Mechanisms by which sheep milk consumption ameliorates insulin resistance in high-fat diet-fed mice.

Sheep milk is rich in fat, protein, vitamins and minerals and is also one of the most important sources of natural bioactives. Several biopeptides in sheep milk have been reported to possess antibacterial, antiviral and anti-inflammatory properties, and they may prevent type 2 diabetes (T2D), disease and cancer. However, the precise mechanism(s) underlying the protective role of sheep milk against T2D development remains unclear. Therefore, in the current study, we investigated the effect of sheep milk on insulin resistance and glucose intolerance in high-fat diet (HFD)-fed mice, by conducting intraperitoneal glucose tolerance tests, metabolic cage studies, genomic sequencing, polymerase chain reaction, and biochemical assays. Hyperinsulinemic-euglycemic clamp-based experiments revealed that mice consuming sheep milk exhibited lower hepatic glucose production than mice in the control group. These findings further elucidate the mechanism by which dietary supplementation with sheep milk alleviates HFD-induced systemic glucose intolerance.

Simultaneous electrochemical aptasensing of patulin and ochratoxin A in apple juice based on gold nanoparticles decorated black phosphorus nanomaterial.

Simultaneous detection of patulin (PAT) and ochratoxin A (OTA) in food products is in great demand, which can prevent toxins from being exposed to human and animal bodies. However, simultaneous detection of multiple targets still faces a challenge. Herein, we developed a novel electrochemical aptasensor for the simultaneous detection of PAT and OTA in apple juice based on gold nanoparticles decorated black phosphorus (AuNPs-BP) nanomaterial. AuNPs-BP function?/work? as a sensing platform for loading much different electrochemical signal molecules functionalized aptamers. In this context, methylene blue functionalized PAT aptamers (Mb-PAT-aptamers) and ferrocene functionalized OTA aptamers (Fc-OTA-aptamers) have been introduced here to fabricate the aptasensor. Fc close to electrode surface showed a strong signal, whereas Mb was far away from electrode surface so exhibited a weak signal in the absence of OTA and PAT. Two kinds of electrochemical signal changes have been recorded dependent on target of OTA and PAT concentrations. So, simultaneous detection of OTA and PAT is achieved. Under the optimum conditions, using this developed biosensor, PAT and OTA can be quantified at a linearity range of 0.01 × 10-7 µg·mL-1 ~ 0.10 µg·mL-1. In addition, it also has good selectivity, stability and repeatability. For the practical application, it shows promising performance for the simultaneous detection of PAT and OTA in apple juice.

Full-Scale Clinical Data and Reshaped Intestinal Microbiome on a Short-Term Low-Phosphorus Diet among Healthy Adults.

OBJECTIVES: During the past few decades, phosphorus intake has dramatically increased along with higher protein intake and overuse of inorganic phosphate additives worldwide. The detrimental effects of overconsumption of phosphorus are well recognized for patients with chronic kidney disease (CKD), and dietary phosphorus restriction was recommended for these patients. However, the effects of dietary phosphorus restriction in healthy people have not been fully studied. METHODS: In this open-label crossover study, healthy adult men (n = 12) consumed normal phosphorus diet (NPD, 1,500 mg/d) for five days. After a 10-day washout period, healthy adults took low phosphorus diet (LPD, 500 mg/d) for another five days. On the fifth day of each intervention, blood, urine and saliva samples were collected at ten time points, and fecal specimens were collected for bacterial taxa identification. RESULTS: We found that 24-h mean levels of serum phosphate (Pi), urinary Pi, serum parathyroid hormone and fibroblast growth factor 23 decreased, while serum calcium (Ca) and 1,25-dihydroxy vitamin D increased significantly under LPD compared with those under NPD. Dietary phosphorus intake did not change salivary Pi, urinary Ca, salivary Ca and magnesium (Mg) metabolism. Compared with NPD, LPD increased the relative abundance of beneficial microbes including Bacteroidetes, Ruminococcaceae and Lachnospiraceae, indicating that multiple bacterial metabolic pathways have been shifted. CONCLUSIONS: Full-scale data of dietary phosphorus restriction on Pi, Ca and Mg metabolism in healthy male adults are provided. More importantly, for the first time, dietary phosphorus restriction was found to reshape the intestinal microbiome, which provides information for benefits of dietary phosphorus restriction in healthy people, and potential clues for treating patients with CKD.

Succinate-GPR-91 receptor signalling is responsible for nonalcoholic steatohepatitis-associated fibrosis: Effects of DHA supplementation.

BACKGROUND AND AIMS: Treatment of non-alcoholic steatohepatitis (NASH) is challenging, because suppressing fibrotic progression has not been achieved consistently by drug candidates currently in clinical trials. The aim of this study was to investigate the molecular interplays underlying NASH-associated fibrosis in a mouse NASH model and human specimens. METHODS: Mice were divided into 4 groups: Controls; NASH (high fat/Calorie diet plus high fructose and glucose in drinking water, HFCD-HF/G) for 16 weeks; HFCD-HF/G plus docosahexaenoic acid (DHA) for 16 or 8 weeks. RESULTS: Along with NASH progression, fibrotic deposition was documented in HFCD-HF/G-fed mice. Liver succinate content was significantly increased along with decreased expression of succinate dehydrogenase-A (SDH-A) in these mice; whereas, GPR-91 receptor expression was much enhanced in histology compared to control mice, and co-localized histologically with hepatic stellate cells (HSCs). Succinate content was increased in fatty acid-overloaded primary hepatocytes with significant oxidant stress and lipotoxicity. Exposure to succinate led to up-regulation of GPR-91 receptor in primary and immortalized HSCs. In contrast, suppression of GPR-91 receptor expression abolished succinate stimulatory role in GPR-91 expression and extracellular matrix production in HSCs. All these changes were minimized or abrogated by DHA supplementation in vivo or in vitro. Moreover, GPR-91 receptor expression correlates with severity of fibrosis in human NASH biopsy specimens. CONCLUSION: Succinate accumulation in steatotoic hepatocytes may result in HSC activation through GPR-91 receptor signalling in NASH progression, and the cross-talk between hepatocytes and HSC through GPR-91 signalling is most likely to be the molecular basis of fibrogenesis in NASH.

Spatially Overlapping Regions Show Abnormal Thalamo-frontal Circuit and Abnormal Precuneus in Disorders of Consciousness.

Understanding the neural mechanisms of disorders of consciousness (DOC) is essential for estimating the conscious level and diagnosing DOC patients. Although previous studies reported brain functional connectivity (FC) and spontaneous neural activity patterns associated with consciousness, the relationship between them remains unclear. In this study, we identified the abnormal brain regions in DOC patients by performing voxel-wise FC strength (FCS) and fractional amplitude of low-frequency fluctuations (fALFF) analyses on resting-state functional magnetic resonance imaging data of 15 DOC patients and 24 healthy controls. Furthermore, we detected spatial intersections between two measures and estimated the correlations between either the FCS or the fALFF and the subscales of the Coma Recovery Scale-Revised (CRS-R). We found that the right superior frontal gyrus, left thalamus and right precuneus in which the DOC patients had a lower local FCS and fALFF than healthy controls, are coincident with regions of the mesocircuit model. In the right precuneus, the local FCS/fALFF was significantly positively correlated with the oromotor and motor scores/motor score of the CRS-R. Our findings may indicate that the co-occurrent pattern of spontaneous neural activity and functional connectivity in the thalamo-frontal circuit and the precuneus are associated with motor function in DOC patients.

Frequency-dependent changes of local resting oscillations in sleep-deprived brain.

Sleep deprivation (SD) adversely affects brain function and is accompanied by frequency dependent changes in EEG. Recent studies have suggested that BOLD fluctuations pertain to a spatiotemporal organization with different frequencies. The present study aimed to investigate the frequency-dependent SD-related brain oscillatory activity by using the amplitude of low-frequency fluctuation (ALFF) analysis. The ALFF changes were measured across different frequencies (Slow-4: 0.027-0.073 Hz; Slow-5: 0.01-0.027 Hz; and Typical band: 0.01-0.08 Hz) in 24 h SD as compared to rested wakeful during resting-state fMRI. Sixteen volunteers underwent two fMRI sessions, once during rested wakefulness and once after 24 h of SD. SD showed prominently decreased ALFF in the right inferior parietal lobule (IPL), bilateral orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC), while increased ALFF in the visual cortex, left sensorimotor cortex and fusiform gyrus. Across the Slow-4 and Slow-5, results differed significantly in the OFC, DLPFC, thalamus and caudate in comparison to typical frequency band; and Slow-4 showed greater differences. In addition, negative correlations of behavior performance and ALFF patterns were found mainly in the right IPL across the typical frequency band. These observations provided novel insights about the physiological responses of SD, identified how it disturbs the brain rhythms, and linked SD with frequency-dependent alterations in amplitude patterns.

MMAR_2770, a new enzyme involved in biotin biosynthesis, is essential for the growth of Mycobacterium marinum in macrophages and zebrafish.

Biotin, which functions as an essential cofactor for certain carboxylases and decarboxylases, is synthesized by a multistep pathway in microorganisms and plants. Biotin biosynthesis has not been studied in detail in mycobacteria. In this study, we isolated a mutant of Mycobacterium marinum in which MMAR_2770, a previously uncharacterized gene encoding a predicted short-chain dehydrogenase/reductase, was inactivated. We found that this mutant is a biotin auxotroph that cannot grow in a minimal medium (Sauton) unless biotin is supplemented. Complementation of the mutant with an intact MMAR_2770 or its homolog Rv1882c of Mycobacterium tuberculosis restored the growth of the mutant, suggesting that MMAR_2770 is involved in biotin biosynthesis. We further showed that the mutant was unable to grow in cultured macrophages and was attenuated in zebrafish. Taken together, our results demonstrate that biotin biosynthesis is essential for the growth of mycobacteria in vitro and in vivo and have provided validation for targeting biotin biosynthetic enzymes for antimycobacterial drug development. The potential role of MMAR_2770 in mycobacterial biotin biosynthesis is discussed.