Effects of feeding restriction on skeletal muscle development and functional analysis of TNNI1 in New Zealand white rabbits.

While restricting nutrition can improve diseases related to the digestive tract, excessive restriction of food intake can also lead to malnutrition and delayed physical growth. Therefore, this brings the demand to study the effect and potential mechanism of restricted feeding on skeletal muscle development in rabbits. This study utilized hematoxylin-eosin (HE) staining to detect muscle fiber area which depicted significant reduction in skeletal muscle fiber upon 30% feed restriction (p < 0.05). The control group and 30% feed restricted group showed 615 deferentially expressed genes (DEGs). Through the GO and KEGG functional enrichment analysis demonstrated 28 DEGs related to muscle development. KEGG analysis showed enrichment of pathways including PI3K/Akt signaling pathway, MAPK signaling pathway, and Hedgehog signaling pathway. Further, the full length of troponin I1, slow skeletal type (TNNI1) was cloned. We studied the expression of skeletal muscle differentiation-related genes such as MyoD, Myf5 gene and Desmin. Specifically, the TNNI1 gene overexpression and knockdown studies were conducted. The over-expression of TNNI1 significantly enhanced the expression of the skeletal muscle development-related genes. Contrastingly, the silencing of TNNI1 gene reduced the expression significantly. These findings showed that TNNI1 may be a regulator for regulating the expression of muscle development-related genes.

Increased Cerebral Level of P2X7R in a Tauopathy Mouse Model by PET Using [18F]GSK1482160.

Neuroinflammation plays an important role in Alzheimer's disease and primary tauopathies. The aim of the current study was to map [18F]GSK1482160 for imaging of purinergic P2X7R in Alzheimer's disease and primary tauopathy mouse models. Small animal PET was performed using [18F]GSK1482160 in widely used mouse models of Alzheimer's disease (APP/PS1, 5×FAD, and 3×Tg), 4-repeat tauopathy (rTg4510) mice, and age-matched wild-type mice. Increased uptake of [18F]GSK1482160 was observed in the brains of 7-month-old rTg4510 mice compared to wild-type mice and compared to 3-month-old rTg4510 mice. A positive correlation between hippocampal tau [18F]APN-1607 and [18F]GSK1482160 uptake was found in rTg4510 mice. No significant differences in the uptake of [18F]GSK1482160 was observed for APP/PS1 mice, 5×FAD mice, or 3×Tg mice. Immunofluorescence staining further indicated the distribution of P2X7Rs in the brains of 7-month-old rTg4510 mice with accumulation of tau inclusion. These findings provide in vivo imaging evidence for an increased level of P2X7R in the brains of tauopathy mice.

In vivo reactive astrocyte imaging using [18F]SMBT-1 in tauopathy and familial Alzheimer's disease mouse models: A multi-tracer study.

BACKGROUND: Reactive astrocytes play an important role in the development of Alzheimer's disease and primary tauopathies. Here, we aimed to investigate the relationships between reactive astrocytes. Microgliosis and glucose metabolism with Tau and amyloid beta pathology by using multi-tracer imaging in widely used tauopathy and familial Alzheimer's disease mouse models. RESULTS: Positron emission tomography imaging using [18F]PM-PBB3 (tau), [18F]florbetapir (amyloid-beta), [18F]SMBT-1 (monoamine oxidase-B), [18F]DPA-714 (translocator protein) and [18F]fluorodeoxyglucose was carried out in 3- and 7-month-old rTg4510 tau mice, 5 × FAD familial Alzheimer's disease mice and wild-type mice. Immunofluorescence staining was performed to validate the pathological distribution in the mouse brain after in vivo imaging. We found increased regional levels of [18F]PM-PBB3, [18F]SMBT-1, and [18F]DPA-714 and hypoglucose metabolism in the brains of 7-month-old rTg4510 mice compared to age-matched wild-type mice. Increased [18F]SMBT-1 uptake was observed in the brains of 3, 7-month-old 5 × FAD mice, with elevated regional [18F]florbetapir and [18F]DPA-714 uptakes in the brains of 7-month-old 5 × FAD mice, compared to age-matched wild-type mice. Positive correlations were shown between [18F]SMBT-1 and [18F]PM-PBB3, [18F]DPA-714 and [18F]PM-PBB3 in rTg4510 mice, and between [18F]florbetapir and [18F]DPA-714 SUVRs in 5 × FAD mice. CONCLUSION: In summary, these findings provide in vivo evidence that reactive astrocytes, microglial activation, and cerebral hypoglucose metabolism are associated with tau and amyloid pathology development in animal models of tauopathy and familial Alzheimer's disease.

Phosphatidylserine in the Nervous System: Cytoplasmic Regulator of the AKT and PKC Signaling Pathways and Extracellular "Eat-Me" Signal in Microglial Phagocytosis.

Phosphatidylserine (PtdSer) is an important anionic phospholipid found in eukaryotic cells and has been proven to serve as a beneficial factor in the treatment of neurodegenerative diseases. PtdSer resides in the inner leaflet of the plasma membrane, where it is involved in regulating the AKT and PKC signaling pathways; however, it becomes exposed to the extracellular leaflet during neurodevelopmental processes and neurodegenerative diseases, participating in microglia-mediated synaptic and neuronal phagocytosis. In this paper, we review several characteristics of PtdSer, including the synthesis and translocation of PtdSer, the functions of cytoplasmic and exposed PtdSer, and different PtdSer-detection materials used to further understand the role of PtdSer in the nervous system.

CRYAA and GJA8 promote visual development after whisker tactile deprivation.

Deprivation of one sense can be followed by enhanced development of other senses via cross-modal plasticity mechanisms. To study the effect of whisker tactile deprivation on vision during the early stages of development, we clipped the bilateral whiskers of young mice and found that their vision was impaired but later recovered to normal levels. Our results demonstrate that inhibition of the PI3K/AKT/ERK signaling pathway caused short-term visual impairment during early development, while high expression levels of Crystallin Alpha A (CRYAA) and Gap Junction Protein Alpha 8 (GJA8) in the retina led to the recovery of developmental visual acuity. Interestingly, analysis of single-cell sequencing results from human embryonic retinas at 9-19 gestational weeks (GW) revealed that CRYAA and GJA8 display stage-specific peak expression during human embryonic retinal development, suggesting potential functions in visual development. Our data show that high expression levels of CRYAA and GJA8 in the retina after whisker deprivation rescue impaired visual development, which may provide a foundation for further research on the mechanisms of cross-modal plasticity and in particular, offer new insights into the mechanisms underlying tactile-visual cross-modal development.

Atp11b Deletion Affects the Gut Microbiota and Accelerates Brain Aging in Mice.

The microbiota-gut-brain axis has attracted significant attention with respect to studying the mechanisms of brain aging; however, the specific connection between gut microbiota and aging remains unclear. The abnormal expression and mutation of proteins belonging to the P4-ATPase family, including Atp11b, results in a variety of neurological diseases. The results of our analysis demonstrate that there was a shift in the abundance of certain gut microbiota in Atp11b-knockout (KO) mice. Specifically, there was an increase in pro-inflammatory bacteria that accelerate aging and a decrease in probiotics that delay aging. Consequently, an enhanced oxidative stress response was observed, which was characterized by a reduction in the superoxide dismutase (SOD) activity and an increase in malondialdehyde (MDA) and reactive oxygen species (ROS) levels. In addition, our data demonstrate that there was a decrease in the number of cells in the dentate gyrus (DG) region of the hippocampus, and aggravation of aging-related pathological features such as senescence ß-galactosidase (SA-ß-Gal), p-HistoneH2AX (Ser139), and p16INK4. Moreover, KO mice show typical aging-associated behavior, such as memory impairment and slow pain perception. Taken together, we demonstrate a possible mechanism of aging induced by gut microbiota in Atp11b-KO mice, which provides a novel perspective for the treatment of aging through the microbiota-gut-brain axis.

Effects of Restricted Feeding on Growth Performance, Intestinal Immunity, and Skeletal Muscle Development in New Zealand Rabbits.

This study aimed to explore the effects of different feeding restriction levels on the growth performance, intestinal immunity, and skeletal muscle development of meat rabbits. Additionally, we studied whether complete compensatory growth could be obtained post 2 weeks of restricted feeding, in order to seek a scientific mode of feeding restriction. Each of three groups was exposed to 3 weeks of feeding restriction and 2 weeks of compensatory growth. The 15% feeding restriction showed a negligible effect on the final body-weight of the rabbits (p > 0.05), but significantly reduced the feed-to-weight ratio (p < 0.05); reduced diarrhea and mortality; and increased digestive enzyme activity and antioxidant capacity. However, a 30% feeding-restriction level substantially reduced the growth rate of the rabbits (p < 0.05), impaired skeletal muscle development, and showed no compensatory growth after 2 weeks of nutritional recovery. Additionally, immunoglobulin and antioxidant enzyme synthesis were impaired due to reduced nutritional levels, and levels of pro-inflammatory factors were increased during the compensation period. The IGF1 mRNA expression decreased significantly (p < 0.05), whereas MSTN and FOXO1 expression increased noticeably (p < 0.05). Moreover, protein levels of p-Akt and p-p70 decreased significantly in the 15% feeding restriction group. Overall, the 15% feeding limit unaffected the weight and skeletal muscle development of rabbits, whereas the 30% feeding limit affected the growth and development of skeletal muscle in growing rabbits. The PI3K/Akt signaling pathway is plausibly a mediator of this process.

The role of phosphatidylserine on the membrane in immunity and blood coagulation.

The negatively charged aminophospholipid, phosphatidylserine (PtdSer), is located in the inner leaflet of the plasma membrane in normal cells, and may be exposed to the outer leaflet under some immune and blood coagulation processes. Meanwhile, Ptdser exposed to apoptotic cells can be recognized and eliminated by various immune cells, whereas on the surface of activated platelets Ptdser interacts with coagulation factors prompting enhanced production of thrombin which significantly facilitates blood coagulation. In the case where PtdSer fails in exposure or mistakenly occurs, there are occurrences of certain immunological and haematological diseases, such as the Scott syndrome and Systemic lupus erythematosus. Besides, viruses (e.g., Human Immunodeficiency Virus (HIV), Ebola virus (EBOV)) can invade host cells through binding the exposed PtdSer. Most recently, the Corona Virus Disease 2019 (COVID-19) has been similarly linked to PtdSer or its receptors. Therefore, it is essential to comprehensively understand PtdSer and its functional characteristics. Therefore, this review summarizes Ptdser, its eversion mechanism; interaction mechanism, particularly with its immune receptors and coagulation factors; recognition sites; and its function in immune and blood processes. This review illustrates the potential aspects for the underlying pathogenic mechanism of PtdSer-related diseases, and the discovery of new therapeutic strategies as well.

MiR-4763-3p targeting RASD2as a Potential Biomarker and Therapeutic Target for Schizophrenia.

Existing diagnostic methods are limited to observing appearance and demeanor, even though genetic factors play important roles in the pathology of schizophrenia. Indeed, no molecular-level test exists to assist diagnosis, which has limited treatment strategies. To address this serious shortcoming, we used a bioinformatics approach to identify 61 genes that are differentially expressed in schizophrenia patients compared with healthy controls. In particular, competing endogenous RNA network revealed the important role of the gene RASD2, which is regulated by miR-4763-3p. Indeed, analysis of blood samples confirmed that RASD2 is downregulated in schizophrenia patients. Moreover, positron emission tomography data collected for 44 human samples identified the prefrontal and temporal lobes as potential key brain regions in schizophrenia patients. Mechanistic studies indicated that miR-4763-3p inhibits RASD2 by base-pairing with the 3' untranslated region of RASD2 mRNA. Importantly, RASD2 has been shown to interact with ß-arrestin2, which contributes to the regulation of the DRD2-dependent CREB response element-binding protein pathway in the dopamine system. Finally, results obtained with a mouse model of schizophrenia revealed that inhibition of miR-4763-3p function alleviated anxiety symptoms and improved memory. The dopamine transporters in the striatal regions were significantly reduced in schizophrenia model mice as compared with wild-type mice, suggesting that inhibition of miR-4763-3p can lessen the symptoms of schizophrenia. Our findings demonstrate that miR-4763-3p may target RASD2 mRNA and thus may serve as a potential biomarker and therapeutic target for schizophrenia, providing a theoretical foundation for further studies of the molecular basis of this disease.

Elucidating the Relationship Between Diabetes Mellitus and Parkinson's Disease Using 18F-FP-(+)-DTBZ, a Positron-Emission Tomography Probe for Vesicular Monoamine Transporter 2.

Diabetes mellitus (DM) and Parkinson's disease (PD) have been and will continue to be two common chronic diseases globally that are difficult to diagnose during the prodromal phase. Current molecular genetics, cell biological, and epidemiological evidences have shown the correlation between PD and DM. PD shares the same pathogenesis pathways and pathological factors with DM. In addition, ß-cell reduction, which can cause hyperglycemia, is a striking feature of DM. Recent studies indicated that hyperglycemia is highly relevant to the pathologic changes in PD. However, further correlation between DM and PD remains to be investigated. Intriguingly, polycystic monoamine transporter 2 (VMAT2), which is co-expressed in dopaminergic neurons and ß cells, is responsible for taking up dopamine into the presynaptic vesicles and can specifically bind to the ß cells. Furthermore, we have summarized the specific molecular and diagnostic functions of VMAT2 for the two diseases reported in this review. Therefore, VMAT2 can be applied as a target probe for positron emission tomography (PET) imaging to detect ß-cell and dopamine level changes, which can contribute to the diagnosis of DM and PD during the prodromal phase. Targeting VMAT2 with the molecular probe 18F-FP-(+)-DTBZ can be an entry point for the ß cell mass (BCM) changes in DM at the molecular level, to clarify the potential relationship between DM and PD. VMAT2 has promising clinical significance in investigating the pathogenesis, early diagnosis, and treatment evaluation of the two diseases.