Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 40
Filter
1.
J Control Release ; 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38972640

ABSTRACT

Lipid nanoparticle-mediated co-delivery of siRNA and small molecule holds a great potential to treat metabolic dysfunction-associated steatotic liver disease (MASLD). However, targeted delivery of therapeutics to hepatocytes remains challenging. Taking the advantage of rising low density lipoprotein receptor/very-low density lipoprotein receptor (LDLR/VLDR) levels in MASLD, the biological fate of dinonylamine-ethylene glycol chlorophosphate-1-nonanol (DNNA-COP-NA) based lipid nanoparticles (LNPs) was oriented to liver tissues via apolipoprotein E (ApoE)-LDLR/VLDLR pathway. We then adopted a three-round screening strategy to optimize the formulation with both high potency and selectivity to deliver siRNA-HIF-1α (siHIF1α) and silibinin (SLB) payloads to hepatocytes. The optimized SLB/siHIF1α-LNPs mediates great siRNA delivery and transfection of hepatocytes. In high fat diet (HFD)- and carbon tetrachloride (CCl4)-induced mouse models of MASLD, SLB/siHIF1α-LNPs enabled the silencing of hypoxia inducible factor-1α (HIF-1α), a therapeutic target primarily expressed by hepatocytes, leading to significantly reduced inflammation and liver fibrosis synergized with SLB. Moreover, it is demonstrated the hepatocyte-targeting delivery of SLB/siHIF1α-LNPs has the potential to restore the immune homeostasis by modulating the population of Tregs and cytotoxic T cells in spleen. This proof-of-concept study enable siRNA and small molecule co-delivery to hepatocytes through intrinsic variation of targeting receptors for MASLD therapy.

2.
Food Chem X ; 22: 101498, 2024 Jun 30.
Article in English | MEDLINE | ID: mdl-38911915

ABSTRACT

A thermally stable co-delivery system for lactoferrin (LF) and iron(II) was developed to address iron deficiency anemia. Complexes were formed between LF, succinylated sodium caseinate (S.NaCas) and FeSO4 with high yield (∼85%). LF-S.NaCas-Fe complexes achieved loading capacities for iron(II) between 2.5 and 12 mg g-1and LF loading capacities between 250 and 690 mg g-1, depending upon initial Fe2+ concentrations and LF ratios. The LF-S.NaCas complex mixtures appeared as smooth cubic particles in SEM, and gradually aggregated to amorphous particles as th iron(II) concentration increased due to iron-facilitated cross-linking. The complexation significantly improved LF thermal stability and addressed the poor solubility of iron(II) under neutral pH. After thermal treatment (95 °C, 5 min), the rehydrated complexes retained 68%-90% LF, with <10% iron(II) release. Circular dichroism spectra showed the secondary structure of the complexed LF was well retained during thermal treatment. This thermally stable system showed great potential in LF thermal protection and iron(II) fortification.

3.
Orphanet J Rare Dis ; 19(1): 144, 2024 Apr 04.
Article in English | MEDLINE | ID: mdl-38575988

ABSTRACT

BACKGROUND: Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the GBA1 gene on osteoporosis progression in GD patients and the specific populations. METHODS: We selected 8115 patients with osteoporosis (T-score ≤ - 2.5) and 55,942 healthy individuals (T-score > - 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient's cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period. RESULTS: The GBA1 gene variant rs11264345 was significantly associated [P < 0.002, Odds Ratio (OR) = 1.06] with an increased risk of bone disease. Upregulation of Calnexin, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) was positively associated with osteoclastogenesis in patients with GD. In vitro AAV9-GBA1 treatment of GD patient cells led to enhanced GBA1 enzyme activity, reduced chitotriosidase activity, diminished ER stress, and decreased osteoclast differentiation. Long-term bone density data suggests that initiating ERT earlier in GD leads to greater improvements in bone density. CONCLUSIONS: Elevated ER stress and inflammasome activation are indicative of osteoporosis development, suggesting the need for clinical monitoring of patients with GD. Furthermore, disease-associated variant in the GBA1 gene may constitute a risk factor predisposing specific populations to osteoporosis.


Subject(s)
Gaucher Disease , Osteoporosis , Humans , Bone Density/genetics , Gaucher Disease/drug therapy , Glucosylceramidase/therapeutic use , Inflammasomes , Osteoporosis/genetics , Osteoporosis/drug therapy
4.
Nat Commun ; 15(1): 42, 2024 01 02.
Article in English | MEDLINE | ID: mdl-38168091

ABSTRACT

To curb viral epidemics and pandemics, antiviral drugs are needed with activity against entire genera or families of viruses. Here, we develop a cell-based multiplex antiviral assay for high-throughput screening against multiple viruses at once, as demonstrated by using three distantly related orthoflaviviruses: dengue, Japanese encephalitis and yellow fever virus. Each virus is tagged with a distinct fluorescent protein, enabling individual monitoring in cell culture through high-content imaging. Specific antisera and small-molecule inhibitors are employed to validate that multiplexing approach yields comparable inhibition profiles to single-virus infection assays. To facilitate downstream analysis, a kernel is developed to deconvolute and reduce the multidimensional quantitative data to three cartesian coordinates. The methodology is applicable to viruses from different families as exemplified by co-infections with chikungunya, parainfluenza and Bunyamwera viruses. The multiplex approach is expected to facilitate the discovery of broader-spectrum antivirals, as shown in a pilot screen of approximately 1200 drug-like small-molecules.


Subject(s)
Virus Diseases , Viruses , Humans , Antiviral Agents/pharmacology , High-Throughput Screening Assays/methods , Cell Culture Techniques , Virus Replication
5.
In Vivo ; 38(1): 437-444, 2024.
Article in English | MEDLINE | ID: mdl-38148059

ABSTRACT

BACKGROUND/AIM: Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder characterized by sphingomyelin accumulation causing progressive lung disease, respiratory failure, and death. PATIENTS AND METHODS: This retrospective observational study used the TriNetX database of electronic health records for 15,108 patients with ASMD from 2000-2020. After exclusions, 8,980 individuals were followed for 10 or 20 years. Outcomes included incidence and prevalence of respiratory disorders. Associations of age, sex and race were assessed. RESULTS: Nearly all respiratory outcomes increased significantly over 20 versus 10 years. Other respiratory disorders, specified respiratory disorders and secondary pulmonary hypertension exhibited the greatest increases, reflecting progressive lung damage in ASMD. While outcomes were poor overall, older age, male sex, and racial minority status associated with greater risks, indicating differences in disease progression or care. CONCLUSION: This study confirms the progressive nature of ASMD and need for close monitoring and treatment of pulmonary complications to reduce long-term morbidity and mortality. Genetic testing enabling diagnosis even for milder, adult-onset forms is critical to optimize outcomes.


Subject(s)
Niemann-Pick Disease, Type A , Niemann-Pick Diseases , Adult , Humans , Male , Follow-Up Studies , Sphingomyelin Phosphodiesterase/genetics , Niemann-Pick Disease, Type A/diagnosis , Niemann-Pick Disease, Type A/genetics , Lung
6.
Cell ; 186(26): 5739-5750.e17, 2023 12 21.
Article in English | MEDLINE | ID: mdl-38070510

ABSTRACT

Conscious perception is greatly diminished during sleep, but the underlying circuit mechanism is poorly understood. We show that cortical ignition-a brain process shown to be associated with conscious awareness in humans and non-human primates-is strongly suppressed during non-rapid-eye-movement (NREM) sleep in mice due to reduced cholinergic modulation and rapid inhibition of cortical responses. Brain-wide functional ultrasound imaging and cell-type-specific calcium imaging combined with optogenetics showed that activity propagation from visual to frontal cortex is markedly reduced during NREM sleep due to strong inhibition of frontal pyramidal neurons. Chemogenetic activation and inactivation of basal forebrain cholinergic neurons powerfully increased and decreased visual-to-frontal activity propagation, respectively. Furthermore, although multiple subtypes of dendrite-targeting GABAergic interneurons in the frontal cortex are more active during wakefulness, soma-targeting parvalbumin-expressing interneurons are more active during sleep. Chemogenetic manipulation of parvalbumin interneurons showed that sleep/wake-dependent cortical ignition is strongly modulated by perisomatic inhibition of pyramidal neurons.


Subject(s)
Electroencephalography , Parvalbumins , Sleep , Animals , Mice , Cholinergic Neurons/physiology , Frontal Lobe/metabolism , Parvalbumins/metabolism , Sleep/physiology , Wakefulness/physiology
7.
Anticancer Res ; 43(11): 5073-5081, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37909967

ABSTRACT

BACKGROUND/AIM: Turner syndrome confers increased cancer susceptibility; however, large-scale epidemiological evidence is lacking. This study aimed to analyze the incidence and prevalence of various malignancies in patients with Turner syndrome over 20 years of age to inform screening strategies. PATIENTS AND METHODS: We performed a retrospective cohort analysis of 11,502 patients with Turner syndrome from 2000 to 2020 utilizing the TriNetX research network database. The outcomes encompassed the incidence and prevalence of 20 cancers. Stratified analyses were used to evaluate variations in age, sex, and race. RESULTS: Key findings demonstrated markedly elevated risks of breast (1.7%), colon (1.0%), renal (0.4%), gonadoblastoma (0.4%), and other cancers. Significant demographic variations were observed in the incidence of cancers, such as gonadoblastoma, renal, and colon cancer. CONCLUSION: This large real-world study offers novel insights into the spectrum of cancer risk across adulthood in Turner syndrome. Our findings elucidate Turner syndrome's complex cancer phenotype to inform clinical decision-making, prognostication, and tailored screening strategies to ultimately advance patient care.


Subject(s)
Colonic Neoplasms , Gonadoblastoma , Ovarian Neoplasms , Turner Syndrome , Humans , Female , Adult , Turner Syndrome/complications , Turner Syndrome/epidemiology , Turner Syndrome/genetics , Retrospective Studies , Cohort Studies , Phenotype
8.
In Vivo ; 37(6): 2609-2617, 2023.
Article in English | MEDLINE | ID: mdl-37905636

ABSTRACT

BACKGROUND/AIM: Fabry disease, an X-linked lysosomal storage disorder, causes progressive globotriaosylceramide accumulation in cells throughout the body. Characteristic multiorgan manifestations include renal dysfunction (Fabry nephropathy) and associated urinary tract complications. Enzyme replacement therapy (ERT) has been available since 2001, but contemporary real-world data are lacking regarding Fabry nephropathy risks and treatment outcomes. PATIENTS AND METHODS: This retrospective cohort study analyzed electronic medical records data for 10,637 Fabry disease patients from the TriNetX research database. Kidney and urinary tract outcomes were evaluated over two decades, 2000-2010 and 2011-2020. Outcomes assessed included chronic kidney disease (CKD), urinary tract infections, urinary incontinence, obstruction, renal insufficiency, and end-stage renal disease (ESRD). RESULTS: The prevalence of stage 4-5 CKD nearly doubled between 2000-2010 and 2011-2020, while ESRD prevalence rose over 4-fold. Incidence rates showed similar marked elevations across renal and urologic complications. Females and Black patients experienced disproportionate escalations in kidney and urinary tract morbidity. CONCLUSION: This large cohort study revealed significantly increased Fabry nephropathy and associated urologic complications over the past two decades, contradicting expectations of reduced morbidity with ERT availability. The findings highlight needs to optimize screening, treatment strategies, monitoring practices, and address disparities to curb rising disease burden and improve patient outcomes.


Subject(s)
Fabry Disease , Kidney Failure, Chronic , Renal Insufficiency, Chronic , Female , Humans , Fabry Disease/complications , Fabry Disease/epidemiology , Cohort Studies , Retrospective Studies , Prevalence , alpha-Galactosidase/adverse effects , Kidney , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/epidemiology , Kidney Failure, Chronic/etiology , Kidney Failure, Chronic/complications
9.
In Vivo ; 37(5): 2276-2283, 2023.
Article in English | MEDLINE | ID: mdl-37652520

ABSTRACT

BACKGROUND/AIM: Gaucher disease (GD) is a rare lysosomal storage disorder that can involve the lungs and pulmonary vasculature. The long-term effects of GD on respiratory health remain unclear due to limited data on the natural history of this disease. We analyzed electronic health records for 11,004 patients with GD over 10-20 years to determine the incidence of pulmonary hypertension (PH), lung disease, and other respiratory comorbidities and better understand disease course to guide management. PATIENTS AND METHODS: We conducted a retrospective cohort study using the TriNetX research database of 130 million international patients. The incidence of primary/secondary PH, pulmonary heart disease, interstitial/obstructive/restrictive lung disease, pulmonary hemorrhage, and pulmonary embolism was assessed in patients with GD from 2000-2020. RESULTS: Incidence rates of all conditions assessed increased from 10 to 20 years of follow-up. Excess risk of PH, lung disease, and pulmonary hemorrhage was significantly higher in GD patients after 20 versus 10 years. CONCLUSION: Extended follow-up in GD is associated with substantially higher risks of PH, lung disease and other respiratory comorbidities, highlighting the need for close monitoring and early intervention to mitigate long-term pulmonary decline. Improved understanding of mechanisms driving respiratory deterioration can support the development of novel treatments to optimize outcomes in this population at high risk of pulmonary morbidity and mortality.


Subject(s)
Gaucher Disease , Lung Diseases , Humans , Gaucher Disease/complications , Gaucher Disease/epidemiology , Incidence , Retrospective Studies , Lung , Lung Diseases/etiology , Lung Diseases/complications , Cohort Studies , Hemorrhage/epidemiology , Hemorrhage/etiology
10.
Children (Basel) ; 10(8)2023 Aug 05.
Article in English | MEDLINE | ID: mdl-37628350

ABSTRACT

BACKGROUND: Individuals with Down syndrome are at a higher risk of cardiac, renal, and other health issues due to a complex disease physiology. However, few data exist on long-term disease risks to guide prevention and care. We aimed to determine the 10-year incidence of cardiac, renal, and urinary tract complications in Down syndrome versus matched controls. METHODS: This retrospective cohort study utilized a large collaborative database. We identified 32,444 patients with Down syndrome and matched controls, excluding those with pre-follow-up target events. Covariates included demographics, lifestyle factors, and comorbidities. Outcomes were ischemic heart disease, hypertension, hypothyroidism, epilepsy, urinary tract infections and chronic kidney disease. We calculated unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox regression and plotted Kaplan-Meier survival curves. FINDINGS: Over 10 years, Down syndrome patients showed a 3.7-fold higher ischemic heart disease risk (95% CI: 3.0-4.6) and a 1.6-fold higher hypertension risk (95% CI: 1.4-1.8) versus controls. Hypothyroidism (HR = 2.0; 95% CI: 1.7-2.4), epilepsy (HR = 4.5; 95% CI: 3.5-5.8), and urinary tract infection (HR = 3.9; 95% CI: 3.4-4.6) risks were also higher. Chronic kidney disease risk was 2.7-fold greater (95% CI: 2.1-3.5). Survival analysis confirmed a significantly higher incidence of all outcomes in Down syndrome (p < 0.0001). INTERPRETATION: This large study found major health challenges in Down syndrome, with risks 3- to 5-fold higher for chronic conditions versus matched controls over 10 years. Though survival remains high with proper care, focusing resources on the prevention and management of complications in this high-risk group can optimize well-being across the lifespan. Future research accounting for limitations here would provide definitive estimates of disease risk in Down syndrome to guide targeted health strategies.

11.
Diabetes Obes Metab ; 25(10): 2928-2936, 2023 10.
Article in English | MEDLINE | ID: mdl-37455666

ABSTRACT

AIMS: To analyse the genome-wide association study (GWAS) data of patients with type 1 diabetes mellitus (T1D) in order to develop a risk score for the genetic effects on T1D risk and age at diagnosis in the Taiwanese population. MATERIALS AND METHODS: We selected 610 patients with T1D and 2511 healthy individuals from an electronic medical record database of more than 300 000 individuals with genetic information, analysed their GWAS data, and developed a polygenic risk score (PRS). RESULTS: The PRS, based on 149 selected single-nucleotide polymorphisms, could effectively predict T1D risk. A PRS increase was associated with increased T1D risk (odds ratio [OR] 2.09, 95% confidence interval [CI] 1.72-2.55). Moreover, a 1-unit increase in standardized T1D PRS decreased the age at diagnosis by 0.74 years. Combined PRS and human leukocyte antigen (HLA) DQA1*03:02-DQA1*05:01 genotypes could accurately predict T1D risk. In multivariable models, HLA variants and PRS were independent risk factors for T1D risk (OR 3.76 [95% CI 1.54-9.16] and 1.71 [95% CI 1.37-2.13] for HLA DQA1*03:02-DQA1*05:01 and PRS, respectively). In a limited study population of those aged ≤18 years, PRS remained significantly associated with T1D risk. The association between T1D PRS and age at diagnosis was more obvious among males and patients aged ≤18 years. CONCLUSIONS: Polygenic risk score and HLA variations enable personalized risk estimates, enhance newborn screening efficiency for ketoacidosis prevention, and addresses the gap in data on T1D prediction in isolated Asian populations.


Subject(s)
Diabetes Mellitus, Type 1 , Male , Infant, Newborn , Humans , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/genetics , Genome-Wide Association Study , Genetic Predisposition to Disease , Risk Factors , Risk Assessment
12.
Cell Oncol (Dordr) ; 46(5): 1301-1316, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37079187

ABSTRACT

Acute myeloid leukemia (AML) is a fast-growing and highly fatal blood cancer, and recent research has shown that targeting metabolism may be a promising therapeutic approach for treating AML. One promising target is the human mitochondrial NAD(P)+-dependent malic enzyme (ME2), which is involved in the production of pyruvate and NAD(P)H and the regulation of the NAD+/NADH redox balance. Inhibition of ME2 via silencing ME2 or utilizing its allosteric inhibitor disodium embonate (Na2EA) causes a decrease in pyruvate and NADH, leading to a decrease in producing ATP via cellular respiration and oxidative phosphorylation. ME2 inhibition also decreases NADPH levels, resulting in an increase in reactive oxygen species (ROS) and oxidative stress, which ultimately leads to cellular apoptosis. Additionally, ME2 inhibition reduces pyruvate metabolism and the biosynthetic pathway. ME2 silencing inhibits the growth of xenotransplanted human AML cells, and the allosteric ME2 inhibitor Na2EA demonstrates antileukemic activity against immune-deficient mice with disseminated AML. Both of these effects are a result of impaired energy metabolism in mitochondria. These findings suggest that the targeting ME2 may be an effective strategy for treating AML. Overall, ME2 plays an essential role in energy metabolism of AML cells, and its inhibition may offer a promising approach for AML treatment.


Subject(s)
Leukemia, Myeloid, Acute , NAD , Humans , Mice , Animals , NAD/metabolism , Cell Line, Tumor , Energy Metabolism , Oxidation-Reduction , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Pyruvates
13.
Cereb Cortex ; 33(3): 622-633, 2023 01 05.
Article in English | MEDLINE | ID: mdl-35253853

ABSTRACT

The social brain hypothesis posits that a disproportionate encephalization in primates enabled to adapt behavior to a social context. Also, it has been proposed that phylogenetically recent brain areas are disproportionally affected by neurodegeneration. Using structural and functional magnetic resonance imaging, the present study investigates brain-behavior associations and neural integrity of hyperspecialized and domain-general cortical social brain areas in behavioral variant frontotemporal dementia (bvFTD). The results revealed that both structure and function of hyperspecialized social areas in the middle portion of the superior temporal sulcus (STS) are compromised in bvFTD, while no deterioration was observed in domain general social areas in the posterior STS. While the structural findings adhered to an anterior-posterior gradient, the functional group differences only occurred in the hyperspecialized locations. Activity in specialized regions was associated with structural integrity of the amygdala and with social deficits in bvFTD. In conclusion, the results are in line with the paleo-neurology hypothesis positing that neurodegeneration primarily hits cortical areas showing increased specialization, but also with the compatible alternative explanation that anterior STS regions degenerate earlier, based on stronger connections to and trans-neuronal spreading from regions affected early in bvFTD.


Subject(s)
Frontotemporal Dementia , Humans , Frontotemporal Dementia/pathology , Brain , Magnetic Resonance Imaging/methods , Brain Mapping , Neuropsychological Tests
14.
In Vivo ; 36(5): 2083-2091, 2022.
Article in English | MEDLINE | ID: mdl-36099092

ABSTRACT

BACKGROUND/AIM: The T cell's flexibility of the immune system to be regulated affects the onset of type 1 diabetes (T1D). However, the mechanisms of endoplasmic reticulum (ER) stress and inflammasome activation in the circulating CD3+CD56+ T cells of patients with T1D remain unclear. This study evaluated the role of CD3+CD56+ T cells in T1D and their correlations with ER stress, inflammasome activation and disease characteristics. MATERIALS AND METHODS: The frequency of circulating CD3+CD56+ T cells was determined using flow cytometry in healthy individuals and patients with T1D. Calnexin, NLR family pyrin domain containing 3 (NLRP3), ASC, caspase-1 (Casp1), cleaved caspase-3 (C-Casp3), and annexin V (AnnV) expression and propidium iodide staining in CD3+/CD56+ T cells were analyzed using flow cytometry. RESULTS: The frequency of CD3+CD56+ T cells was reduced in patients with T1D relative to that in healthy individuals. In addition, high calnexin, NLRP3, ASC and Casp1 expression in CD3+CD56+ T cells was negatively correlated with the percentage of CD3+CD56+ T cells in patients with T1D. CONCLUSION: ER stress, inflammasome activation, and a lower peripheral frequency of circulating CD3+CD56+ T cells might indicate disease progression and necessitate clinical T1D immunological self-tolerance monitoring.


Subject(s)
Diabetes Mellitus, Type 1 , Inflammasomes , Calnexin/metabolism , Humans , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , T-Lymphocytes/metabolism
15.
J Clin Endocrinol Metab ; 107(9): 2556-2570, 2022 08 18.
Article in English | MEDLINE | ID: mdl-35731579

ABSTRACT

CONTEXT: Nephropathy is a severe complication of type 1 diabetes (T1DM). However, the interaction between the PDHA1-regulated mechanism and CD4+ T cells in the early stage of kidney tubular injury remains unknown. OBJECTIVE: To evaluate the role of PDHA1 in the regulation of tubular cells and CD4+ T cells and further to study its interaction in tubular cell injury in T1DM. METHODS: Plasma and total RNA were collected from T cells of T1DM patients (n = 35) and healthy donors (n = 33) and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1, PDHA1, and biomarkers of CD4+ T cells including T helper 1 cells (Th1) and regulatory T cells (Treg) markers. HK-2 cells cocultured with CD4+ T cells from T1DM patients or healthy donors (HDs) to evaluate the interaction with CD4+ T cells. RESULTS: Increased PDHA1 gene expression levels in CD4+ T cells were positively associated with the plasma level of NGAL in T1DM patients and HDs. Our data demonstrated that the Th1/Treg subsets skewed Th1 in T1DM. Knockdown of PDHA1 in kidney tubular cells decreased ATP/ROS production, NAD/NADH ratio, mitochondrial respiration, and cell apoptosis. Furthermore, PDHA1 depletion induced impaired autophagic flux. Coculture of tubular cells and T1DM T cells showed impaired CPT1A, upregulated FASN, and induced kidney injury. CONCLUSION: Our findings indicate that Th1 cells induced tubular cell injury through dysregulated metabolic reprogramming and autophagy, thereby indicating a new therapeutic approach for kidney tubular injury in T1DM.


Subject(s)
Diabetes Mellitus, Type 1 , Autophagy , Biomarkers/metabolism , Diabetes Mellitus, Type 1/metabolism , Humans , Kidney/metabolism , Kidney Tubules/metabolism , Lipocalin-2 , Pyruvate Dehydrogenase (Lipoamide) , T-Lymphocytes
16.
Commun Biol ; 4(1): 712, 2021 06 10.
Article in English | MEDLINE | ID: mdl-34112924

ABSTRACT

Repetition suppression (RS) reflects a neural attenuation during repeated stimulation. We used fMRI and the subsequent memory paradigm to test the predictive coding hypothesis for RS during visual memory processing by investigating the interaction between RS and differences due to memory in category-selective cortex (FFA, pSTS, PPA, and RSC). Fifty-six participants encoded face and house stimuli twice, followed by an immediate and delayed (48 h) recognition memory assessment. Linear Mixed Model analyses with repetition, subsequent recognition performance, and their interaction as fixed effects revealed that absolute RS during encoding interacts with probability of future remembrance in face-selective cortex. This effect was not observed for relative RS, i.e. when controlled for adapter-response. The findings also reveal an association between adapter response and RS, both for short and long term (48h) intervals, after controlling for the mathematical dependence between both measures. These combined findings are challenging for predictive coding models of visual memory and are more compatible with adapter-related and familiarity accounts.


Subject(s)
Memory, Long-Term , Visual Perception , Adult , Cerebral Cortex/physiology , Eye Movements , Face/anatomy & histology , Female , Humans , Linear Models , Magnetic Resonance Imaging , Male , Middle Aged , Perception , Young Adult
17.
iScience ; 24(2): 102034, 2021 Feb 19.
Article in English | MEDLINE | ID: mdl-33554057

ABSTRACT

Human mitochondrial NAD(P)+-dependent malic enzyme (ME2) is well recognized to associate with cancer cell metabolism, and the single nucleotide variants (SNVs) of ME2 may play a role in enzyme regulation. Here we reported that the SNVs of ME2 occurring in the allosteric sites lead to inactivation or overactivation of ME2. Two ME2-SNVs, ME2_R67Q and ME2-R484W, that demonstrated inactivating or overactivating enzyme activities of ME2, respectively, have different impact toward the cells. The cells with overactivating SNV enzyme, ME2_R484W, grow more rapidly and are more resistant to cellular senescence than the cells with wild-type or inactivating SNV enzyme, ME2_R67Q. Crystal structures of these two ME2-SNVs reveal that ME2_R67Q was an inactivating "dead form," and ME2_R484W was an overactivating "closed form" of the enzyme. The resolved ME2-SNV structures provide a molecular basis to explain the abnormal kinetic properties of these SNV enzymes.

18.
Int J Mol Sci ; 22(4)2021 Feb 09.
Article in English | MEDLINE | ID: mdl-33572095

ABSTRACT

Long non-coding RNA steroid receptor RNA activators (LncRNA SRAs) are implicated in the ß-cell destruction of Type 1 diabetes mellitus (T1D), but functional association remains poorly understood. Here, we aimed to verify the role of LncRNA SRA regulation in ß-cells. LncRNA SRAs were highly expressed in plasma samples and peripheral blood mononuclear cells (PBMCs) from T1D patients. LncRNA SRA was strongly upregulated by high-glucose treatment. LncRNA SRA acts as a microRNA (miR)-146b sponge through direct sequence-structure interactions. Silencing of lncRNA SRA increased the functional genes of Tregs, resulting in metabolic reprogramming, such as decreased lactate levels, repressed lactate dehydrogenase A (LDHA)/phosphorylated LDHA (pLDHA at Tyr10) expression, decreased reactive oxygen species (ROS) production, increased ATP production, and finally, decreased ß-cell apoptosis in vitro. There was a positive association between lactate level and hemoglobin A1c (HbA1c) level in the plasma from patients with T1D. Recombinant human interleukin (IL)-2 treatment repressed lncRNA SRA expression and activity in ß-cells. Higher levels of lncRNA-SRA/lactate in the plasma are associated with poor regulation in T1D patients. LncRNA SRA contributed to T1D pathogenesis through the inhibition of miR-146b in ß-cells, with activating signaling transduction of interleukin-1 receptor-associated kinase 1 (IRAK1)/LDHA/pLDHA. Taken together, LncRNA SRA plays a critical role in the function of ß-cells.


Subject(s)
Carrier Proteins/genetics , Diabetes Mellitus, Type 1/pathology , Insulin-Secreting Cells/pathology , MicroRNAs/metabolism , RNA, Long Noncoding/metabolism , Adolescent , Antagomirs/pharmacology , Apoptosis/drug effects , Apoptosis/genetics , Cell Line , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/genetics , Feedback, Physiological/drug effects , Female , Gene Knockdown Techniques , Glycated Hemoglobin/analysis , Humans , Insulin-Secreting Cells/drug effects , Interleukin-1 Receptor-Associated Kinases/metabolism , L-Lactate Dehydrogenase/metabolism , Lactic Acid/metabolism , Male , MicroRNAs/agonists , MicroRNAs/antagonists & inhibitors , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Transcriptional Activation/drug effects , Up-Regulation/drug effects , Young Adult
19.
J Agric Food Chem ; 68(31): 8471-8482, 2020 Aug 05.
Article in English | MEDLINE | ID: mdl-32663391

ABSTRACT

Interfacial self-assembly has become a powerful force for regulating the amphipathy of Pickering emulsions on the oil/water interface. Herein, metal-phenolic supramolecular coatings, acting as a regulator on the oil/water interface, were fabricated on the surface of zein nanoparticles (NPs), as a consequence of which the prepared Pickering emulsions stabilized by the decorated zein NPs exhibited diverse properties, decided by different concentrations of zein, tannic acid (TA), and metal ions (Fe3+). Metal-phenolic network-decorated zein NPs named ZTFex NPs (ZTFe NPs represented zein/TA/Fe3+ NPs, and x represented different concentrations of compounds) exhibited increasing diameters of 100-110 nm. Three-phase contact angles also showed that the strong hydrophobicity of zein NPs could be decreased as a result of the formation of metal-phenolic networks. As for corresponding Pickering emulsions, the covering of TA-Fe3+ networks on zein NPs could enhance the stability of zein NP-based emulsion obviously, which might be due to the fact that ZTFex NPs revealed the ability to form strong films on the oil/water interfaces. ZTFe4 was selected as an optimal concentration because of its minimum size and excellent storage stability. Besides, it was also found that the diameter of ZTFe4-based emulsion enhanced with the increase in the oil phase. The rheological measurement results showed that both G' and G″ increased with the increase of x and the oil phase. In general, our paper not only highlighted a straightforward method for the interfacial nanofabrication of solid particles but also provided a novel and potential strategy in Pickering emulsion applications.


Subject(s)
Iron/chemistry , Nanoparticles/chemistry , Oils/chemistry , Phenols/chemistry , Water/chemistry , Zein/chemistry , Emulsions/chemistry , Hydrophobic and Hydrophilic Interactions , Particle Size , Rheology , Tannins/chemistry
20.
J Neurosci Methods ; 344: 108829, 2020 10 01.
Article in English | MEDLINE | ID: mdl-32663550

ABSTRACT

BACKGROUND: Anatomically and physiologically, there is strong relationship between the brain and body. A new MRI platform covering both the brain and the limb would be beneficial for a more thorough understanding of the brain-body interactions. NEW METHOD: A new arm-over-head (AOH) position was developed to collect MRI of the brain and one arm simultaneously. Subject's tolerability and SNR of both the brain and limb under a serial of seven different TR (250-3000 ms) were tested. Then, blocked motor imagery tasks were performed to test the possible brain-body oscillations. RESULTS: The new MRI position provided structural images with good quality, and the AOH position had the best SNR under TR 3000 ms (p = 0.03 for the brain; p = 0.064 for the limb). Then, by using both hypothesis-free independent component analysis (ICA) and a priori seed-based functional connectivity (FC) analysis, it is demonstrated during motionless motor imagery tasks there existed possible brain-body BOLD oscillations connecting especially arm flexors to default mode, vision, and sensorimotor networks. The FC appeared at network density as low as 5%. COMPARISON WITH EXISTING METHODS: We have developed a new MRI subject position to explore the possibilities of more extensive neuronal and physiological networks. CONCLUSIONS: The results of this preliminary experiment indicate that functional brain networks might extend outside the brain. A bottom-up circulatory effect might explain this phenomenon. Nonetheless, considering the mechanism of neural top-down control and the nature of complex brain networks, the existence of a more extensive whole-body functional network is rational and possible.


Subject(s)
Brain Mapping , Brain , Brain/diagnostic imaging , Magnetic Resonance Imaging
SELECTION OF CITATIONS
SEARCH DETAIL
...