A Pilot Study on a Possible Mechanism behind Olfactory Dysfunction in Parkinson's Disease: The Association of TAAR1 Downregulation with Neuronal Loss and Inflammation along Olfactory Pathway.

Parkinson's disease (PD) is characterized not only by motor symptoms but also by non-motor dysfunctions, such as olfactory impairment; the cause is not fully understood. Our study suggests that neuronal loss and inflammation in brain regions along the olfactory pathway, such as the olfactory bulb (OB) and the piriform cortex (PC), may contribute to olfactory dysfunction in PD mice, which might be related to the downregulation of the trace amine-associated receptor 1 (TAAR1) in these areas. In the striatum, although only a decrease in mRNA level, but not in protein level, of TAAR1 was detected, bioinformatic analyses substantiated its correlation with PD. Moreover, we discovered that neuronal death and inflammation in the OB and the PC in PD mice might be regulated by TAAR through the Bcl-2/caspase3 pathway. This manifested as a decrease of anti-apoptotic protein Bcl-2 and an increase of the pro-apoptotic protein cleaved caspase3, or through regulating astrocytes activity, manifested as the increase of TAAR1 in astrocytes, which might lead to the decreased clearance of glutamate and consequent neurotoxicity. In summary, we have identified a possible mechanism to elucidate the olfactory dysfunction in PD, positing neuronal damage and inflammation due to apoptosis and astrocyte activity along the olfactory pathway in conjunction with the downregulation of TAAR1.

Systematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis.

Linear ubiquitination catalyzed by HOIL-1-interacting protein (HOIP), the key component of the linear ubiquitination assembly complex, plays fundamental roles in tissue homeostasis by executing domain-specific regulatory functions. However, a proteome-wide analysis of the domain-specific interactome of HOIP across tissues is lacking. Here, we present a comprehensive mass spectrometry-based interactome profiling of four HOIP domains in nine mouse tissues. The interaction dataset provides a high-quality HOIP interactome resource with an average of approximately 90 interactors for each bait per tissue. HOIP tissue interactome presents a systematic understanding of linear ubiquitination functions in each tissue and also shows associations of tissue functions to genetic diseases. HOIP domain interactome characterizes a set of previously undefined linear ubiquitinated substrates and elucidates the cross-talk among HOIP domains in physiological and pathological processes. Moreover, we show that linear ubiquitination of Integrin-linked protein kinase (ILK) decreases focal adhesion formation and promotes the detachment of Shigella flexneri-infected cells. Meanwhile, Hoip deficiency decreases the linear ubiquitination of Smad ubiquitination regulatory factor 1 (SMURF1) and enhances its E3 activity, finally causing a reduced bone mass phenotype in mice. Overall, our work expands the knowledge of HOIP-interacting proteins and provides a platform for further discovery of linear ubiquitination functions in tissue homeostasis.

Identification of hub genes in calcific aortic valve disease.

Calcific aortic valve disease (CAVD) is a heart valve disorder characterized primarily by calcification of the aortic valve, resulting in stiffness and dysfunction of the valve. CAVD is prevalent among aging populations and is linked to factors such as hypertension, dyslipidemia, tobacco use, and genetic predisposition, and can result in becoming a growing economic and health burden. Once aortic valve calcification occurs, it will inevitably progress to aortic stenosis. At present, there are no medications available that have demonstrated effectiveness in managing or delaying the progression of the disease. In this study, we mined four publicly available microarray datasets (GSE12644 GSE51472, GSE77287, GSE233819) associated with CAVD from the GEO database with the aim of identifying hub genes associated with the occurrence of CAVD and searching for possible biological targets for the early prevention and diagnosis of CAVD. This study provides preliminary evidence for therapeutic and preventive targets for CAVD and may provide a solid foundation for subsequent biological studies.

Design, Synthesis, Biological Evaluation and Molecular Docking of Novel F-18-Labeled Focal Adhesion Kinase Inhibitors as Potential Tumor Radiotracers.

Tumor diagnosis, especially at the early stages, holds immense significance. Focal adhesion kinase (FAK) is often highly expressed across various types of tumors, making it a promising target for both therapy and diagnosis. In this study, seven novel inhibitors were designed and synthesized. The inhibitory activity of these compounds against FAK was notably potent, with an IC50 range of 1.27-1968 nM. In particular, compounds 7a and 7c, with IC50 values of 5.59 nM and 1.27 nM, respectively, were radiolabeled with F-18 and then evaluated with S-180 tumor-bearing mice. Subsequently, they exhibited moderate-to-high tumor uptake values, with [18F]7a showing 1.39 ± 0.30%ID/g at 60 min post injection and [18F]7c demonstrating 6.58 ± 0.46%ID/g at 30 min post injection. In addition, the results from docking studies revealed the binding specifics of the studied compounds. Overall, these findings hold the potential to offer valuable guidance for enhancing the development of radiotracers and enzyme inhibitors.

Akkermansia muciniphila Is Beneficial to a Mouse Model of Parkinson's Disease, via Alleviated Neuroinflammation and Promoted Neurogenesis, with Involvement of SCFAs.

Increasing evidence suggests that the gut microbiota may represent potential strategies for Parkinson's disease (PD) treatment. Our previous research revealed a decreased abundance of Akkermansia muciniphila (Akk) in PD mice; however, whether Akk is beneficial to PD is unknown. To answer this question, the mice received MPTP intraperitoneally to construct a subacute model of PD and were then supplemented with Akk orally for 21 consecutive days. Motor function, dopaminergic neurons, neuroinflammation, and neurogenesis were examined. In addition, intestinal inflammation, and serum and fecal short-chain fatty acids (SCFAs) analyses, were assessed. We found that Akk treatment effectively inhibited the reduction of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and partially improved the motor function in PD mice. Additionally, Akk markedly alleviated neuroinflammation in the striatum and hippocampus and promoted hippocampal neurogenesis. It also decreased the level of colon inflammation. Furthermore, these aforementioned changes are mainly accompanied by alterations in serum and fecal isovaleric acid levels, and lower intestinal permeability. Our research strongly suggests that Akk is a potential neuroprotective agent for PD therapy.

Energy focusing of broadband Lamb wave by designing excitation waveforms and elastic metamaterials.

In the field of structure health monitoring (SHM), the use of Lamb wave to locate damage is a common method. Energy focusing is beneficial for damage localization because of higher SNR and higher resolution. Optimization design of elastic metamaterials is promising for energy focusing based on speed modulation. However, current design scheme is effective only for narrowband Lamb waves. Compared to narrowband waves, broadband Lamb waves with a larger frequency range carry richer structural information. In this study, an energy focusing method based on broadband Lamb waves by simultaneous designing excitation waveforms and elastic metamaterials is proposed. Firstly, COMSOL finite element simulation software is used to calculate the relationship between the metamaterial structure and the excitation wave. Subsequently, the metamaterial structure and the excitation signal form are designed according to the relationship. Finally, the metamaterial structure is bonded with the aluminum plate using 3D printing PA2200 nylon to verify the effectiveness of the method.

Conductive nanofiltration membranes via in situ PEDOT-polymerization for electro-assisted membrane fouling mitigation.

Nanofiltration (NF) membranes play a pivotal role in water treatment; however, the persistent challenge of membrane fouling hampers their stable application. This study introduces a novel approach to address this issue through the creation of a poly(3,4-ethylenedioxythiophene) (PEDOT)-based conductive membrane, achieved by synergistically coupling interfacial polymerization (IP) with in situ self-polymerization of EDOT. During the IP reaction, the concurrent generation of HCl triggers the protonation of EDOT, activating its self-polymerization into PEDOT. This interwoven structure integrates with the polyamide network to establish a stable selective layer, yielding a remarkable 90 % increase in permeability to 20.4 L m-2 h-1 bar-1. Leveraging the conductivity conferred by PEDOT doping, an electro-assisted cleaning strategy is devised, rapidly restoring the flux to 98.3 % within 5 min, outperforming the 30-minute pure water cleaning approach. Through simulations in an 8040 spiral-wound module and the utilization of the permeated salt solution for cleaning, the electro-assisted cleaning strategy emerges as an eco-friendly solution, significantly reducing water consumption and incurring only a marginal electricity cost of 0.055 $ per day. This work presents an innovative avenue for constructing conductive membranes and introduces an efficient and cost-effective electro-assisted cleaning strategy to effectively combat membrane fouling.

Refining the 8th edition TNM classification for EBV related nasopharyngeal carcinoma.

The AJCC/UICC TNM classification describes anatomic extent of tumor progression and guides treatment decisions. Our comprehensive analysis of 8,834 newly diagnosed patients with non-metastatic Epstein-Barr virus related nasopharyngeal carcinoma (NPC) from six Chinese centers indicates certain limitations in the current staging system. The 8th edition of the AJCC/UICC TNM classification inadequately differentiates patient outcomes, particularly between T2 and T3 categories and within the N classification. We propose reclassifying cases of T3 NPC with early skull-base invasion as T2, and elevating N1-N2 cases with grade 3 image-identified extranodal extension (ENE) to N3. Additionally, we suggest combining T2N0 with T1N0 into a single stage IA. For de novo metastatic (M1) NPC, we propose subdivisions of M1a, defined by 1-3 metastatic lesions without liver involvement, and M1b, characterized by >3 metastatic lesions or liver involvement. This proposal better reflects responses of NPC patients to the up-to-date treatments and their evolving risk profiles.

Reducing polypyrimidine tract­binding protein 1 fails to promote neuronal transdifferentiation on HT22 and mouse astrocyte cells under physiological conditions.

In contrast to prior findings that have illustrated the conversion of non-neuronal cells into functional neurons through the specific targeting of polypyrimidine tract-binding protein 1 (PTBP1), accumulated evidence suggests the impracticality of inducing neuronal transdifferentiation through suppressing PTBP1 expression in pathological circumstances. Therefore, the present study explored the effect of knocking down PTBP1 under physiological conditions on the transdifferentiation of mouse hippocampal neuron HT22 cells and mouse astrocyte (MA) cells. A total of 20 µM negative control small interfering (si)RNA and siRNA targeting PTBP1 were transfected into HT22 and MA cells using Lipo8000™ for 3 and 5 days, respectively. The expression of early neuronal marker ßIII-Tubulin and mature neuronal markers NeuN and microtubule-associated protein 2 (MAP2) were detected using western blotting. In addition, ßIII-tubulin, NeuN and MAP2 were labeled with immunofluorescence staining to evaluate neuronal cell differentiation in response to PTBP1 downregulation. Under physiological conditions, no significant changes in the expression of ßIII-Tubulin, NeuN and MAP2 were found after 3 and 5 days of knockdown of PTBP1 protein in both HT22 and MA cells. In addition, the immunofluorescence staining results showed no apparent transdifferentiation in maker levels and morphology. The results suggested that the knockdown of PTBP1 failed to induce neuronal differentiation under physiological conditions.

Quantitative Framework Fabrication with Autogenous Costal Cartilage in Microtia Reconstruction.

Hearing improvement is another basic requirement for microtia patients in addition to aesthetic needs. This quantitative framework fabrication method can reduce the learning curve, obtain satisfactory aesthetic results with few complications, and reserve a certain space for future canalplasty. Laryngoscope, 134:148-153, 2024.

Structural, functional properties, and in vitro digestibility of sunflower protein concentrate as affected by extraction method: Isoelectric precipitation vs ultrafiltration.

This study was the first to compare the structural features, functional properties and in vitro digestibility of two protein concentrates produced from defatted sunflower meal via two different three-stage processes (chlorogenic acid removal-alkaline extraction-isoelectric precipitation versus chlorogenic acid removal-alkaline extraction-ultrafiltration; concentrates termed AI-SPC and AU-SPC, respectively). Compared with AI-SPC, AU-SPC with a darker brown color had much higher protein recovery yield and purity, much higher solubility at pH 4-7, higher oil-holding capacity, greater emulsifying and foaming capacities at pH 7 and 9, and slightly lower foaming capacity at pH 3. The bioavailability was higher for AU-SPC after oral-gastric-intestinal digestion. Moreover, AI-SPC occurred as clumps/lumps of particles, whilst AU-SPC appeared as flat blocks with continuous surfaces. AU-SPC was more negatively charged, and had a smaller particle size, less ß-sheet, more ß-turn, slightly more α-helix structure. These results confirmed the close relationship between protein production methods and its functional properties and digestibility.

Enhancement of functional properties, digestive properties, and in vitro digestion product physiological activity of extruded corn gluten meal by enzymatic modification.

BACKGROUND: Enzymatic modification is an effective means of improving the functional properties, digestive properties, and in vitro digestion product physiological activity of proteins, thus significantly expanding protein uses in various food applications. RESULTS: In this study, the addition of chymotrypsin (CT) at pH 9.0 and 11.0 was found to significantly improve the functional properties (solubility, foaming properties, water holding capacity, oil holding capacity, etc.) and digestive properties of extruded corn gluten meal (ECGM). Similar changes were observed when treating ECGM with glutaminase, protein glutaminase, and papain. These changes were likely due to the increase in number of carboxyl groups and the multiple effects of change in protein net charge and conformation caused by enzymatic deamidation. Of note, ECGM deamidated by CT showed the highest degree of deamidation, solubility, and gastrointestinal digestibility at pH 11.0, up to 44.92%, 43.75%, and 82.22%, respectively. In addition, CT-ECGM digestion product exhibited strong antioxidant activity and potential to promote alcohol metabolism in both a static digestion model and dynamic digestion model, even comparable to commercial corn peptides (CCP), while being inexpensive and of low bitterness compared to CCP. Meanwhile, the physiological activity enhanced as the molecular weight of digestion product decreased with the digested component having strongest activity. CONCLUSION: This study may promote the application of ECGM as a food component in the food industry or even as a substitute for CCP. © 2023 Society of Chemical Industry.

Screening of novel bovine-elastin-derived peptides with elastase inhibition and photoprotective potential: a combined in silico and in vitro study.

BACKGROUND: The demand for food-based anti-photoaging products is surging because of the rising recognition of health and beauty, as well as enhanced comprehension of the detrimental impact of ultraviolet (UV) radiation. This study aimed to investigate the potential of bioactive peptides derived from bovine elastin, specifically focusing on identifying novel elastase inhibitory peptides and assessing their photoprotective properties using bioinformatics techniques. RESULTS: A total of 48 bioactive peptides were screened in bovine elastin hydrolysate (EH) utilizing Peptide Ranker analysis. Three novel elastase inhibitory peptides, GAGQPFPI, FFPGAG and FPGIG (in descending order of activity), exhibited potent inhibitory effects on elastase in vitro, surpassing the inhibitory effect of EH by a factor of 1-2 and reaching significantly lower concentrations (8-15 times lower) than EH. The cumulative inhibitory effect of GAGQPFPI, FFPGAG, and FPGIG reached 91.5%. Further analysis revealed that FFPGAG and FPGIG exhibited mixed inhibition, whereas GAGQPFPI displayed non-competitive inhibition. Molecular simulations showed that these peptides interacted effectively with the elastase active site through hydrogen bonding and hydrophobic interactions. Furthermore, GAGQPFPI, FFPGAG, and FPGIG demonstrated high stability in gastrointestinal digestion, demonstrated transcellular permeability across Caco-2 cell monolayers, and exhibited remarkable photoprotective properties against UVB-irradiated HaCaT cells. CONCLUSION: GAGQPFPI showed the most promising potential as a functional food with photoprotective effects against UVB damage and inhibitory properties against elastase. © 2023 Society of Chemical Industry.

Predictive model for epileptogenic tubers from all tubers in patients with tuberous sclerosis complex based on 18F-FDG PET: an 8-year single-centre study.

BACKGROUND: More than half of patients with tuberous sclerosis complex (TSC) suffer from drug-resistant epilepsy (DRE), and resection surgery is the most effective way to control intractable epilepsy. Precise preoperative localization of epileptogenic tubers among all cortical tubers determines the surgical outcomes and patient prognosis. Models for preoperatively predicting epileptogenic tubers using 18F-FDG PET images are still lacking, however. We developed noninvasive predictive models for clinicians to predict the epileptogenic tubers and the outcome (seizure freedom or no seizure freedom) of cortical tubers based on 18F-FDG PET images. METHODS: Forty-three consecutive TSC patients with DRE were enrolled, and 235 cortical tubers were selected as the training set. Quantitative indices of cortical tubers on 18F-FDG PET were extracted, and logistic regression analysis was performed to select those with the most important predictive capacity. Machine learning models, including logistic regression (LR), linear discriminant analysis (LDA), and artificial neural network (ANN) models, were established based on the selected predictive indices to identify epileptogenic tubers from multiple cortical tubers. A discriminating nomogram was constructed and found to be clinically practical according to decision curve analysis (DCA) and clinical impact curve (CIC). Furthermore, testing sets were created based on new PET images of 32 tubers from 7 patients, and follow-up outcome data from the cortical tubers were collected 1, 3, and 5 years after the operation to verify the reliability of the predictive model. The predictive performance was determined by using receiver operating characteristic (ROC) analysis. RESULTS: PET quantitative indices including SUVmean, SUVmax, volume, total lesion glycolysis (TLG), third quartile, upper adjacent and standard added metabolism activity (SAM) were associated with the epileptogenic tubers. The SUVmean, SUVmax, volume and TLG values were different between epileptogenic and non-epileptogenic tubers and were associated with the clinical characteristics of epileptogenic tubers. The LR model achieved the better performance in predicting epileptogenic tubers (AUC = 0.7706; 95% CI 0.70-0.83) than the LDA (AUC = 0.7506; 95% CI 0.68-0.82) and ANN models (AUC = 0.7425; 95% CI 0.67-0.82) and also demonstrated good calibration (Hosmer‒Lemeshow goodness-of-fit p value = 0.7). In addition, DCA and CIC confirmed the clinical utility of the nomogram constructed to predict epileptogenic tubers based on quantitative indices. Intriguingly, the LR model exhibited good performance in predicting epileptogenic tubers in the testing set (AUC = 0.8502; 95% CI 0.71-0.99) and the long-term outcomes of cortical tubers (1-year outcomes: AUC = 0.7805, 95% CI 0.71-0.85; 3-year outcomes: AUC = 0.8066, 95% CI 0.74-0.87; 5-year outcomes: AUC = 0.8172, 95% CI 0.75-0.87). CONCLUSIONS: The 18F-FDG PET image-based LR model can be used to noninvasively identify epileptogenic tubers and predict the long-term outcomes of cortical tubers in TSC patients.

Enhancing Kokumi Sensation and Reducing Bitterness in Acid-Hydrolyzed Vegetable Proteins through Lactate and Thermal Processing.

Previous studies have demonstrated that thermal processing in the presence of lactate and amino acids can produce taste-active N-lactoyl amino acids. This study aimed to investigate the impact of lactate and thermal processing on the sensory characteristics of acid-hydrolyzed vegetable proteins (aHVP). The results showed that the processed aHVP exhibited enhanced kokumi, a milder umami taste, and reduced bitterness on treatment with 1% lactate at 110 °C for 3 h or 3% lactate at 120 °C for 2 h compared to the unprocessed samples. Partial or orthogonal least-squares discriminant analysis and variable importance in projection (VIP) analyses revealed the significant contributions of N-,l-Lac-l-hydrophobic AAs [-Met, -Ile, -Leu, -Val, and -Phe (VIP > 1.2)] to the observed differences between the processed and unprocessed samples. Electronic tongue analysis confirmed the sensory findings and indicated a decrease in the aftertaste of bitterness in the processed samples. Furthermore, the study identified the sensory characteristics of N-l-Lac-l-Met, -Ile, and -Leu, highlighting their potential to enhance salty, umami, and kokumi perception in simulated broth. Furthermore, the study incorporated the addition of bitter amino acids (Val, Ile, Leu, Tyr, Phe, Lys, His, and Arg) and the aforementioned N-l-Lac-l-AAs to aHVP, providing further evidence for their contributions to bitterness and aftertaste-B as well as the kokumi differences, respectively. This study provides valuable insights into the sensory effects of lactate and thermal processing on aHVP, facilitating the development of improved taste-enhancing strategies.

Preparation and Kokumi Properties of N-Acetyl-Val/Leu/Ile/Met/Phe in the Presence of Acetic Acid and Amino Acid: A Commercially Available Transglutaminase and Protease A 2SD.

Kokumi is a beneficial feeling for the evaluation of food quality, and thus, preparing and understanding the taste properties of kokumi compounds are important for the flavor of food. N-acetyl-Val/Leu/Ile/Met/Phe/Trp/Tyr is a type of kokumi compound found in food and usually prepared by chemical reagents. In this study, we first prepared these six kokumi compounds using transglutaminase and protease A2SD in aqueous solution by using amino acids and acetic acid as substrates and evaluated their kokumi characteristics. HPLC and LC-MS were used to identify quantitative N-acetyl amino acids. Using Phe and acetic acid as substrates, transglutaminase and protease A2SD showed the highest yields for N-acetyl-Phe of 22.75 and 42.21%, respectively, under the optimal conditions. For N-acetyl-Val/Leu/Ile/Met/Trp/Tyr, these two enzymes showed the synthesis yield in the ranges of 2.22-20.12 and 0.75-12.91%, respectively. Six N-acetyl-amino acids were succesully enriched by ethyl acetate with a recovery over 50% and purity over 95%. Sensory evaluation found that N-acetyl-Val/Leu/Ile/Met/Phe are kokumi compounds that enhance sweet, umami, and salt tastes in 5% sucrose, 0.3% NaCl, and 0.5% sodium glutamate, especially N-acetyl-Val, with the salt- and umami-enhancing threshold values of 0.63 and 1.25 g/L, respectively. Therefore, transglutaminase and protease A2SD for the synthesis of partial N-acetyl amino acid might have the potential to be applied in food as a kokumi compound.

5-HT4 Receptor is Protective for MPTP-induced Parkinson's Disease Mice Via Altering Gastrointestinal Motility or Gut Microbiota.

Serotonergic dysfunction is related to both motor and nonmotor symptoms in Parkinson's disease (PD). As a 5-HT receptor, 5-HT4 receptor (5-HT4R) is well-studied and already-used in clinical therapy of constipation, which is a typical non-motor symptom in PD. In this study, we investigated the role of 5-HT4R as a regulator of gut function in MPTP-induced acute PD mice model. Daily intraperitoneal injection of GR 125487 (5-HT4R antagonist) was administered 3 days before MPTP treatment until sacrifice. Seven days post-MPTP treatment, feces were collected and gastrointestinal transit time (GITT) was measured, 8 days post-MPTP treatment, behavioral tests were performed, and then animals were sacrificed for the further analysis. We found GR 125487 pretreatment not only increased GITT, but also aggravated MPTP-induced motor bradykinesia. In addition, GR 125487 pretreatment exacerbated the loss of dopaminergic neurons probably by suppressing JAK2/PKA/CREB signaling pathway and increased reactive glia and neuroinflammation in the striatum. 16 S rRNA sequencing of fecal microbiota showed that GR 125487 pretreatment altered the composition of gut microbiota, in which the abundance of Akkermansia muciniphila and Clostridium clostridioforme was increased, whereas that of Parabacteroides distasonis and Bacteroides fragilis was decreased, which are closely associated with inflammation condition. Taken together, we demonstrated that GR 125487 pretreatment exacerbates MPTP-induced striatal neurodegenerative processes possibly via the JAK2/PKA/CREB pathway and neuroinflammation by altering gut microbiota composition. In the microbiota-gut-brain axis of PD, 5-HT4R should be further explored and might serve as a target for PD diagnosis and treatment.

Kokumi-Enhancing Mechanism of N-l-lactoyl-l-Met Elucidated by Sensory Experiments and Molecular Simulations.

Recent research indicates that N-lactoyl amino acid derivatives have the potential as kokumi substances, with their kokumi profile closely linked to that of amino acids. This study aimed to explore the unexplored effects resulting from the introduction of lactate groups into l-Methional (l-Met), a prevalent flavor compound found in foods, such as tomatoes, known for its ability to activate the monosodium glutamate response. N-l-Lac-l-Met was enzymatically synthesized using food grade, and its taste profile and underlying mechanisms were investigated. The structure of N-l-Lac-l-Met was determined by high-performance liquid chromatography (HPLC)-mass spectrometry (MS)/MS. Sensory evaluation revealed the presence of astringency, kokumi, and bitterness of N-l-Lac-l-Met. In a stimulated broth, N-l-Lac-l-Met exhibited enhanced umami and kokumi taste perception compared to l-Met while demonstrating good stability within pH 5 to 9. A molecular simulation and quantum mechanics analysis indicated that the formation of an amide bond played a crucial role in the kokumi-enhancing effect of N-l-Lac-l-Met, specifically by increasing its affinity with umami receptors T1R1-T1R3 and a kokumi receptor CaSR. These findings established the relationship between amide bond formation and the kokumi-enhancing effect of N-l-Lac-l-Met, presenting its potential application as the kokumi substance in the food industry.

Effect of dapagliflozin on liver and pancreatic fat in patients with type 2 diabetes and non-alcoholic fatty liver disease.

AIMS: To evaluate the effect of dapagliflozin on liver fat content (LFC) and pancreatic fat content (PFC). MATERIALS AND METHODS: 84 patients with type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) were randomly assigned to receive either dapagliflozin (n = 42) or serve as controls (n = 42). The primary endpoint is changes in LFC and PFC using magnetic resonance imaging estimated proton density fat fraction. Secondary outcomes include liver fibrosis index, inflammatory cytokine levels, and liver enzyme levels. RESULTS: At week 24, the dapagliflozin group significantly reduced LFC (P < 0.001) and PFC (P = 0.033) compared to the control group. Differences were also observed in serum levels of tumor necrosis factor-α (TNF-α) (P = 0.004), interleukin-6 (IL-6) (P = 0.001), and alanine aminotransferase (ALT) (P < 0.001) between the two groups. CONCLUSIONS: Dapagliflozin can significantly decrease LFC and PFC in patients with T2D and NAFLD. It also improves serum ALT, TNF-α, and IL-6 levels, making it a promising treatment option for NAFLD. The trial is registered on Chinese Clinical Trial Registry (Registration No. ChiCTR2100054612).

Fecal Microbiota Transplantation from Aged Mice Render Recipient Mice Resistant to MPTP-Induced Nigrostriatal Degeneration Via a Neurogenesis-Dependent but Inflammation-Independent Manner.

Accumulating data support a crucial role of gut microbiota in Parkinson's disease (PD). However, gut microbiota vary with age and, thus, will affect PD in an age-dependent, but unknown manner. We examined the effects of fecal microbiota transplantation (FMT) pretreatment, using fecal microbiota from young (7 weeks) or aged mice (23 months), on MPTP-induced PD model. Motor function, pathological changes, striatal neurotransmitters, neuroinflammation, gut inflammation and gut permeability were examined. Gut microbiota composition and metabolites, namely short-chain fatty acids (SCFAs), were analyzed. Neurogenesis was also evaluated by measuring the number of doublecortin-positive (DCX+) neurons and Ki67-positive (Ki67+) cells in the hippocampus. Expression of Cd133 mRNA, a cellular stemness marker, in the hippocampus was also examined. Mice who received FMT from young mice showed MPTP-induced motor dysfunction, and reduction of striatal dopamine (DA), dopaminergic neurons and striatal tyrosine hydroxylase (TH) levels. Interestingly and unexpectedly, mice that received FMT from aged mice showed recovery of motor function and rescue of dopaminergic neurons and striatal 5-hydroxytryptamine (5-HT), as well as decreased DA metabolism after MPTP challenge. Further, they showed improved metabolic profiling and a decreased amount of fecal SCFAs. High-throughput sequencing revealed that FMT remarkably reshaped the gut microbiota of recipient mice. For instance, levels of genus Akkermansia and Candidatus Saccharimonas were elevated in fecal samples of recipient mice receiving aged microbiota (AM + MPTP mice) than YM + MPTP mice. Intriguingly, both young microbiota and aged microbiota had no effect on neuroinflammation, gut inflammation or gut permeability. Notably, AM + MPTP mice showed a marked increase in DCX+ neurons, as well as Ki67+ cells and Cd133 expression in the hippocampal dentate gyrus (DG) compared to YM + MPTP mice. These results suggest that FMT from aged mice augments neurogenesis, improves motor function and restores dopaminergic neurons and neurotransmitters in PD model mice, possibly through increasing neurogenesis.