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Acetylcholine regulates various cognitive functions through broad cholinergic innervation. However, specific cholinergic subpopulations, circuits and molecular mechanisms underlying recognition memory remain largely unknown. Here we show that Ngfr+ cholinergic neurons in the substantia innominate (SI)/nucleus basalis of Meynert (nBM)-medial prefrontal cortex (mPFC) circuit selectively underlies recency judgements. Loss of nerve growth factor receptor (Ngfr−/− mice) reduced the excitability of cholinergic neurons in the SI/nBM-mPFC circuit but not in the medial septum (MS)-hippocampus pathway, and impaired temporal order memory but not novel object and object location recognition. Expression of Ngfr in Ngfr−/− SI/nBM restored defected temporal order memory. Fiber photometry revealed that acetylcholine release in mPFC not only predicted object encounters but also mediated recency judgments of objects, and such acetylcholine release was absent in Ngfr−/− mPFC. Chemogenetic and optogenetic inhibition of SI/nBM projection to mPFC in ChAT-Cre mice diminished mPFC acetylcholine release and deteriorated temporal order recognition. Impaired cholinergic activity led to a depolarizing shift of GABAergic inputs to mPFC pyramidal neurons, due to disturbed KCC2-mediated chloride gradients. Finally, potentiation of acetylcholine signaling upregulated KCC2 levels, restored GABAergic driving force and rescued temporal order recognition deficits in Ngfr−/− mice. Thus, NGFR-dependent SI/nBM-mPFC cholinergic circuit underlies temporal order recognition memory. Functional roles of the diverse cholinergic subpopulations such as those in the substantia innominate (SI) and the nucleus basalis of Meynert (nBM) are not fully understood. Here the authors show that Ngfr+ cholinergic neurons in the SI/nBM-mPFC circuit selectively regulates recency judgement in recognition memory. [ABSTRACT FROM AUTHOR]

Objective To explore the dynamic changes of femur microstructure in ovariectomized osteoporosis mice at different stages. Methods Female C57 mice (8 weeks old) were randomly divided into sham-operation (Sham) and ovariectomy (OVX) groups. Each group was subdivided into 1-week, 1-month and 3-month subgroups on the basis of different postoperative time, which representeing early, middle and late menopause, respectively. The femurs were extracted for HE staining, immunohistochemistry and micro-CT analysis, and the changes in the bone microstructure of cancellous bone in the distal femurs, cortical bone in the middle femurs and the levels of osteogenic associated proteins in each group were evaluated. Results Compared with the Sham group, the bone microstructure of the OVX group showed no significant destruction at 1 week after operation, trabecula fracture and bone marrow cavity enlargement from 1 month to 3 months after operation, and significant changes in CT bone parameters BV/TV, Tb.N and Tb.Sp (P < 0.01, P < 0.001) except Tb.Th (P > 0.05). In the Sham group, the bone mass was significantly reduced until 3 months after operation compared with that in the 1-week group (P < 0.01). Bone loss in the OVX groups was worsened in a time dependent manner (P < 0.05, P < 0.01, P < 0.001). The expression level of Runx2 by immunohistochemistry was consistent with the results of micro-CT analysis. No significant differences were found in morphologic indices of cortical bone between the Sham subgroups and the OVX subgroups (P > 0.05). Conclusion Trabecular bone microarchitecture is impaired progressively after OVX operation in 8-week-old C57 mice from 1 week to 1 month, prior to cortical bone. This period can be regarded as the key time for studies on pathogenesis and prevention and treatment of osteoporosis.

Background: A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with type 2 diabetes mellitus (T2DM). Few previous prospective studies have addressed associations between the changes in TMAO and T2DM incidence. Methods: Data were derived from a longitudinal cohort conducted from 2019 to 2021 in rural areas of Fuxin County, Liaoning Province, China, and 1515 diabetes-free participants aged above 35 years were included. The concentrations of serum TMAO and its precursors were measured at two time points, namely in 2019 and 2021. TMAO and TMAO changes (ΔTMAO) were separately tested in a logistic regression model. For further examination, the odds ratios (ORs) for T2DM were calculated according to a combination of TMAO levels and ΔTMAO levels. Results: During a median follow-up of 1.85 years, 81 incident cases of T2DM (5.35%) were identified. Baseline TMAO levels exhibited a nonlinear relationship, first decreasing and then increasing, and only at the highest quartile was it associated with the risk of T2DM. The OR for T2DM in the highest quartile of serum TMAO was 3.35 (95%CI: 1.55–7.26, p = 0.002), compared with the lowest quartile. As for its precursors, only choline level was associated with T2DM risk and the OR for T2DM in the Q3 and Q4 of serum choline was 3.37 (95%CI: 1.41–8.05, p = 0.006) and 4.72 (95%CI: 1.47–15.13, p = 0.009), respectively. When considering both baseline TMAO levels and ΔTMAO over time, participants with sustained high TMAO levels demonstrated a significantly increased risk of T2DM, with a multivariable-adjusted OR of 8.68 (95%CI: 1.97, 38.34). Conclusion: Both initial serum TMAO levels and long-term serum TMAO changes were collectively and significantly associated with the occurrence of subsequent T2DM events. Interventions aimed at normalizing TMAO levels, such as adopting a healthy dietary pattern, may be particularly beneficial in T2DM prevention. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-β in neurons, which is a key step in senile plaque formation. Therefore, restoring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease. Microtubule acetylation/deacetylation plays a central role in lysosomal acidification. Here, we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease. Furthermore, we found that treatment with valproic acid markedly enhanced autophagy, promoted clearance of amyloid-β aggregates, and ameliorated cognitive deficits in a mouse model of Alzheimer's disease. Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease, in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification., (Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)

Osteoporosis (OP) is a debilitating skeletal abnormality involving bone remodeling and bone cell homeostasis characterized by decreased bone strength and high fracture risk. A novel therapeutic intervention for OP by manipulating cellular autophagy-apoptosis processes to promote skeletal homeostasis is presented. Protective effects of the naturally occurring plant extract Liquiritigenin (LG) were demonstrated in an ovariectomy (OVX)-OP mouse model and preosteoblast MC3T3-E1 cells. Micro-CT and histological staining assessments of skeletal phenotype were applied alongside detection of autophagy activity in osteocytes and MC3T3-E1 cells by transmission electron microscopy (TEM). The effects of LG on chloroquine (CQ)- and the apoptosis-inducing TS-treated osteogenic differentiations and status of lysosomes within MC3T3-E1 cells were analyzed by Neutral red, Alizarin red S and alkaline phosphatase (ALP) staining and Western blot assays. Treatment with LG prevented bone loss, increased osteogenic differentiation in vivo and in vitro , and inhibited osteoclast formation to some extent. TEM analyses revealed that LG can improve auto-lysosomal degradation within osteocytes from OVX mice and MC3T3-E1 cells. The abnormal status of lysosomes associated with CQ and TS treatments was notably alleviated by LG which also reduced levels of apoptosis-induced inhibition of osteogenic differentiation and averted abnormal osteogenic differentiation as a consequence of a blockage in autolysosome degradation. Overall, LG stimulates bone growth in OVX mice through increased osteogenic differentiation and regulation of autophagy-apoptosis mechanisms, presenting an auspicious natural therapy for OP., (© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Alterations in glucose metabolism occur in the brain in the early stage of Alzheimer's disease (AD), and menopausal women have more severe metabolic dysfunction and are more prone to dementia than men. Although estrogen deficiency-induced changes in glucose metabolism have been previously studied in animal models, their molecular mechanisms in AD remain elusive. To investigate this issue, double transgenic (APP/PS1) female mice were subjected to bilateral ovariectomy at 3 months of age and were sacrificed 1 week, 1 month and 3 months after surgery to simulate early, middle and late postmenopause, respectively. Our analysis demonstrated that estrogen deficiency exacerbates learning and memory deficits in this mouse model of postmenopause. Estrogen deficiency impairs the function of mitochondria in glucose metabolism. It is possible that the occurrence of AD is associated with the aberrant mitochondrial ERβ-mediated IGF-1/IGF-1R/GSK-3β signaling pathway. In this study, we established a potential mechanism for the increased risk of AD in postmenopausal women and proposed a therapeutic target for AD due to postmenopause., (© 2022 Chongqing Medical University. Production and hosting by Elsevier B.V.)

Objective: To assess the effectiveness and safety of traditional Chinese medical therapy for cancer-related fatigue., Methods: We systematically searched eight electronic databases up to June 2017 for randomized clinical trials of traditional Chinese medical therapy for cancer-related fatigue. Two authors independently extracted data and assessed the risk bias of the included trials using the Cochrane Handbook. Data were analyzed by RevMan 5.2 software., Results: A total of 23 trials involving 1832 participants identified with cancer-related fatigue were included. Twenty trials reported a beneficial effect of traditional Chinese medical therapy on cancer-related fatigue. On pooling the data from Chinese herbal medicine therapy and acupuncture or moxibustion therapy, respectively, significant differences were found between experimental groups and control groups. Fatigue improvement rates showed significant differences between traditional Chinese medical therapy and control groups [odds ratio (OR), 7.62; 95% confidence interval (CI), 3.75-15.49; P < 0.000 01; and OR, 3.78; 95% CI, 2.29-6.23; P < 0.000 01). Fatigue change scores also showed significant differences between the two groups (mean difference, -0.91; 95% CI, -0.16 to -0.65; P < 0.000 01). Eleven trials demonstrated that traditional Chinese medical therapy improved the quality of life of cancer patients. No severe adverse effects occurred in traditional Chinese medical therapy groups., Conclusion: Meta-analysis showed that Chinese medical therapy seems to be effective and safe in the treatment of cancer-related fatigue.