Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, causing dementia and affecting millions of individuals. One prominent characteristic in the brains of AD patients is glucose hypometabolism. In the context of galactose metabolism, intracellular glucose levels are heightened. Galactose mutarotase (GALM) plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion of β-D-galactose into α-D-galactose (α-D-G). The latter is then converted into glucose-6-phosphate, improving glucose metabolism levels. However, the involvement of GALM in AD progression is still unclear. In the present study, we found that the expression of GALM was significantly increased in AD patients and model mice. Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein (APP) and APP-cleaving enzymes including a disintegrin and metalloprotease 10 (ADAM10), β-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PS1). Interestingly, genetic overexpression of GALM reduced APP and Aβ deposition by increasing the maturation of ADAM10, although it did not alter the expression of BACE1 and PS1. Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory in AD model mice. Importantly, direct α-D-G (20 mg/kg, i.p.) also inhibited Aβ deposition by increasing the maturation of ADAM10, thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, our results indicate that GALM shifts APP processing towards α-cleavage, preventing Aβ generation by increasing the level of mature ADAM10. These findings indicate that GALM may be a potential therapeutic target for AD, and α-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD.
Animals ; ADAM10 Protein/metabolism* ; Alzheimer Disease/pathology* ; Amyloid Precursor Protein Secretases/metabolism* ; Disease Models, Animal ; Humans ; Mice ; Amyloid beta-Peptides/metabolism* ; Male ; Mice, Transgenic ; Membrane Proteins/metabolism* ; Cognitive Dysfunction/pathology* ; Mice, Inbred C57BL ; Amyloid beta-Protein Precursor/metabolism* ; Female ; Hippocampus/metabolism* ; Long-Term Potentiation/physiology*

Objective:To detect the level of N6-methyladenosine(m6A)methylation modifier regulator in peripheral blood mononuclear cell(PBMC)of patients with rheumatoid arthritis(RA),and to investigate its expression level and clinical significance in RA.Methods:PBMC from 50 RA patients and 36 healthy controls(HC)were examined by RT-qPCR to compare the mRNA expres-sion levels of m6A methylation modifier regulators(METTL3,METTL14,WTAP,ALKBH5,FTO,YTHDF2)on PBMC from RA and HC groups and their correlation with laboratory test data was analyzed.Results:①The expression levels of m6A methylation modifica-tion regulators on PBMC in peripheral blood were significantly lower in the RA group than in the HC group,and the differences were statistically significant;②The expression levels of METTL3,METTL14,WTAP and YTHDF2 on PBMC of RA patients were negatively correlated with rheumatoid factor;③The expression levels of YTDHF2 on PBMC of RA patients were negatively correlated with inflam-matory indexes CRP,ESR,N,N%,NLR and dNLR,and positively correlated with L%and LMR;the expression levels of WTAP on PBMC of RA patients were negatively correlated with N,N%,NLR and dNLR,and positively correlated with L%and LMR;④The expression level of YTDHF2 on PBMC of RA patients increased significantly after treatment,and the difference was statistically signifi-cant;⑤The expression levels of m6A methylation modifier regulators on PBMC of RA patients were positively correlated with each other;⑥Logistic regression analysis showed that the decreased expression levels of FTO and YTHDF2 in PBMC of RA patients were risk factors for the development of RA.Conclusion:The expression levels of m6A methylation-modified regulators on PBMC are gener-ally reduced in the RA group.m6A methylation-modified regulators are clearly correlated with inflammation levels,autoantibody pro-duction and disease severity,and can be used as an indicator to assess the severity and activity of the disease.

Objective:To detect the level of N6-methyladenosine(m6A)methylation modifier regulator in peripheral blood mononuclear cell(PBMC)of patients with rheumatoid arthritis(RA),and to investigate its expression level and clinical significance in RA.Methods:PBMC from 50 RA patients and 36 healthy controls(HC)were examined by RT-qPCR to compare the mRNA expres-sion levels of m6A methylation modifier regulators(METTL3,METTL14,WTAP,ALKBH5,FTO,YTHDF2)on PBMC from RA and HC groups and their correlation with laboratory test data was analyzed.Results:①The expression levels of m6A methylation modifica-tion regulators on PBMC in peripheral blood were significantly lower in the RA group than in the HC group,and the differences were statistically significant;②The expression levels of METTL3,METTL14,WTAP and YTHDF2 on PBMC of RA patients were negatively correlated with rheumatoid factor;③The expression levels of YTDHF2 on PBMC of RA patients were negatively correlated with inflam-matory indexes CRP,ESR,N,N%,NLR and dNLR,and positively correlated with L%and LMR;the expression levels of WTAP on PBMC of RA patients were negatively correlated with N,N%,NLR and dNLR,and positively correlated with L%and LMR;④The expression level of YTDHF2 on PBMC of RA patients increased significantly after treatment,and the difference was statistically signifi-cant;⑤The expression levels of m6A methylation modifier regulators on PBMC of RA patients were positively correlated with each other;⑥Logistic regression analysis showed that the decreased expression levels of FTO and YTHDF2 in PBMC of RA patients were risk factors for the development of RA.Conclusion:The expression levels of m6A methylation-modified regulators on PBMC are gener-ally reduced in the RA group.m6A methylation-modified regulators are clearly correlated with inflammation levels,autoantibody pro-duction and disease severity,and can be used as an indicator to assess the severity and activity of the disease.

AIM: To investigate the effect of an effective component total sterone (TSR) of Echinops latifolius Tausch, the main component of a Chinese patent medicine Cuiru Keli (national drug standard WS3-413 (Z-085)-2003 (Z), on lactation and its possible mechanism. METHODS: After mating between male and female SD rats, 60 female rats were randomly divided into normal control group, model group, TSR low-dose and high-dose groups and prolactin granule positive control group, with 12 female rats in each group and 8 newborn rats in each nest. In addition to the normal control group, the rats in each group were intraperitoneally injected with levodopa 2 mg/kg once a day for 7 days from the second day of delivery. The rats in the normal control group were given normal saline by gavage once a day for 14 days. From the beginning of self-sufficiency, the single lactation of the female rats was measured every day until the 14th day, and then the female rats in each group were killed. Pathological HE staining was used to observe the morphological changes of mammary gland tissue in each group. ELISA was used to detect the levels of serum prolactin (PRL) and 5-hydroxytryptamine (5-HT). Immunohistochemistry was used to detect the distribution of PRL in mammary gland tissue of each group. Furthermore, Real-time qPCR was used to detect the expression of milk protein, milk fat related genes β-casein, FAS, ACC and the expression of canonical Wnt signaling pathway related genes β-catenin, c-Myc, CCND1, SFRP4, DNMT1, MeCP2 in mammary gland of each group. RESULTS: Both low and high dose TSR could significantly increase the single lactation volume, improve the pathological morphology of mammary gland, and increase the serum levels of PRL and 5-HT. TSR increased the distribution of PRL and up-regulated the expression of milk protein, milk fat related genes β-casein, FAS, ACC and canonical Wnt signaling pathway related genes β-catenin, c-Myc, CCND1, SFRP4, DNMT1, MeCP2.CONCLUSION: TSR can significantly promote lactation in lactation deficient rats, and its mechanism may be related to promoting the release of PRL and 5-HT in serum, increasing the distribution of PRL in mammary gland, up-regulating the milk protein and milk fat related genes and activating the canonical Wnt signal.

Objective To explore the change in heme oxygenase-1 (HO-1) level in cerebrospinal fluid(CSF)and serum in patients with mild cognitive impairment(MCI),and the correlation between HO-1 and the rating scale,to provide a new marker for the diagnosis of MCI.Methods The HO-1 levels in CSF and serum in 45 MCI patients (MCI group) and 85 normal cases (control group) were analyzed with sensitive enzyme linked immunosorbent assays (ELISA).MMSE and MoCA scores were evaluated.Results The level of HO-1 was higher in MCI group than in control group both in CSF [(631.38±32.17)vs(480.75±17.98)ng/ L,P＜0.05],and in serum [(612.52±111.48)vs.(384.16±56.86)ng/ L,P＜0.05].The MCI and normal people HO-1 level had no significant difference between CSF group and serum group (P＞0.05).In MCI group,the levels of serum and CSF HO-1 had a positive correlation with MMSE scores (P＜0.05),but had no obvious correlation with MoCA scores (P＞0.05).In the normal group,the level of HO-1 was negatively related with MMSE scores in serum and CSF,and with MoCA scores in CSF (P＜0.05),but no obvious correlation in serum (P＞0.05).The levels of serum and CSF HO-1 had no obvious correlation with age in both groups (P＞0.05).Conclusions HO-1 concentration in both CSF and serum is significantly higher in MCI group than in normal group,and positively related with MMSE score.Thus the increase of HO-1concentration in both CSF and/or serum might be a new marker for the diagnosis of MCI.

OBJECTIVETo investigate the features of regional cerebral metabolic rate of glucose (rCMRglc) in patients with mild cognitive impairment (MCI) by positron emission-tomography and its relationship with neuropsychological test.

METHODSPositron emission tomography, mini-mental state examination and Wechsler memory scale were applied in 10 patients with MCI and 10 healthy volunteers as the control group.

RESULTSScores of mini-mental state examination and Wechsler memory scale in MCI patients were lower than those in the control group (P < 0.01). rCMRglc of the left orbital gyrus, right middle temporal gyrus and right putamen was lower in the MCI group than in the control group (P < 0.05). Correlation analysis in the MCI group indicated that rCMRglc of many brain regions such as the orbital gyrus, putamen, left hippocampus and parahippocampal gyrus, cingulate gyrus, left amygdaloid body, precentral gyrus, postcentral gyrus, and medial occipitotemporal gyrus in MCI patients, were correlated negatively with age; while the rCMRglc of many parts of the brain such as the left putamen, temporal lobe, anterior cingulate gyrus, left insular lobe, amygdaloid body, precentral gyrus, postcentral gyrus and medial occipitotemporal gyrus were correlated positively with mini-mental state examination; and rCMRglc of the left putamen, temporal lobe, left insular lobe, precentral gyrus and postcentral gyrus were correlated positively with Wechsler memory scale. The right putamen, the right inferior temporal gyrus, precentral gyrus, and left postcentral gyrus were correlated positively with the length of education. However, only rCMRglc of the left amygdaloid body were correlated positively with gender.

CONCLUSIONThe rCMRglc was lower in the orbital gyrus and putamen of MCI patients. Their rCMRglc were correlated with their cognitive impairment severity, age, length of education and sex.

Aged ; Brain ; metabolism ; Cognition Disorders ; metabolism ; psychology ; Female ; Glucose ; metabolism ; Humans ; Male ; Middle Aged ; Neuropsychological Tests ; Tomography, Emission-Computed

Objective To study the feature of regional cerebral metabolism rate of glucose (rCMRglc) in patients with Alzheimer’s disease (AD) and the value of positron emission tomography (PET) scanning in diagnosis of AD. Methods 13 AD patients and 13 health controls ,Who matched in age,sex and education years,were scanned with PET. Results (1) Watching by naked eyes,there was mild decreasing of rCMRglc at parietal lobe in healthy elders. While in AD patients,there was widely decreasing of cerebral metabolism rate of glucose. The most significant region was parietal lobe, the next was temporal lobe,and the last was frontal lobe. (2) Detecting with PET and dealing with statistical parametric mapping (SPM) of 99 software,there was more significant decreasing of rCMRglc in regions 7,23,30,31 of cingulate gyrus,region 39 and 40 of pario-occipital lobe,region 20 of temporal lobe and region 6,8,9 of frontal lobe in AD group( P