = 0.001; log-rank test). CONCLUSION: AAPR is an independent risk factor for OVRFs after PVA in postmenopausal women, and it can be used as an effective index to predict OVRFs.

Membranous nephropathy: pathogenesis and treatments.

Membranous nephropathy (MN), an autoimmune disease, can manifest at any age and is among the most common causes of nephrotic syndrome in adults. In 80% of cases, the specific etiology of MN remains unknown, while the remaining cases are linked to drug use or underlying conditions like systemic lupus erythematosus, hepatitis B virus, or malignancy. Although about one-third of patients may achieve spontaneous complete or partial remission with conservative management, another third face an elevated risk of disease progression, potentially leading to end-stage renal disease within 10 years. The identification of phospholipase A2 receptor as the primary target antigen in MN has brought about a significant shift in disease management and monitoring. This review explores recent advancements in the pathophysiology of MN, encompassing pathogenesis, clinical presentations, diagnostic criteria, treatment options, and prognosis, with a focus on emerging developments in pathogenesis and therapeutic strategies aimed at halting disease progression. By synthesizing the latest research findings and clinical insights, this review seeks to contribute to the ongoing efforts to enhance our understanding and management of this challenging autoimmune disorder.

Cerebral involvement in sitosterolemia.

BACKGROUND: Sitosterolemia, an autosomal recessive condition, is characterized by impaired metabolism of plant sterols. Clinical symptoms include skin xanthoma, premature atherosclerotic disease, arthritis, and unexplained hematological abnormalities. However, there is a dearth of studies on sitosterolemia-related brain damage. METHODS: This study focused on the family of two sitosterolemia patients who presented with severe hypercholesterolemia and xanthoma. Radiological examinations, biopsies, whole-exome sequencing (WES), and plant sterol tests were conducted. RESULTS: The index patient, a 66-year-old female, initially exhibited weakness in both lower limbs and later developed urinary and fecal incontinence. Neuroimaging showed that the falx of the brain had irregular fusiform thickening. Significant tissue edema was observed around the lesions in the bilateral frontal-parietal lobes. Pathological analysis of the biopsied brain lesion revealed extensive cholesterol crystal deposition and lymphocyte infiltration in the matrix. The index patient who experienced cerebral impairment and her sister both carried two compound heterozygous variants in ATP binding cassette transporter G5 (ABCG5). These included the nonsense variants NM_022436: c.751 C > T (p.Q251X) in exon 6 and NM_022436: c.1336 C > T (p.R446X) in exon 10. A notable increase in plant sterol levels was observed in the younger sister of the index patient. CONCLUSION: This study highlights a previously unreported neurological aspect of sitosterolemia. Imaging and pathology findings suggest that cholesterol crystals may be deposited in connective tissues such as the cerebral falx and pia mater through blood circulation.