Caloric restriction leading to attenuation of experimental Alzheimer's disease results from alterations in gut microbiome.

BACKGROUND: Caloric restriction (CR) might be effective for alleviating/preventing Alzheimer's disease (AD), but the biological mechanisms remain unclear. In the current study, we explored whether CR caused an alteration of gut microbiome and resulted in the attenuation of cognitive impairment of AD animal model. METHODS: Thirty-week-old male APP/PS1 transgenic mice were used as AD models (AD mouse). CR was achieved by 30% reduction of daily free feeding (ad libitum, AL) amount. The mice were fed with CR protocol or AL protocol for six consecutive weeks. RESULTS: We found that with CR treatment, AD mice showed improved ability of learning and spatial memory, and lower levels of Aß40, Aß42, IL-1ß, TNF-α, and ROS in the brain. By sequencing 16S rDNA, we found that CR treatment resulted in significant diversity in composition and abundance of gut flora. At the phylum level, Deferribacteres (0.04%), Patescibacteria (0.14%), Tenericutes (0.03%), and Verrucomicrobia (0.5%) were significantly decreased in CR-treated AD mice; at the genus level, Dubosiella (10.04%), Faecalibaculum (0.04%), and Coriobacteriaceae UCG-002 (0.01%) were significantly increased in CR-treated AD mice by comparing with AL diet. CONCLUSIONS: Our results demonstrate that the attenuation of AD following CR treatment in APP/PS1 mice may result from alterations in the gut microbiome. Thus, gut flora could be a new target for AD prevention and therapy.

Analysis of gait characteristics and related factors in patients with Parkinson's disease based on wearable devices.

BACKGROUND: Postural instability and gait disorder dominant (PIGD) is one of the most common disabling symptoms of Parkinson's disease (PD), which seriously affects patients' quality of life. Therefore, it is essential to identify PIGD and develop targeted interventions to reduce the risk of PIGD in PD patients. AIM: This study aimed to investigate the gait characteristics of PD patients based on wearable devices and to establish a predictive model for their related influencing factors. METHODS: The retrospective medical records of patients from January 2020 to September 2023 were collected, including 159 patients with PD (divided into PIGD [n = 73] and non-PIGD [n = 86] groups) and 200 healthy patients (as the healthy control group). Information from social demographic data, a blood test, scale scores, gait analysis based on wearable devices, white matter lesions, and the Fazekas scale was extracted and analyzed. RESULTS: Compared with the healthy control group, the mean step length, mean rate, mean angular velocity, and step length were lower in the PD group, while the mean steps were higher in the turning test. The incidence of PIGD was 46% in PD patients, and PD patients with the non-tremor onset mode were more likely to develop PIGD than those with the tremor onset mode. Compared to the non-PIGD group, the PIGD group showed more serious gait problems in different experimental tasks and had a higher Hoehn and Yahr (H-Y) stage, Hamilton Anxiety Scale (HAMA) score, Hamilton Depression Scale score, periventricular white matter (PVWM) score, deep white matter score, and Fazekas scale score, but they had lower hemoglobin levels, D-dimer levels, Tinetti Balance scores, Tinetti Gait scores, Berg Balance Scale scores, and Mini-Mental State Examination (MMSE) scores. Logistic regression analysis showed that the MMSE score was negatively correlated with the occurrence of PIGD, while the HAMA score, H-Y stage, PVWM score, and non-tremor form of onset were positively correlated with the occurrence of PIGD CONCLUSION: The incidence of gait disorder in PD patients is higher than that in the normal population. Moreover, cognitive dysfunction, anxiety state, H-Y stage, PVWM score, and the non-tremor mode of onset can be considered independent risk factors for PIGD.

A Cascade Targeted and Mitochondrion-Dysfunctional Nanomedicine Capable of Overcoming Drug Resistance in Hepatocellular Carcinoma.

Chemoresistance is a formidable issue in clinical anticancer therapy and is pertinent to the lowered efficacies of chemotherapeutics and the activated tumor self-repairing proceedings. Herein, bifunctional amphiphiles containing galactose ligands and high-density disulfide are synthesized for encapsulating mitochondrion-targeting tetravalent platinum prodrugs to construct a cascade targeted and mitochondrion-dysfunctional nanomedicine (Gal-NP@TPt). Subsequent investigations verify that Gal-NP@TPt with sequential targeting functions toward tumors and mitochondria improved the spatiotemporal level of platinum. In addition, glutathione depletion by Gal-NP@TPt appear to substantially inhibit the proceedings of platinum detoxification, inducing the susceptibility to the mitochondrial platinum. Moreover, the strategic transportation of platinum to mitochondria lacking DNA repair machinery by Gal-NP@TPt lowers the possibility of platinum deactivation. Eventually, Gal-NP@TPt demonstrates appreciable antitumor effects for the systemic treatment of patient-derived tumor xenografts of hepatocellular carcinoma. Note that these strategies in overcoming drug resistance have also been confirmed to be valid based on genome-wide analysis via RNA-sequencing. Therefore, an intriguing multifunctional nanomedicine capable of resolving formidable chemoresistance is achieved, which should be greatly emphasized in practical applications for the treatment of intractable tumors.

NO-dependent vasodilation and deep tumor penetration for cascade-amplified antitumor performance.

Nonspecific biodistribution and poor permeability of conventional therapeutic agents in solid tumors severely compromised the antitumor efficacy. Herein, we report a cascade tumor therapeutic nanoplatform consisting of docosahexaenoic acid (DHA) and nicorandil (NI), namely DNP, to specifically produce cytotoxic agents in tumor cells as well as dilating blood vessels to increase the intratumoral oxidative stress levels. The DHA embedded in the membrane could generate reactive oxygen species (ROS) meanwhile NI produced nitric oxide (NO) in response to intracellular glutathione (GSH) in tumors. Notably, the two functional species could further react in situ to form a more tumoricidal reactive nitrogen species (RNS), causing selectively cascade amplification of antitumor performance. In addition, NO-induced vasodilation could consequently result in a series of functions, including hypoxia relief and deep tumor transportation. In general, we anticipate that the DNP could show great potential for tumor-specific treatment by selectively producing RNS precursors in response to the interior environment of tumor cells for hypoxia normalization and tumor inhibition.

Alteration of the Neuromuscular Junction and Modifications of Muscle Metabolism in Response to Neuron-Restricted Expression of the CHMP2Bintron5 Mutant in a Mouse Model of ALS-FTD Syndrome.

CHMP2B is a protein that coordinates membrane scission events as a core component of the ESCRT machinery. Mutations in CHMP2B are an uncommon cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative diseases with clinical, genetic, and pathological overlap. Different mutations have now been identified across the ALS-FTD spectrum. Disruption of the neuromuscular junction is an early pathogenic event in ALS. Currently, the links between neuromuscular junction functionality and ALS-associated genes, such as CHMP2B, remain poorly understood. We have previously shown that CHMP2B transgenic mice expressing the CHMP2Bintron5 mutant specifically in neurons develop a progressive motor phenotype reminiscent of ALS. In this study, we used complementary approaches (behavior, histology, electroneuromyography, and biochemistry) to determine the extent to which neuron-specific expression of CHMP2Bintron5 could impact the skeletal muscle characteristics. We show that neuronal expression of the CHMP2Bintron5 mutant is sufficient to trigger progressive gait impairment associated with structural and functional changes in the neuromuscular junction. Indeed, CHMP2Bintron5 alters the pre-synaptic terminal organization and the synaptic transmission that ultimately lead to a switch of fast-twitch glycolytic muscle fibers to more oxidative slow-twitch muscle fibers. Taken together these data indicate that neuronal expression of CHMP2Bintron5 is sufficient to induce a synaptopathy with molecular and functional changes in the motor unit reminiscent of those found in ALS patients.

Construction of iron-mineralized black phosphorene nanosheet to combinate chemodynamic therapy and photothermal therapy.

Chemodynamic therapy (CDT) by triggering Fenton reaction or Fenton-like reaction to generate hazardous hydroxyl radical (•OH), is a promising strategy to selectively inhibit tumors with higher H2O2 levels and relatively acidic microenvironment. Current Fe-based Fenton nanocatalysts mostly depend on slowly releasing iron ions from Fe or Fe oxide-based nanoparticles, which leads to a limited rate of Fenton reaction. Herein, we employed black phosphorene nanosheets (BPNS), a biocompatible and biodegradable photothermal material, to develop iron-mineralized black phosphorene nanosheet (BPFe) by in situ deposition method for chemodynamic and photothermal combination cancer therapy. This study demonstrated that the BPFe could selectively increase cytotoxic ·OH in tumor cells whereas having no influence on normal cells. The IC50 of BPFe for tested tumor cells was about 3-6 µg/mL, which was at least one order of magnitude lower than previous Fe-based Fenton nanocatalysts. The low H2O2 level in normal mammalian cells guaranteed the rare cytotoxicity of BPFe. Moreover, the combination of photothermal therapy (PTT) with CDT based on BPFe was proved to kill tumors more potently with spatiotemporal accuracy, which exhibited excellent anti-tumor effects in xenografted MCF-7 tumor mice models.

Trichosanthin cooperates with Granzyme B to restrain tumor formation in tongue squamous cell carcinoma.

BACKGROUND: Tongue squamous cell carcinoma (TSCC) is a common type of oral cancer, with a relatively poor prognosis and low post-treatment survival rate. Various strategies and novel drugs to treat TSCC are emerging and under investigation. Trichosanthin (TCS), extracted from the root tubers of Tian-Hua-Fen, has been found to have multiple biological and pharmacological functions, including inhibiting the growth of cancer cells. Granzyme B (GrzB) is a common toxic protein secreted by natural killer cells and cytotoxic T cells. Our group has reported that TCS combined with GrzB might be a superior approach to inhibit liver tumor progression, but data relating to the use of this combination to treat TSCC remain limited. The aim of this study was to examine the effectiveness of TCS on TSCC processes and underlying mechanisms. METHODS: First, we screened the potential antitumor activity of TCS using two types of SCC cell lines. Subsequently, a subcutaneous squamous cell carcinoma xenograft model in nude mice was established. These model mice were randomly divided into four groups and treated as follows: control group, TCS treatment group, GrzB treatment group, and TCS/GrzB combination treatment group. Various tumorigenesis parameters, such as Ki67, PCNA, caspase-3, Bcl-2 and VEGFA, et al., were performed to determine the effects of these treatments on tumor development. RESULTS: Screening confirmed that the SCC25 line exhibited greater sensitivity than the SCC15 line to TCS in vitro studies. TCS or GrzB treatment significantly inhibited tumor growth compared with the inhibition seen in the control group. The TCS/GrzB combination inhibited tumor growth more than either drug alone. TCS treatment inhibited tumor proliferation by downregulating Ki67 and Bcl2 protein expression while accelerating tumor apoptosis. In the TCS/GrzB-treated group, expression of Ki67 was further downregulated, while the level of activated caspase-3 was increased, compared with their expression in either of the single drug treatment groups. CONCLUSION: These results suggest that the TCS/GrzB combination could represent an effective immunotherapy for TSCC.

Neurotropin reduces memory impairment and neuroinflammation via BDNF/NF-κB in a transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disease with limited treatments and no cure. Neurotropin (NTP) is an analgesic drug widely prescribed for neuropathic pain. Increasing evidence suggests that NTP may also protect against neurodegeneration, but NTP's treatment potential against memory impairments of AD remains to be explored. APP/PS1 mice, which model AD, were given NTP for three months then cognitively tested with the Morris water maze. Their Aß burden, microglial and astrocytic activation, and BDNF levels were compared to untreated controls using immunofluorescent staining. Expression of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and NF-κB pathway related proteins (p65 and IκB-α) were examined by ELISA or Western blots in vivo and in vitro in the microglia cell line. Lastly, BV-2 cells were pre-treated with the selective BDNF inhibitor ANA-12 and with NTP to examine mechanistic pathways. Taken together, NTP treatment reduced cognitive impairment, Aß deposits, and glial activation in cortex and hippocampus APP/PS1 mice. IL-1ß, IL-6 and TNF-α also decreased after NTP treatment in vivo and in vitro, and BDNF levels rose. Also, NTP reduced p65 and IκB-α activation and the effect of NTP on pro-inflammatory cytokines and NF-κB pathway related proteins was abolished by BDNF inhibitor. Our results indicate that NTP reduces neuroinflammation and improves the cognitive deficits in APP/PS1 mice possibly via BDNF/NF-κB pathway. NTP may be a new promising drug candidate for patients with AD.

Concurrent mapping of brain activation from multiple subjects during social interaction by hyperscanning: a mini-review.

Social interaction plays an essential role in acquiring knowledge and developing our own personalities in our daily life. Meanwhile, functional magnetic resonance imaging (fMRI)-, electroencephalograph (EEG)-, and functional near inferred spectroscopy (fNIRS)-hyperscanning, enables us to concurrently map brain activation from two or more participants who are engaged in social interaction simultaneously. In this review, we first highlight the recent technologies advances and the most significant findings towards social interaction by using the hyperscanning method. In addition, we also illustrate several well-designed hyperscanning tasks that have been extensively adopted for the study of social interaction. Basically, hyperscanning contains six categories of experimental paradigms that can track the interactive neural process of interest. Furthermore, it contains two main elucidated neural systems which are involved in social interaction, including the mirror neuron system (MNS) and mentalizing system (MS). Finally, future research directions and clinical implications that are associated with hyperscanning are also highlighted and discussed.

Optical Mapping of Brain Activation and Connectivity in Occipitotemporal Cortex During Chinese Character Recognition.

In this study, functional near-infrared spectroscopy (fNIRS) was used to examine the brain activation and connectivity in occipitotemporal cortex during Chinese character recognition (CCR). Eighteen healthy participants were recruited to perform a well-designed task with three categories of stimuli (real characters, pseudo characters, and checkerboards). By inspecting the brain activation difference and its relationship with behavioral data, the left laterality during CCR was clearly identified in the Brodmann area (BA) 18 and 19. In addition, our novel findings also demonstrated that the bilateral superior temporal gyrus (STG), bilateral BA 19, and left fusiform gyrus were also involved in high-level lexical information processing such as semantic and phonological ones. Meanwhile, by examining functional brain networks, we discovered that the right BA 19 exhibited enhanced brain connectivity. In particular, the connectivity in the right fusiform gyrus, right BA 19, and left STG showed significant correlation with the performance of CCR. Consequently, the combination of fNIRS technique with functional network analysis paves a new avenue for improved understanding of the cognitive mechanism underlying CCR.

Predictive power of abnormal electroencephalogram for post-cerebral infarction depression.

Electroencephalography is a sensitive indicator for measuring brain condition, and can reflect early changes in brain function and severity of cerebral ischemia. However, it is not yet known whether electroencephalography can predict development of post-cerebral infarction depression. A total of 321 patients with ischemic stroke underwent electroencephalography and Hamilton Depression Rating Scale assessment to analyze the relationship between electroencephalography and post-cerebral infarction depression. Our results show that electroencephalograms of ischemic stroke patients with depression exhibit low-amplitude alpha activity and slow theta activity. In contrast, electroencephalograms of ischemic stroke patients without depression show fast beta activity and slow delta activity. These findings confirm that low-amplitude alpha activity and slow theta activity can be considered as independent predictors for post-cerebral infarction depression.

Neurotropin® alleviates hippocampal neuron damage through a HIF-1α/MAPK pathway.

AIMS: The main purpose was to verify the potent capacity of Neurotropin® against neuronal damage in hippocampus and to explore its underlying mechanisms. METHODS: HT22 cells were treated with 40 µmol/L Aß25-35 in the presence of various concentrations of Neurotropin® or in its absence. The cell viability was assessed with a CCK-8 assay, and flow cytometry was used to measure cell apoptosis, intracellular ROS levels, and mitochondrial membrane potential. Aß plaques were examined by Bielschowsky silver staining, and the activities of antioxidants were detected in hippocampus of APP/PS1 mice after Neurotropin® treatment. The expression of proteins, including HIF-1α, Bcl-2, Bax, and MAPKs signaling molecules was evaluated by Western blot. RESULTS: Neurotropin® significantly reversed the cell injury induced by Aß25-35 through increasing cell viability and mitochondrial membrane potential, decreasing intracellular ROS and cell apoptosis of HT22 cells (P<.05). Furthermore, Neurotropin® markedly reduced the formation of Aß plaques and upregulated the activities of antioxidants (P<.05). Additionally, the protein expression of HIF-1α, p-ERK1/2, p-JNK, and p-P38 was significantly inhibited in hippocampus of APP/PS1 mice. CONCLUSIONS: Neurotropin® exhibited a potent neuroprotective effect on inhibiting Aß-induced oxidative damage and alleviating Aß deposition in hippocampus via modulation of HIF-1α/MAPK signaling pathway.

Graphene quantum dots conjugated neuroprotective peptide improve learning and memory capability.

Alzheimer disease (AD) is a neurodegenerative disorder and the most common form of dementia. Histopathologically is characterized by the presence extracellular neuritic plaques and with a large number of neurons lost. In this paper, we design a new nanomaterial, graphene quantum dots (GQDs) conjugated neuroprotective peptide glycine-proline-glutamate (GQDG) and administer it to APP/PS1 transgenic mice. The in vitro assays including ThT and CD proved that GQDs and GQDG could inhibit the aggregation of Aß1-42 fibrils. Morris water maze was performed to exanimate learning and memory capacity of APP/PS1 transgenic mice. The surface area of Aß plaque deposits reduced in the GQDG group compared to the Tg Ctrl groups. Furthermore, newly generated neuronal precursor cell and neuron were test by immunohistochemical. Besides, neurons were impregnated by DiI using gene gun to show dendritic spine. Results indicated enhancement of learning and memory capacity and increased amounts of dendritic spine were observed. Inflammation factors and amyloid-ß (Aß) were tested with suspension array and ELISA, respectively. Several pro-inflammatory cytokines (IL-1α, IL-1ß, IL-6, IL-33, IL-17α, MIP-1ß and TNF-α) had decreased in GQDG group compared with Control group. Reversely, anti-inflammatory cytokines (IL-4, IL-10) had increased in GQDG group compared with Control group. Thus, we demonstrate that the GQDG is a promising drug in treatment of neurodegenerative diseases such as AD.

PI3K/AKT/mTOR/p70S6K Pathway Is Involved in Aß25-35-Induced Autophagy.

Disruption or deregulation of the autophagy system has been implicated in neurodegenerative disorders such as Alzheimer's disease (AD). Aß plays an important role in this autophagic system. In many cases, autophagy is regulated by the phosphatidylinositol 3-phosphate kinase/AKT/mammalian target of rapamycin/p70 ribosomal protein S6 kinase (PI3K/AKT/mTOR/p70S6K) signaling pathway. However, whether this signaling pathway is involved in Aß-induced autophagy in neuronal cells is not known. Here, we studied whether Aß25-35 induces autophagy in HT22 cells and C57 mice and investigated whether PI3K is involved in the autophagy induction. We found that Aß25-35 inhibited HT22 cell viability in a dose- and time-dependent manner. Aß25-35 induced autophagosome formation, the conversion of microtubule-associated protein light chain 3 (LC3), and the suppression of the mTOR pathway both in vitro and in vivo. Furthermore, Aß25-35 impaired the learning abilities of C57 mice. Our study suggests that Aß25-35 induces autophagy and the PI3K/AKT/mTOR/p70S6K pathway is involved in the process, which improves our understanding of the pathogenesis of AD and provides an additional model for AD research.

Fascia and Primo Vascular System.

The anatomical basis for the concept of acupuncture points/meridians in traditional Chinese medicine (TCM) has not been resolved. This paper reviews the fascia research progress and the relationship among acupuncture points/meridians, primo vascular system (PVS), and fascia. Fascia is as a covering, with common origins of layers of the fascial system despite diverse names for individual parts. Fascia assists gliding and fluid flow and holds memory and is highly innervated. Fascia is intimately involved with nourishment of all cells of the body, including those of disease and cancer. The human body's fascia network may be the physical substrate represented by the meridians of TCM. The PVS is a newly found circulatory system; recent increased interest has led to new research and new discoveries in the anatomical and functional aspects of the PVS. The fasciology theory provides new insights into the physiological effects of acupuncture needling on basic cellular mechanisms including connective tissue mechanotransduction and regeneration. This view represents a theoretical basis and means for applying modern biomedical research to examining TCM principles and therapies, and it favors a holistic approach to diagnosis and treatment.

Heavy ethanol consumption aggravates the ischemic cerebral injury by inhibiting ALDH2.

BACKGROUND: Heavy ethanol consumption is widely accepted as a risk for ischemic stroke. The molecular mechanisms of ethanol-induced brain injury have not been fully understood. AIM: This study aims to find out the mechanism of the ischemic cerebral injury. METHODS: We used Sprague-Dawley rats with transient middle cerebral artery occlusion for acute experiment and stroke-prone spontaneously hypertensive rats for long-term experiment in vivo, and oxygen-glucose deprivation model in vitro to define a detrimental effect of different doses of ethanol on ischemic stroke injury. We also used mitochondrial aldehyde dehydrogenase 2 knockdown/overexpression or inhibitor/activator to investigate mechanism of the adverse effects of ethanol. RESULTS: High-dose ethanol (36% of calorie derived from ethanol) significantly increased the infarct size in rats (P < 0·01) and decreased the survival time of stroke-prone spontaneously hypertensive rats by about 20%. Six-week treatment with high-dose ethanol changed a distribution of isoelectric point of aldehyde dehydrogenase 2 and inhibited aldehyde dehydrogenase 2 activity in brain. High dose of ethanol increased the cerebral acetaldehyde level, and increased 4-hydroxy-2-nonenal and malondialdehyde in serum of rats with middle cerebral artery occlusion. The activator of aldehyde dehydrogenase 2, Alda-1 abolished neuronal cells death and ischemic injury induced by ethanol and the inhibitor reversed the injurious effects. An overexpression of aldehyde dehydrogenase 2 completely abolished the increased infarct size and neurological deficit score by ethanol. Conversely, knockdown of aldehyde dehydrogenase 2 increased the infarct size and exaggerated the cerebral injury induced by ethanol. CONCLUSIONS: High concentrations of ethanol aggravate cerebral injury by inhibiting of aldehyde dehydrogenase 2 and inducing excess accumulation of aldehydes.

Increasing the Permeability of the Blood-brain Barrier in Three Different Models in vivo.

AIMS: Blood-brain barrier (BBB) plays significant roles in the circumstance maintains for the central nervous system (CNS). The dysfunction of the BBB could occur in all pathological conditions of CNS diseases, such as ischemic stroke, cerebral edema, or inflammatory disorders. However, the comparisons among different animal models with a broken BBB in vivo are still need to be further studied. METHODS: Here we used three different mice models in vivo, including MCAO induce, LPS treatment, and cold injury to mimic the situation in clinic. The permeability of BBB in three models was detected by perfusion of Evan's blue dye. The functional proteins of the BBB including claudin-5, VE-cadherin, and caveolin-1 were compared in three different models in vivo. RESULTS: With the hyperpermeability of Evan's blue in the three models, both claudin-5 and VE-cadherin were decreased, while the expression of caveolin-1 was increased. Our study showed that BBB dysfunction induced by MCAO in mice was relatively stable, reliable, and moderate compared with LPS or cold injury-induced BBB permeability models, although the procedural time was generally long and operation complexity was hard. Moreover, our study also found that the model of the increased BBB permeability by cold injury was severe in the regional cerebral tissue and the model treated with LPS was mild in the global cerebral tissue. The operation of the two models in vivo was easy, quick, and stable. CONCLUSION: The MCAO model was the most suitable for studying the permeability of BBB among the three models in vivo.