Targeting VDAC: A potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease.

Mitochondrial dysfunction has been implicated in the pathogenesis of Alzheimer's disease, a neurodegenerative disorder characterized by progressive cognitive decline. Voltage-dependent anion channel (VDAC), a protein located in the outer mitochondrial membrane, plays a critical role in regulating mitochondrial function and cellular energy metabolism. Recent studies have identified VDAC as a potential therapeutic target for Alzheimer's disease. This article aims to provide an overview of the role of VDAC in mitochondrial dysfunction, its association with Alzheimer's disease, and the potential of targeting VDAC for developing novel therapeutic interventions. Understanding the involvement of VDAC in Alzheimer's disease may pave the way for the development of effective treatments that can restore mitochondrial function and halt disease progression.

Exploring the potential of treating chronic liver disease targeting the PI3K/Akt pathway and polarization mechanism of macrophages.

Chronic liver disease is a significant public health issue that can lead to considerable morbidity and mortality, imposing an enormous burden on healthcare resources. Understanding the mechanisms underlying chronic liver disease pathogenesis and developing effective treatment strategies are urgently needed. In this regard, the activation of liver resident macrophages, namely Kupffer cells, plays a vital role in liver inflammation and fibrosis. Macrophages display remarkable plasticity and can polarize into different phenotypes according to diverse microenvironmental stimuli. The polarization of macrophages into M1 pro-inflammatory or M2 anti-inflammatory phenotypes is regulated by complex signaling pathways such as the PI3K/Akt pathway. This review focuses on investigating the potential of using plant chemicals targeting the PI3K/Akt pathway for treating chronic liver disease while elucidating the polarization mechanism of macrophages under different microenvironments. Studies have demonstrated that inhibiting M1-type macrophage polarization or promoting M2-type polarization can effectively combat chronic liver diseases such as alcoholic liver disease, non-alcoholic fatty liver disease, and liver fibrosis. The PI3K/Akt pathway acts as a pivotal modulator of macrophage survival, migration, proliferation, and their responses to metabolism and inflammatory signals. Activating the PI3K/Akt pathway induces anti-inflammatory cytokine expression, resulting in the promotion of M2-like phenotype to facilitate tissue repair and resolution of inflammation. Conversely, inhibiting PI3K/Akt signaling could enhance the M1-like phenotype, which exacerbates liver damage. Targeting the PI3K/Akt pathway has tremendous potential as a therapeutic strategy for regulating macrophage polarization and activity to treat chronic liver diseases with plant chemicals, providing new avenues for liver disease treatment.

Functional Dissociation of the Posterior and Anterior Insula in Moral Disgust.

The insula is thought to be involved in disgust. However, the roles of the posterior insula (PI) and anterior insula (AI) in moral disgust have not been clearly dissociated in previous studies. In this functional magnetic resonance imaging study, the participants evaluated the degree of disgust using sentences related to mild moral violations with different types of behavioral agents (mother and stranger). The activation of the PI in response to the stranger agent was significantly higher than that in response to the mother agent. In contrast, the activation of the AI in response to the mother agent was significantly higher than that in response to the stranger agent. These data suggest a clear functional dissociation between the PI and AI in which the PI is more involved in the primary level of moral disgust than is the AI, and the AI is more involved in the secondary level of moral disgust than is the PI. Our results provide key evidence for understanding the principle of embodied cognition and particularly demonstrate that high-level moral disgust is built on more basic disgust via a mental construction approach through a process of embodied schemata.

Delta Subunit-Containing Gamma-Aminobutyric Acid A Receptor Disinhibits Lateral Amygdala and Facilitates Fear Expression in Mice.

BACKGROUND: Maintaining gamma-aminobutyric acidergic (GABAergic) inhibition in the amygdala within a physiological range is critical for the appropriate expression of emotions such as fear and anxiety. The synaptic GABA type A receptor (GABAAR) is generally known to mediate the primary component of amygdala inhibition and prevent inappropriate expression of fear. However, little is known about the contribution of the extrasynaptic GABAAR to amygdala inhibition and fear. METHODS: By using mice expressing green fluorescent protein in interneurons (INs) and lacking the δ subunit-containing GABAAR (GABAA(δ)R), which is exclusively situated in the extrasynaptic membrane, we systematically investigated the role of GABAA(δ)R in regulating inhibition in the lateral amygdala (LA) and fear learning using the combined approaches of immunohistochemistry, electrophysiology, and behavior. RESULTS: In sharp contrast to the established role of synaptic GABAAR in mediating LA inhibition, we found that either pharmacological or physiological recruitment of GABAA(δ)R resulted in the weakening of GABAergic transmission onto projection neurons in LA while leaving the glutamatergic transmission unaltered, suggesting disinhibition by GABAA(δ)R. The disinhibition arose from IN-specific expression of GABAA(δ)R with its activation decreasing the input resistance of local INs and suppressing their activation. Genetic deletion of GABAA(δ)R attenuated its role in suppressing LA INs and disinhibiting LA. Importantly, the GABAA(δ)R facilitated long-term potentiation in sensory afferents to LA and permitted the expression of learned fear. CONCLUSIONS: Our findings suggest that GABAA(δ)R serves as a brake rather than a mediator of GABAergic inhibition in LA. The disinhibition by GABAA(δ)R may help to prevent excessive suppression of amygdala activity and thus ensure the expression of emotion.

Exendin-4, a glucagon-like peptide 1 receptor agonist, protects against amyloid-ß peptide-induced impairment of spatial learning and memory in rats.

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share specific molecular mechanisms, and agents with proven efficacy in one may be useful against the other. The glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 has similar properties to GLP-1 and is currently in clinical use for T2DM treatment. Thus, this study was designed to characterize the effects of exendin-4 on the impairment of learning and memory induced by amyloid protein (Aß) and its probable molecular underlying mechanisms. The results showed that (1) intracerebroventricular (i.c.v.) injection of Aß1-42 resulted in a significant decline of spatial learning and memory of rats in water maze tests; (2) pretreatment with exendin-4 effectively and dose-dependently protected against the Aß1-42-induced impairment of spatial learning and memory; (3) exendin-4 treatment significantly decreased the expression of Bax and cleaved caspase-3 and increased the expression of Bcl2 in Aß1-42-induced Alzheimer's rats. The vision and swimming speed of the rats among all groups in the visible platform tests did not show any difference. These findings indicate that systemic pretreatment with exendin-4 can effectively prevent the behavioral impairment induced by neurotoxic Aß1-42, and the underlying protective mechanism of exendin-4 may be involved in the Bcl2, Bax and caspase-3 pathways. Thus, the application of exendin-4 or the activation of its signaling pathways may be a promising strategy to ameliorate the degenerative processes observed in AD.

Meditation promotes insightful problem-solving by keeping people in a mindful and alert conscious state.

Although previous studies have shown that sleep can inspire insight, it is still unclear whether meditation can promote insight. Meditation differs from other types of passive rest such as relaxation and sleep because it requires full consciousness and mindfulness of targets such as one's breathing. Forty-eight university students without meditation experience were recruited to learn a simple meditation technique. They were given a list of 10 insight problems to solve (the pre-test session). In this study, we focused on the unsolved problems and examined if they could be successfully solved after a 20 min rest interval with or without meditation. Results showed that relative to the control group that listened to Chinese or English words and made a language judgment, the groups who learned meditation successfully solved significantly more failed problems from the pre-test session, providing direct evidence for the role of meditation in promoting insight. Further analysis showed that maintaining a mindful and alert state during meditation (raising a hand to report every 10 deep breaths compared to every 100 deep breaths) resulted in more insight regarding the failed items from the pre-test session. This implies that it was watchfulness in meditation, rather than relaxation, that actually contributed to insight. Consistently, in the meditation session or control task, the percentage of alpha waves-a brain index of mental relaxation-was negatively correlated with insight. These results suggest a meditation-based insight-promoting mechanism different from that involved in passive rest such as relaxation and sleep.

Can Sophie's choice be adequately captured by cold computation of minimizing losses? An fMRI study of vital loss decisions.

The vast majority of decision-making research is performed under the assumption of the value maximizing principle. This principle implies that when making decisions, individuals try to optimize outcomes on the basis of cold mathematical equations. However, decisions are emotion-laden rather than cool and analytic when they tap into life-threatening considerations. Using functional magnetic resonance imaging (fMRI), this study investigated the neural mechanisms underlying vital loss decisions. Participants were asked to make a forced choice between two losses across three conditions: both losses are trivial (trivial-trivial), both losses are vital (vital-vital), or one loss is trivial and the other is vital (vital-trivial). Our results revealed that the amygdala was more active and correlated positively with self-reported negative emotion associated with choice during vital-vital loss decisions, when compared to trivial-trivial loss decisions. The rostral anterior cingulate cortex was also more active and correlated positively with self-reported difficulty of choice during vital-vital loss decisions. Compared to the activity observed during trivial-trivial loss decisions, the orbitofrontal cortex and ventral striatum were more active and correlated positively with self-reported positive emotion of choice during vital-trivial loss decisions. Our findings suggest that vital loss decisions involve emotions and cannot be adequately captured by cold computation of minimizing losses. This research will shed light on how people make vital loss decisions.

Immunolocalisation of heat shock protein 72 and glycoprotein 96 in colonic adenocarcinoma.

Heat shock protein 72 (HSP72) and glycoprotein 96 (gp96) are highly expressed in cancer tissues. Recent studies indicate the possible roles of HSP72 and gp96 in the development and progression of colonic carcinomas, but detailed information is still ambiguous. In this study, we investigated the correlation between clinical pathology and immunolocalisation of HSP72 and gp96 in human colonic carcinoma. The distribution of HSP72 and gp96 was studied in 160 human colonic carcinomas, with or without metastasis, as well as in mucous membranes adjacent to cancers by means of immunohistochemistry. HSP72 immunoreactivity was detected in 145 of 160 primary tumours (90.6%) and in 44 of 160 mucous membranes adjacent to cancers (27.5%). Gp96 was detected in 81.3% colonic carcinomas and in 13.8% mucous membranes adjacent to cancer. Immunolocalisation of HSP72 and gp96 was mainly cytoplasmic. HSP72 and gp96 immunolabelling was significantly higher in colonic carcinomas with metastasis than in those without metastasis (P<0.05). The results indicate a significant correlation between the immunopositivity of HSP72 and gp96 and the progression of colonic carcinomas. Immunolabelling of HSP72 and gp96 may be useful as diagnostic or prognostic markers in colonic carcinoma.

Correlation between clinicopathology and expression of heat shock protein 72 and glycoprotein 96 in human gastric adenocarcinoma.

Heat shock protein 72 (HSP72) and glycoprotein 96 (gp96) are highly expressed in cancer tissues. Recent studies indicate the possible roles of HSP72 and gp96 in the development and progression of gastric carcinomas but detailed information is still ambiguous. In this study, we investigated the correlation between clinicopathology and expression of HSP72 and gp96 in human gastric carcinoma. The expression of HSP72 and gp96 was studied in 60 human gastric carcinomas with or without metastasis as well as in mucous membrane adjacent to cancers by way of immunohistochemistry. HSP72 immunoreactivities were detected in 54 of 60 primary tumors (90.0%) and in 22 of 60 mucous membranes adjacent to cancers (36.7%). Likewise, gp96 immunoreactivities were detected in 49 cases of gastric carcinoma (81.7%) and in 15 samples of mucous membrane adjacent to cancer (25.0%). Both HSP72 and gp96 were stained in cytoplasm. HSP72 and gp96 expression in colonic carcinomas with metastasis was significantly higher than those with non-metastasis (p < 0.05). The results indicate that there exists a significant correlation between the expression of HSP72 and gp96 and the progression of gastric carcinomas. The high-level expression of HSP72 and gp96 may be used as diagnostic or prognostic markers for gastric carcinoma.

Interaction between heat shock protein 72 and alpha-fetoprotein in human hepatocellular carcinomas.

BACKGROUND: AFP in adult serum often signals pathological conditions, particularly the presence of hepatocellular carcinoma (HCC) and germ cell tumors containing yolk sac cell elements. Heat shock protein 72 (HSP72) as a molecular chaperone has been confirmed to overexpress in epithelial carcinoma cells. There may be a possible correlation between the expression of HSP72 and AFP during the growth and differentiation of hepatocellular carcinoma cells. We investigated the interaction between heat shock protein 72 (HSP72) and alpha-fetoprotein (AFP) in human hepatocellular carcinomas. METHODS: The expression and localization of HSP72 and AFP in human hepatocellular carcinomas were determined by immunohistochemistry and confocal laser microscopy. The interaction between HSP72 and AFP in hepatocellular carcinoma cells was analyzed by immunoprecipitation and Western immunoblots. RESULTS: Hepatocellular carcinoma synchronously co-expressed higher level of HSP72 and AFP than in adjacent normal liver tissues. HSP72 were stained in cell nuclei and cytoplasm respectively, while AFP stained in cell plasma. Based on Western blotting methods, AFP was detected in the immunoprecipitate of anti-HSP72 monoclonal antibody (mAb), while HSP72 existed in the immunoprecipitate of anti-AFP mAb. CONCLUSIONS: HSP72 and AFP expression are higher in hepatocellular carcinoma tissues. HSP72 was associated with alpha-fetoprotein in human hepatocellular carcinoma cells. The interaction between HSP72 and AFP in human hepatocellular carcinoma cells can be a new route for studying the pathogenesis and immunotherapy of hepatocellular carcinoma.