Neurotoxic ß-amyloid oligomers cause mitochondrial dysfunction-the trigger for PANoptosis in neurons.

As the global population ages, the incidence of elderly patients with dementia, represented by Alzheimer's disease (AD), will continue to increase. Previous studies have suggested that ß-amyloid protein (Aß) deposition is a key factor leading to AD. However, the clinical efficacy of treating AD with anti-Aß protein antibodies is not satisfactory, suggesting that Aß amyloidosis may be a pathological change rather than a key factor leading to AD. Identification of the causes of AD and development of corresponding prevention and treatment strategies is an important goal of current research. Following the discovery of soluble oligomeric forms of Aß (AßO) in 1998, scientists began to focus on the neurotoxicity of AßOs. As an endogenous neurotoxin, the active growth of AßOs can lead to neuronal death, which is believed to occur before plaque formation, suggesting that AßOs are the key factors leading to AD. PANoptosis, a newly proposed concept of cell death that includes known modes of pyroptosis, apoptosis, and necroptosis, is a form of cell death regulated by the PANoptosome complex. Neuronal survival depends on proper mitochondrial function. Under conditions of AßO interference, mitochondrial dysfunction occurs, releasing lethal contents as potential upstream effectors of the PANoptosome. Considering the critical role of neurons in cognitive function and the development of AD as well as the regulatory role of mitochondrial function in neuronal survival, investigation of the potential mechanisms leading to neuronal PANoptosis is crucial. This review describes the disruption of neuronal mitochondrial function by AßOs and elucidates how AßOs may activate neuronal PANoptosis by causing mitochondrial dysfunction during the development of AD, providing guidance for the development of targeted neuronal treatment strategies.

Lactate/Hydroxycarboxylic Acid Receptor 1 in Alzheimer's Disease: Mechanisms and Therapeutic Implications-Exercise Perspective.

Lactate has a novel function different from previously known functions despite its traditional association with hypoxia in skeletal muscle. It plays various direct and indirect physiological functions. It is a vital energy source within the central nervous system (CNS) and a signal transmitter regulating crucial processes, such as angiogenesis and inflammation. Activating lactate and its associated receptors elicits effects like synaptic plasticity and angiogenesis alterations. These effects can significantly influence the astrocyte-neuron lactate shuttle, potentially impacting cognitive performance. Decreased cognitive function relates to different neurodegenerative conditions, including Alzheimer's disease (AD), ischemic brain injury, and frontotemporal dementia. Therefore, lactic acid has significant potential for treating neurodegenerative disorders. Exercise is a method that induces the production of lactic acid, which is similar to the effect of lactate injections. It is a harmless and natural way to achieve comparable results. Animal experiments demonstrate that high-intensity intermittent exercise can increase vascular endothelial growth factor (VEGF) levels, thus promoting angiogenesis. In vivo, lactate receptor-hydroxycarboxylic acid receptor 1 (HCAR1) activation can occur by various stimuli, including variations in ion concentrations, cyclic adenosine monophosphate (cAMP) level elevations, and fluctuations in the availability of energy substrates. While several articles have been published on the benefits of physical activity on developing Alzheimer's disease in the CNS, could lactic acid act as a bridge? Understanding how HCAR1 responds to these signals and initiates associated pathways remains incomplete. This review comprehensively analyzes lactate-induced signaling pathways, investigating their influence on neuroinflammation, neurodegeneration, and cognitive decline. Consequently, this study describes the unique role of lactate in the progression of Alzheimer's disease.

Status of research on the development and regeneration of hair follicles.

Hair loss, or alopecia, is a prevalent condition in modern society that imposes substantial mental and psychological burden on individuals. The types of hair loss, include androgenetic alopecia, alopecia areata, and telogen effluvium; of them, androgenetic alopecia is the most common condition. Traditional treatment modalities mainly involve medical options, such as minoxidil, finasteride and surgical interventions, such as hair transplantation. However, these treatments still have many limitations. Therefore, exploring the pathogenesis of hair loss, specifically focusing on the development and regeneration of hair follicles (HFs), and developing new strategies for promoting hair regrowth are essential. Some emerging therapies for hair loss have gained prominence; these therapies include low-level laser therapy, micro needling, fractional radio frequency, platelet-rich plasma, and stem cell therapy. The aforementioned therapeutic strategies appear promising for hair loss management. In this review, we investigated the mechanisms underlying HF development and regeneration. For this, we studied the structure, development, cycle, and cellular function of HFs. In addition, we analyzed the symptoms, types, and causes of hair loss as well as its current conventional treatments. Our study provides an overview of the most effective regenerative medicine-based therapies for hair loss.

Treadmill exercise can regulate the redox balance in the livers of APP/PS1 mice and reduce LPS accumulation in their brains through the gut-liver-kupffer cell axis.

A growing body of clinical data has shown that patients with Alzheimer's disease (AD) have symptoms such as liver dysfunction and microbial-gut-brain axis dysfunction in addition to brain pathology, presenting a systemic multisystemic pathogenesis. Considering the systemic benefits of exercise, here, we first observed the effects of long-term treadmill exercise on liver injuries in APP/PS1 transgenic AD mice and explored the potential mechanisms of the gut-liver-brain axis's role in mediating exercise's ability to reduce bacterial lipopolysaccharide (LPS) pathology in the brain. The results showed that the livers of the AD mice were in states of oxidative stress, while the mice after long-term treadmill exercise showed alleviation of their oxidative stress, their intestinal barriers were protected, and the ability of their Kupffer cells to hydrolyze LPS was improved, in addition to the accumulation of LPS in their brains being reduced. Notably, the livers of the AD mice were in immunosuppressed states, with lower pro-oxidative and antioxidative levels than the livers of the wild-type mice, while exercise increased both their oxidative and antioxidative levels. These results suggest that long-term exercise modulates hepatic redox homeostasis in AD mice, attenuates oxidative damage, and reduces the accumulation of LPS in the brain through the combined action of the intestine-liver-Kupffer cells.

Effect of Exercise and Oral Niacinamide Mononucleotide on Improving Mitochondrial Autophagy in Alzheimer's Disease.

Oral niacinamide mononucleotide (NMN) and aerobic exercise have been shown to enhance niacinamide adenine dinucleotide (NAD+) in the body. NAD+ plays a critical role in the body and can directly and indirectly affect many key cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cell aging, and immune cell function. It is noteworthy that the level of NAD+ decreases gradually with increasing age. Decreased levels of NAD+ have been causally associated with a number of diseases associated with aging, including cognitive decline, cancer, metabolic diseases, sarcopenia, and frailty. Many diseases related to aging can be slowed down or even reversed by restoring NAD+ levels. For example, oral NMN or exercise to increase NAD+ levels in APP/PS1 mice have been proven to improve mitochondrial autophagy, but currently, there is no regimen combining oral NMN with exercise. This review summarizes recent studies on the effect of oral NMN on the enhancement of NAD+ in vivo and the improvements in mitochondrial autophagy abnormalities in AD through aerobic exercise, focusing on (1) how oral NMN improves the internal NAD+ level; (2) how exercise regulates the content of NAD+ in the body; (3) the relationship between exercise activation of NAD+ and AMPK; (4) how SIRT1 is regulated by NAD+ and AMPK and activates PGC-1α to mediate mitochondrial autophagy through changes in mitochondrial dynamics. By summarizing the results of the above four aspects, and combined with the synthesis of NAD+ in vivo, we can infer how exercise elevates the level of NAD+ in vivo to mediate mitochondrial autophagy, so as to propose a new hypothesis that exercise interferes with Alzheimer's disease (AD).

The Effects of n-3 PUFA Supplementation on Bone Metabolism Markers and Body Bone Mineral Density in Adults: A Systematic Review and Meta-Analysis of RCTs.

Supplemental n-3 polyunsaturated fatty acids (PUFA) on bone metabolism have yielded inconsistent results. This study aimed to examine the effects of n-3 PUFA supplementation on bone metabolism markers and bone mineral density through a meta-analysis of randomized controlled trials. A systematic literature search was conducted using the PubMed, Web of Science, and EBSCO databases, updated to 1 March 2023. The intervention effects were measured as standard mean differences (SMD) and mean differences (MD). Additionally, n-3 PUFA with the untreated control, placebo control, or lower-dose n-3 PUFA supplements were compared, respectively. Further, 19 randomized controlled trials (RCTs) (22 comparisons, n = 2546) showed that n-3 PUFA supplementation significantly increased blood n-3 PUFA (SMD: 2.612; 95% CI: 1.649 to 3.575). However, no significant effects were found on BMD, CTx-1, NTx-1, BAP, serum calcium, 25(OH)D, PTH, CRP, and IL-6. Subgroup analyses showed significant increases in femoral neck BMD in females (0.01, 95% CI: 0.01 to 0.02), people aged <60 years (0.01, 95% CI: 0.01 to 0.01), and those people in Eastern countries (0.02, 95% CI: 0.02 to 0.03), and for 25(OH)D in people aged ≥60 years (0.43, 95% CI: 0.11 to 0.74), treated with n-3 PUFA only (0.36, 95% CI: 0.06 to 0.66), and in studies lasting ≤6 months (0.29, 95% CI: 0.11 to 0.47). NTx-1 decreased in both genders (-9.66, 95% CI: -15.60 to -3.71), and serum calcium reduction was found in studies lasting >6 months (-0.19, 95% CI: -0.37 to -0.01). The present study demonstrated that n-3 PUFA supplementation might not have a significant effect on bone mineral density or bone metabolism markers, but have some potential benefits for younger postmenopausal subjects in the short term. Therefore, additional high-quality, long-term randomized controlled trials (RCTs) are warranted to fully elucidate the potential benefits of n-3 PUFA supplementation, as well as the combined supplementation of n-3 PUFA, on bone health.

[Nitrogen Metabolism and Flora Characteristics of Bacteria Algae Complex System].

In order to denitrify the urban tail water deeply and control the eutrophication of surface water, the molecular biology methods were used to study the nitrogen metabolism performance of the denitrification complex flora and the algal-bacteria symbiotic system. The results showed that the nitrogen metabolism complex flora was high ammonification and denitrification performance. The removal effect of ammonia nitrogen of group JZ was very well in urban tailwater, and the degradation rate was as high as 95%. The removal effect of total nitrogen of group JZ was better than that of group J in the experimental water distribution. High-throughput sequencing showed that the main dominant flora and proportion of group J were Firmicutes 44.53%, Proteobacteria 43.41%, Actinobacteria 5.37%, Bacteroidetes 3.04%, and Chloroflexi 1.35%. The main dominant bacterial groups in the group JZ were 33.89% Cyanobacteria, 25.34% Chloroflexi, 19.38% Proteobacteria, 10.02% Firmicutes, and 4.20% Acidobacteria. The dominant species in group J were compared with those in group JZ; the proportions were 82% and 18% in Firmicutes, 69% and 31% in Proteobacteria, 1% and 99% in Cyanobacteria, 5.1% and 95% in Chloroflexi, 73% and 27% in Actinobacteria. It was concluded that the removal effect of ammonia nitrogen of group JZ was high in the urban tailwater. With the addition and growth of Micrococcus in group J, the nitrogen metabolism flora in group JZ changed accordingly, so as to adapt to the environment in which the dominant algae formed. It forms a new nitrogen metabolism system of bacteria and algae with Micrococcus. This research provides a theoretical and data basis for the application of algal-bacterial co-metabolism systems.

Punicalagin protects against impaired skeletal muscle function in high-fat-diet-induced obese mice by regulating TET2.

The function of skeletal muscles can be markedly hampered by obesity. Ten-eleven translocation 2 (TET2) is an important therapeutic target for ameliorating skeletal muscle dysfunction. Our previous study revealed that punicalagin (PUN) regulated TET2 in obese mice; however, whether PUN can prevent obesity-induced skeletal muscle dysfunction by regulating TET2 remains unclear. In the present study, 40 male C57BL/6J mice were divided into four groups (n = 10 per group): the control (CON) group, the high-fat-diet (HFD, negative control) group, the resveratrol (positive control) group, and the PUN group. The ratio of gastrocnemius weight to body weight (0.0097 ± 0.0016 vs. 0.0080 ± 0.0011), the grip strength (120.04 g ± 11.10 vs. 98.89 g ± 2.79), and the muscle fiber count (314.56 per visual field ± 92.73 vs. 236.44 per visual field ± 50.58) in the PUN group were higher than those in the HFD group. Moreover, the levels of the TET2 protein, 5-hydroxymethylcytosine (5hmC), and 5-formylcytosine (5fC) in skeletal muscles were significantly lower in the HFD group than those in the CON group; these levels increased after PUN treatment. Compared with the HFD group, the phosphorylation level of AMP-activated protein kinase (AMPK) α in the PUN group was higher, which effectively enhanced the stability of the TET2 protein. Besides, the ratio of (succinic acid + fumaric acid)/α-ketoglutarate in the PUN group was lower than that in the HFD group (43.21 ± 12.42 vs. 99.19 ± 37.07), and a lower ratio led to a higher demethylase activity of TET2 in the PUN group than in the HFD group. This study highlights that PUN supplementation protects against obesity-induced impairment of the skeletal muscle function via regulating the protein stability of TET2 and the enzymatic activity of TET2 demethylation.

Unraveling the Impact of Long-Term Rice Monoculture Practice on Soil Fertility in a Rice-Planting Meadow Soil: A Perspective from Microbial Biomass and Carbon Metabolic Rate.

Global agricultural intensification leads to a decline in soil quality; however, the extent to which long-term rice cultivation adversely impacts soil, based on chemical and microbial perspectives, remains unclear. The present study was conducted on a seed multiplication farm in Wuchang, Heilongjiang Province, China, to quantify changes in the nutrient properties and microbial profiles of meadow soil in cultivated (rhizosphere and bulk soil) and uncultivated paddy plots from spring to winter. A non-parametric method was used to compare carbon metabolism characteristics among the three groups of soil samples. Principal component analysis was used to distinguish soil chemical properties and carbon source utilization profiles among the soil samples across different seasons. Under rice cultivation, pH, organic matter, total nitrogen, and alkali-hydrolyzed nitrogen concentrations were generally higher in rhizosphere soils than in bulk or uncultivated soils. However, microbial biomass in cultivated soils was consistently lower than in uncultivated soils. There was a discernible difference in carbon substrate preference between summer and other seasons in the three sample groups. In conclusion, agricultural activities in rice cultivation could reshape soil microbial communities in the long term. Notably, specific cultivation activity may induce distinct soil microbial responses, which are more sensitive than chemical responses.

Apremilast exerts protective effects on stroke outcomes and blood-brain barrier (BBB) dysfunction through regulating Rho-associated protein kinase 2 expression.

AIMS: Stroke is a devastating event and a huge public health concern worldwide. Apremilast (APR) is a selective inhibitor of phosphodiesterase-4 involved in various neurological diseases, including stroke. However, the protective effects of APR on stroke have not been investigated. Here, we explored the effects of APR on stroke outcomes and blood-brain barrier (BBB) dysfunction using a middle cerebral artery occlusion (MCAO) stroke mice model. RESULTS: The results show that APR attenuated neurological injury in MCAO mice with decreased neurological deficit scores and infarct size, as well as increased hanging grip time. The increased BBB permeability and decreased expression of the tight junction protein Claudin-5 in MCAO mice were attenuated by APR treatment. APR treatment also mitigated neuroinflammation in MCAO mice, as shown by the decreased levels of inflammatory cytokines. In vitro assays also proved that APR ameliorated the oxygen/glucose deprivation/reoxygenation (OGD/R)-induced increase in endothelial permeability and restored the expression of Claudin-5 in bEnd.3 brain endothelial cells. Moreover, overexpression of ROCK2 in bEnd.3 cells abolished the protective effects of APR on endothelial permeability against OGD/R induction. CONCLUSION: Taken together, our results demonstrate that APR showed significant efficacy on ischemic stroke outcomes by alleviating enhanced BBB permeability and neuroinflammation by inhibiting ROCK2. These findings suggest a novel therapeutic window for ischemic stroke.

Protective effects of apple polyphenols on bone loss in mice with high fat diet-induced obesity.

Obesity-induced inflammation can lead to an imbalance in bone formation and resorption. Our previous studies have demonstrated that apple polyphenols (APs) can reduce body weight and inflammation. But their effect on bone is still unclear. In this study, we investigated the protective effects of APs on bone loss in mice with high-fat-diet (HFD)-induced obesity. Forty male C57BL/6J mice were divided into control group (10% fat diet), HFD group (60% fat diet), resveratrol group (60% fat diet), and AP group (60% fat diet). Micro-computed tomography revealed a significant increase in bone volume fraction and bone mineral density, and more trabecular bone and less trabecular bone separation in the AP group compared with the HFD group. In addition, serum tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), and tartrate-resistant acid phosphatase (TRACP) levels were decreased; runt-related transcription factor 2 (Runx2) levels were increased; the collagen area was enlarged; and femur biomechanical property was enhanced in the AP group compared with the HFD group. APs significantly increased the ratio of osteoprotegerin to the receptor activator for the nuclear factor-κB ligand (OPG/RANKL) compared with the HFD group. Resveratrol could also improve the glucolipid regulation, but poorer osteogenic promotion was found compared to APs. The present study demonstrated that APs prevent loss of bone mass induced by obesity, which has potential implications for the prevention and treatment of obesity-related osteoporosis.

Punicalagin Attenuates Neuronal Apoptosis by Upregulating 5-Hydroxymethylcytosine in the Diabetic Mouse Brain.

Punicalagin exerts neuroprotective activity by improving AMP-activated kinase (AMPK) and mitochondrial Krebs cycle. AMPK and Krebs cycle metabolites regulate 5-hydroxymethylcytosine (5hmC) via acting on ten-eleven translocation (TET) enzymes. Therefore, we hypothesized that punicalagin inhibits diabetes-related neuronal apoptosis by upregulating 5hmC in the diabetic mouse brain. C57BL/6J mice aged 8 weeks were randomly separated into five groups (n = 10), normal control (NC), diabetes mellitus (DM), resveratrol (RES), low-dose punicalagin (LPU), and high-dose punicalagin (HPU). Compared with other groups, the neuronal apoptosis rate was significantly higher and the 5hmC level of the cerebral cortex was significantly lower in the DM group. The levels of TET2 and P-AMPKα/AMPKα were significantly lower in the DM group than in both LPU and HPU groups. The ratio of (succinic acid + fumaric acid)/α-ketoglutarate was significantly higher in the DM group than in other groups. The present results suggest that punicalagin upregulates 5hmC via activating AMPK and maintaining Krebs cycle homeostasis, thus inhibiting neuronal apoptosis in the diabetic mouse brain.

Preventive Effect of Ellagic Acid on Cardiac Dysfunction in Diabetic Mice through Regulating DNA Hydroxymethylation.

Ellagic acid (EA) improves mitochondrial dysfunction and protects diabetic hearts. The mitochondrial tricarboxylic acid (TCA) cycle regulates DNA 5-hydroxymethylcytosine (5hmC) levels by affecting activity of 10-11 translocation enzymes (TETs). Therefore, we hypothesized that EA prevents diabetic cardiac dysfunction by modulating DNA 5hmC levels. C57BL/6J mice were fed a high-fat diet to induce diabetes and treated with EA (100 mg kg-1 day-1) for 8 weeks. Serum concentrations of glucose, insulin, and triglyceride and aspartate transaminase and creatine kinase activities were significantly lower in the EA group than the diabetes mellitus (DM) group. DNA 5hmC levels of mice hearts were significantly higher in the EA group than the DM group. The protein levels of TET, complexes I/III/V were significantly higher in the EA group than the DM group. The results shows that EA has a preventive effect on diabetic cardiac dysfunction, which may be achieved by upregulating TET activity through improving the TCA cycle, to reshape DNA 5hmC levels of mice hearts.

Punicalagin alleviates renal injury via the gut-kidney axis in high-fat diet-induced diabetic mice.

Diabetic renal injury was associated with dysbiosis of the gut microbiota and intestinal barrier. Punicalagin (PU) from pomegranates potentially impacts the microbial ecosystem, intestinal barrier, and renal function. Therefore, we hypothesized that PU may improve diabetic renal injury by modulating the gut-kidney axis. The present study evaluated the effect of PU on the gut-kidney axis and kidney function in a diabetic renal injury mouse model induced by a high-fat diet (HFD). Mice were fed a HFD without PU or with at doses of 50 and 100 mg kg-1 d-1 for 8 weeks. Targeted metabolomics by GC-MS and 16S rRNA sequencing were implemented to determine short-chain fatty acids (SCFAs) and microbes. Further RNA sequencing analyses were performed to determine which differentially expressed genes were changed by PU. Compared with the DM model group, PU supplementation improved diabetic renal injury, ameliorated kidney architecture and function, and reshaped gut microbial ecology. Additionally, PU reversed HFD-induced gut barrier dysfunction, promoted cecal SCFA concentrations and inhibited serum lipopolysaccharide (LPS) and diamine oxidase (DAO) levels. Moreover, correlation analysis found that cecal SCFAs were significantly negatively correlated with inflammation-related genes in the kidney. The present results indicated that PU, a promising bioactive polyphenol, successfully improved diabetic renal injury, most likely through the gut-kidney axis.

[Effects of Water Supply Quality and Social Activity on the Microbial Community in Baiyangdian Wetland].

To clarify the impact of water quality and social activity in the Baiyangdian wetland on the biological community, the change characteristics of bacterial, fungal, and archaeal communities in different areas of the Dian District were studied. Samples were collected at the entrance of Fuhe District (NBB), tourist areas with frequent human social activities (NBD), residential breeding areas (NBX), and village sparse areas (NBN). The physical and chemical characteristics and biological communities of the samples were evaluated. The results of the study show that the COD concentration of organic pollutants in the NBB was 12.35 mg·L-1, and the total nitrogen concentration was 10.12 mg·L-1, that the concentration was highest. Moreover, the water quality in NBD and NBX was better than that of NBB. The NBN area exhibited the best water quality, with COD and total nitrogen concentration values of 6.9 mg·L-1 and 1.82 mg·L-1, respectively. Many types of NBB bacteria were recorded, with a diversity index of 5.86, and NBN diversity index exceeding 4.78. The dominant bacterial flora in all samples was the Proteobacteria, which accounts for 68.8% of the total bacterial communities in NBN samples. The diversity index of fungi in NBB was only 2.14. There were many types of fungi in NBN, with a diversity index of 3.23. Chytridiomycota was found in the NBD and NBN, accounting for 5.4% and 9.8% of the total number of fungi, respectively. The Chytridiomycota was main decomposer of hard to degrade organic carbon. The diversity of archaea of NBN was the lowest among all the samples. Crenarchaeota was the dominant phylum, which accounts for 39.0%, 51.9%, 47.3%, and 30.1% of NBB, NBD, NBX, and NBN samples, respectively. The number of Halobacterota was lower than Crenarchaeota. The main factor of eutrophication and microbial community changes in Baiyangdian wetland was the results of the combined action of external and internal pollution. Both external and internal pollution increased the organic matter, nitrogen and phosphorus content in the water, and the microbial community structure has changed significantly. The contents of organic matter, nitrogen, and phosphorus in water were increased and the microbial community structures were changed significantly by the increase of both external and internal pollution.