Senescent-like macrophages mediate angiogenesis for endplate sclerosis via IL-10 secretion in male mice.

Endplate sclerosis is a notable aspect of spine degeneration or aging, but the mechanisms remain unclear. Here, we report that senescent macrophages accumulate in the sclerotic endplates of lumbar spine instability (LSI) or aging male mouse model. Specifically, knockout of cdkn2a (p16) in macrophages abrogates LSI or aging-induced angiogenesis and sclerosis in the endplates. Furthermore, both in vivo and in vitro studies indicate that IL-10 is the primary elevated cytokine of senescence-related secretory phenotype (SASP). Mechanistically, IL-10 increases pSTAT3 in endothelial cells, leading to pSTAT3 directly binding to the promoters of Vegfa, Mmp2, and Pdgfb to encourage their production, resulting in angiogenesis. This study provides information on understanding the link between immune senescence and endplate sclerosis, which might be useful for therapeutic approaches.

Prenatal progesterone treatment modulates fetal brain transcriptome and impacts adult offspring behavior in mice.

Maternal exposure to elevated levels of steroid hormones during pregnancy is associated with the development of chronic conditions in offspring that manifest in adulthood. However, the effects of progesterone (P4) administration during early pregnancy on fetal development and subsequent offspring behavior remain poorly understood. In this study, we aimed to investigate the effects of P4 treatment during early pregnancy on the transcript abundance in the fetal brain and assess the behavioral consequences in the offspring during adolescence and adulthood. Using RNA-seq analysis, we examined the impact of P4 treatment on the fetal brain transcriptome in a dosage-dependent manner. Our results revealed differential regulation of genes involved in neurotransmitter transport, synaptic transmission, and transcriptional regulation. Specifically, we observed bidirectional regulation of transcription factors (TFs) by P4 at different doses, highlighting the critical role of these TFs in neurodevelopment. To assess behavioral outcomes, we conducted open field and elevated plus maze tests. Offspring treated with low-dose P4 (LP4) displayed increased exploratory behavior during both adolescence and adulthood. In contrast, the high-dose P4 (HP4) group exhibited impaired exploration and heightened anxiety-like behaviors compared to the control mice. Moreover, in a novel object recognition test, HP4-treated offspring demonstrated impaired object recognition memory during both developmental stages. Additionally, both LP4 and HP4 groups showed reduced social interaction in the three-chamber test. These results suggest that prenatal exposure to P4 exerts a notable influence on the expression of genes associated with neurodevelopment and may induce alterations in behavioral characteristics in progeny, highlighting the need to monitor progesterone levels during pregnancy for long-term impacts on fetal brain development and behavior.

Potential Application Prospects of Biomolecule-Modified Two-Dimensional Chiral Nanomaterials in Biomedicine.

Chirality, one of the most fundamental properties of natural molecules, plays a significant role in biochemical reactions. Nanomaterials with chiral characteristics have superior properties, such as catalytic properties, optoelectronic properties, and photothermal properties, which have significant potential for specific applications in nanomedicine. Biomolecular modifications such as nucleic acids, peptides, proteins, and polysaccharides are sources of chirality for nanomaterials with great potential for application in addition to intrinsic chirality, artificial macromolecules, and metals. Two-dimensional (2D) nanomaterials, as opposed to other dimensions, due to proper surface area, extensive modification sites, drug loading potential, and simplicity of preparation, are prepared and utilized in diagnostic applications, drug delivery research, and tumor therapy. Current advanced studies on 2D chiral nanomaterials for biomedicine are focused on novel chiral development, structural control, and materials sustainability applications. However, despite the advances in biomedical research, chiral 2D nanomaterials still confront challenges such as the difficulty of synthesis, quality control, batch preparation, chiral stability, and chiral recognition and selectivity. This review aims to provide a comprehensive overview of the origins, synthesis, applications, and challenges of 2D chiral nanomaterials with biomolecules as cargo and chiral modifications and highlight their potential roles in biomedicine.

Deficiency of Acetyltransferase nat10 in Zebrafish Causes Developmental Defects in the Visual Function.

Purpose: N4-acetylcytidine (ac4C) is a post-transcriptional RNA modification catalyzed by N-acetyltransferase 10 (NAT10), a critical factor known to influence mRNA stability. However, the role of ac4C in visual development remains unexplored. Methods: Analysis of public datasets and immunohistochemical staining were conducted to assess the expression pattern of nat10 in zebrafish. We used CRISPR/Cas9 and RNAi technologies to knockout (KO) and knockdown (KD) nat10, the zebrafish ortholog of human NAT10, and evaluated its effects on early development. To assess the impact of nat10 knockdown on visual function, we performed comprehensive histological evaluations and behavioral analyses. Transcriptome profiling and real-time (RT)-PCR were utilized to detect alterations in gene expression resulting from the nat10 knockdown. Dot-blot and RNA immunoprecipitation (RIP)-PCR analyses were conducted to verify changes in ac4C levels in both total RNA and opsin mRNA specifically. Additionally, we used the actinomycin D assay to examine the stability of opsin mRNA following the nat10 KD. Results: Our study found that the zebrafish NAT10 protein shares similar structural properties with its human counterpart. We observed that the nat10 gene was prominently expressed in the visual system during early zebrafish development. A deficiency of nat10 in zebrafish embryos resulted in increased mortality and developmental abnormalities. Behavioral and histological assessments indicated significant vision impairment in nat10 KD zebrafish. Transcriptomic analysis and RT-PCR identified substantial downregulation of retinal transcripts related to phototransduction, light response, photoreceptors, and visual perception in the nat10 KD group. Dot-blot and RIP-PCR analyses confirmed a pronounced reduction in ac4C levels in both total RNA and specifically in opsin messenger RNA (mRNA). Additionally, by evaluating mRNA decay in zebrafish treated with actinomycin D, we observed a significant decrease in the stability of opsin mRNA in the nat10 KD group. Conclusions: The ac4C-mediated mRNA modification plays an essential role in maintaining visual development and retinal function. The loss of NAT10-mediated ac4C modification results in significant disruptions to these processes, underlining the importance of this RNA modification in ocular development.

Astrocyte-derived lactoferrin reduces ß-amyloid burden by promoting the interaction between p38 kinase and PP2A phosphatase in male APP/PS1 transgenic mice.

BACKGROUND AND PURPOSE: Overexpression of astrocytic lactoferrin (Lf) was observed in the brain of Alzheimer's disease (AD) patients, whereas the role of astrocytic Lf in AD progression remains unexplored. In this study, we aimed to evaluate the effects of astrocytic Lf on AD progression. EXPERIMENTAL APPROACH: Male APP/PS1 mice with astrocytes overexpressing human Lf were developed to evaluate the effects of astrocytic Lf on AD progression. N2a-sw cells also were employed to further uncover the mechanism of astrocytic Lf on ß-amyloid (Aß) production. KEY RESULTS: Astrocytic Lf overexpression increased protein phosphatase 2A (PP2A) activity and reduced amyloid precursor protein (APP) phosphorylation, Aß burden and tau hyperphosphorylation in APP/PS1 mice. Mechanistically, astrocytic Lf overexpression promoted the uptake of astrocytic Lf into neurons in APP/PS1 mice, and conditional medium from astrocytes overexpressing Lf inhibited p-APP (Thr668) expression in N2a-sw cells. Furthermore, recombinant human Lf (hLf) significantly enhanced PP2A activity and inhibited p-APP expression, whereas inhibition of p38 or PP2A activities abrogated the hLf-induced p-APP down-regulation in N2a-sw cells. Additionally, hLf promoted the interaction of p38 and PP2A via p38 activation, thereby enhancing PP2A activity, and low-density lipoprotein receptor-related protein 1 (LRP1) knockdown significantly reversed the hLf-induced p38 activation and p-APP down-regulation. CONCLUSIONS AND IMPLICATIONS: Our data suggested that astrocytic Lf promoted neuronal p38 activation, via targeting to LRP1, subsequently promoting p38 binding to PP2A to enhance PP2A enzyme activity, which finally inhibited Aß production via APP dephosphorylation. In conclusion, promoting astrocytic Lf expression may be a potential strategy against AD. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

From zinc homeostasis to disease progression: Unveiling the neurodegenerative puzzle.

Zinc is a crucial trace element in the human body, playing a role in various physiological processes such as oxidative stress, neurotransmission, protein synthesis, and DNA repair. The zinc transporters (ZnTs) family members are responsible for exporting intracellular zinc, while Zrt- and Irt-like proteins (ZIPs) are involved in importing extracellular zinc. These processes are essential for maintaining cellular zinc homeostasis. Imbalances in zinc metabolism have been linked to the development of neurodegenerative diseases. Disruptions in zinc levels can impact the survival and activity of neurons, thereby contributing to the progression of neurodegenerative diseases through mechanisms like cell apoptosis regulation, protein phase separation, ferroptosis, oxidative stress, and neuroinflammation. Therefore, conducting a systematic review of the regulatory network of zinc and investigating the relationship between zinc dysmetabolism and neurodegenerative diseases can enhance our understanding of the pathogenesis of these diseases. Additionally, it may offer new insights and approaches for the treatment of neurodegenerative diseases.

Graphdiyne nanoplatforms for photothermal-ferroptosis combination therapy against glioblastoma.

Glioblastoma (GBM) is one of the most malignant tumors of the central nervous system and has a poor prognosis. GBM cells are highly sensitive to ferroptosis and heat, suggesting thermotherapy-ferroptosis as a new strategy for GBM treatment. With its biocompatibility and photothermal conversion efficiency, graphdiyne (GDY) has become a high-profile nanomaterial. Here, the ferroptosis inducer FIN56 was employed to construct GDY-FIN56-RAP (GFR) polymer self-assembled nanoplatforms against GBM. GDY could effectively load FIN56 and FIN56 released from GFR in a pH-dependent manner. The GFR nanoplatforms possessed the advantages of penetrating the BBB and acidic environment-induced in situ FIN56 release. Moreover, GFR nanoplatforms induced GBM cell ferroptosis by inhibiting GPX4 expression, and 808 nm irradiation reinforced GFR-mediated ferroptosis by elevating the temperature and promoting FIN56 release from GFR. In addition, the GFR nanoplatforms were inclined to locate in tumor tissue, inhibit GBM growth, and prolong lifespan by inducing GPX4-mediated ferroptosis in an orthotopic xenograft mouse model of GBM; meanwhile, 808 nm irradiation further improved these GFR-mediated effects. Hence, GFR may be a potential nanomedicine for cancer therapy, and GFR combined with photothermal therapy may be a promising strategy against GBM.

Secreted endogenous macrosomes reduce Aß burden and ameliorate Alzheimer's disease.

Innovative therapeutic strategies are urgently needed for Alzheimer's disease (AD) due to the increasing size of the aging population and the lack of effective drug treatment. Here, we report the therapeutic effects of extracellular vesicles (EVs) secreted by microglia, including macrosomes and small EVs, on AD-associated pathology. Macrosomes strongly inhibited ß-amyloid (Aß) aggregation and rescued cells from Aß misfolding-induced cytotoxicity. Furthermore, macrosome administration reduced Aß plaques and ameliorated cognitive impairment in mice with AD. In contrast, small EVs slightly promoted Aß aggregation and did not improve AD pathology. Proteomic analysis of small EVs and macrosomes revealed that macrosomes harbor several important neuroprotective proteins that inhibit Aß misfolding. In particular, the small integral membrane protein 10-like protein 2B in macrosomes has been shown to inhibit Aß aggregation. Our observations provide an alternative therapeutic strategy for the treatment of AD over conventional ineffective drug treatments.

The metal ion hypothesis of Alzheimer's disease and the anti-neuroinflammatory effect of metal chelators.

Alzheimer's disease (AD), characterized by the ß-amyloid protein (Aß) deposition and tau hyperphosphorylation, is the most common dementia with uncertain etiology. The clinical trials of Aß monoclonal antibody drugs have almost failed, giving rise to great attention on the other etiologic hypothesis regarding AD such as metal ions dysmetabolism and chronic neuroinflammation. Mounting evidence revealed that the metal ions (iron, copper, and zinc) were dysregulated in the susceptible brain regions of AD patients, which was highly associated with Aß deposition, tau hyperphosphorylation, neuronal loss, as well as neuroinflammation. Further studies uncovered that iron, copper and zinc could not only enhance the production of Aß but also directly bind to Aß and tau to promote their aggregations. In addition, the accumulation of iron and copper could respectively promote ferroptosis and cuproptosis. Therefore, the metal ion chelators were recognized as promising agents for treating AD. This review comprehensively summarized the effects of metal ions on the Aß dynamics and tau phosphorylation in the progression of AD. Furthermore, taking chronic neuroinflammation contributes to the progression of AD, we also provided a summary of the mechanisms concerning metal ions on neuroinflammation and highlighted the metal ion chelators may be potential agents to alleviate neuroinflammation under the condition of AD. Nevertheless, more investigations regarding metal ions on neuroinflammation should be taken into practice, and the effects of metal ion chelators on neuroinflammation should gain more attention. Running title: Metal chelators against neuroinflammation.

Energy Crisis Links to Autophagy and Ferroptosis in Alzheimer's Disease: Current Evidence and Future Avenues.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases worldwide. The occult nature of the onset and the uncertainty of the etiology largely impede the development of therapeutic strategies for AD. Previous studies revealed that the disorder of energy metabolism in the brains of AD patients appears far earlier than the typical pathological features of AD, suggesting a tight association between energy crisis and the onset of AD. Energy crisis in the brain is known to be induced by the reductions in glucose uptake and utilization, which may be ascribed to the diminished expressions of cerebral glucose transporters (GLUTs), insulin resistance, mitochondrial dysfunctions, and lactate dysmetabolism. Notably, the energy sensors such as peroxisome proliferators-activated receptor (PPAR), transcription factor EB (TFEB), and AMP-activated protein kinase (AMPK) were shown to be the critical regulators of autophagy, which play important roles in regulating beta-amyloid (Aß) metabolism, tau phosphorylation, neuroinflammation, iron dynamics, as well as ferroptosis. In this study, we summarized the current knowledge on the molecular mechanisms involved in the energy dysmetabolism of AD and discussed the interplays existing between energy crisis, autophagy, and ferroptosis. In addition, we highlighted the potential network in which autophagy may serve as a bridge between energy crisis and ferroptosis in the progression of AD. A deeper understanding of the relationship between energy dysmetabolism and AD may provide new insight into developing strategies for treating AD; meanwhile, the energy crisis in the progression of AD should gain more attention.

Alteration of m6A epitranscriptomic tagging of ribonucleic acids after spinal cord injury in mice.

The m6A methylation is reported to function in multiple physiological and pathological processes. However, the functional relevance of m6A modification to post-spinal cord injured (SCI) damage is not yet clear. In the present study, methylated RNA immunoprecipitation combined with microarray analysis showed that the global RNA m6A levels were decreased following SCI. Then, gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analyses were conducted to demonstrate the potential function of differential m6A-tagged transcripts and the altered transcripts with differential m6A levels. In addition, we found that the m6A "writer," METTL3, significantly decreased after SCI in mice. The immunostaining validated that the expression of METTL3 mainly changed in GFAP or Iba-1+ cells. Together, this study shows the alteration of m6A modification following SCI in mice, which might contribute to the pathophysiology of the spinal cord after trauma.

Novel melatonin-trientine conjugate as potential therapeutic agents for Alzheimer's disease.

Researchers continue to explore drug targets to treat the characteristic pathologies of Alzheimer's disease (AD). Some drugs relieve the pathological processes of AD to some extent, but the failed clinical trials indicate that multifunctional agents seem more likely to achieve the therapy goals for this neurodegenerative disease. Herein, a novel compound named melatonin-trientine (TM) has been covalently synthesized with the natural antioxidant compounds melatonin and the metal ion chelator trientine. After toxicological and pharmacokinetic verification, we elucidated the effects of intraperitoneal administration of TM on AD-like pathology in 6-month-old mice that express both the ß-amyloid (Aß) precursor protein and presenilin-1 (APP/PS1). We found that TM significantly decreased Aß deposition and neuronal degeneration in the brains of the APP/PS1 double transgenic mice. This result may be due to the upregulation of iron regulatory protein-2 (IRP2), insulin degrading enzyme (IDE), and low density lipoprotein receptor related protein 1 (LRP1), which leads to decreases in APP and Aß levels. Additionally, TM may promote APP non-amyloidogenic processing by activating the melatonin receptor-2 (MT2)-dependent signaling pathways, but not MT1. In addition, TM plays an important role in blocking γ-secretase, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal ion dyshomeostasis. Our results suggest that TM may effectively maximize the therapeutic efficacy of targeting multiple mechanisms associated with AD pathology.

Astrocyte-specific loss of lactoferrin influences neuronal structure and function by interfering with cholesterol synthesis.

Growing evidence indicates that circulating lactoferrin (Lf) is implicated in peripheral cholesterol metabolism disorders. It has emerged that the distribution of Lf changes in astrocytes of aging brains and those exhibiting neurodegeneration; however, its physiological and/or pathological role remains unknown. Here, we demonstrate that astrocyte-specific knockout of Lf (designated cKO) led to decreased body weight and cognitive abnormalities during early life in mice. Accordingly, there was a reduction in neuronal outgrowth and synaptic structure in cKO mice. Importantly, Lf deficiency in the primary astrocytes led to decreased sterol regulatory element binding protein 2 (Srebp2) activation and cholesterol production, and cholesterol content in cKO mice and/or in astrocytes was restored by exogenous Lf or a Srebp2 agonist. Moreover, neuronal dendritic complexity and total dendritic length were decreased after culture with the culture medium of the primary astrocytes derived from cKO mice and that this decrease was reversed after cholesterol supplementation. Alternatively, these alterations were associated with an activation of AMP-activated protein kinase (AMPK) and inhibition of SREBP2 nuclear translocation. These data suggest that astrocytic Lf might directly or indirectly control in situ cholesterol synthesis, which may be implicated in neurodevelopment and several neurological diseases.

The preliminary outcomes of vertebral body tethering in treating adolescent idiopathic scoliosis: a systematic review.

PURPOSE: VBT is a novel alternative to spinal fusion surgery to treat skeletally immature AIS and was approved to correct idiopathic scoliosis in August 2019 by US Federal Drug Administration (FDA). To systemically review the preliminary outcomes of vertebral body tethering (VBT) in treating adolescent idiopathic scoliosis. METHODS: The electronic databases PubMed, EMBASE, and Web of Science were queried up to January 2022 for articles regarding VBT. Basic characteristics of patients, changes of radiographic parameters in coronal and sagittal planes, and clinical outcomes of surgical treatment of VBT including complication and revision rates were summarized. RESULTS: Twenty five studies met the inclusion criteria. Most studies (23/25) included patients with only skeletal immaturity. The average % correction of the main/tethered curve at final follow-up, and % correction of thoracic kyphosis at final follow-up were reported to be 15.6-106.5% and - 31.8 to 20.0%, respectively. The most common complications for VBT were tether breakage (n = 145;21.3%), pulmonary complications (n = 49; 6.9%), and overcorrection (n = 30; 4.2%). The revision rate was 13.1%. CONCLUSION: VBT could effectively and safely correct spinal deformity in skeletally immature patients with AIS and preserve the motion and growth of the spine. However, VBT has a relatively high complication and revision rates. Therefore, surgeons should cautiously consider VBT for treating AIS. Future research efforts are needed to lower the complication and revision rates. Whatever, VBT is still in its infancy and may have a promising future as a non-fusion solution for AIS.

Co-exposure of polystyrene microplastics and iron aggravates cognitive decline in aging mice via ferroptosis induction.

The objective of this study was to investigate the effects of co-exposure of iron and microplastics (MPs) on the cognitive function of aged humans and animals. It was already known that individual iron or MPs exposure can initiate potential neurotoxicity. However, the combined effect of MPs and iron remained to be elucidated. In this study, the toxicity of iron, MPs, co-treatment of MPs & iron, and the underlying mechanisms were evaluated in vivo. Our findings suggest that 5 µm MPs could enter the aging mice brain and accumulate in cortex and hippocampus. In addition, MPs and iron have a good binding ability, therefore, co-exposure of MPs & iron cause significant iron overload and cognitive deficits as compared to control and individual treatments of iron and MPs. Moreover, the lipid peroxidation and inflammation, which are involved in ferroptosis, get significantly elevated by co-exposure of iron and MPs. Taken together, our results provide compelling evidence that co-exposure of iron and MPs could aggravate the cognitive impairment via disturbing brain iron homeostasis and inducing ferroptosis in cognitive-related brain areas, what's more, the results warn that MPs may act as vectors of pollutants (mostly heavy metals) increasing the health burden on body.

Association between Healthy Eating Index-2015 total and component food scores with osteoporosis in middle-aged and older Americans: a cross-sectional study with U.S. National Health and Nutrition Examination Survey.

We used NHANES data to explore the association between dietary quality estimated by the HEI-2015 and osteoporosis in middle-aged and elderly US adults. We found that higher dietary quality is significantly associated with a reduced risk of osteoporosis among middle-aged and elderly Americans. INTRODUCTION: Through this research, we assess whether increasing the overall dietary quality reduces the risk of osteoporosis. METHODS: For our analyses, we combined data collected from four NHANES 2-year cycles (2007-2008, 2009-2010, 2013-2014, and 2017-2018), including 10,033 participants. Associations between osteoporosis and HEI-2015 total/component scores among middle-aged and elderly adults were examined using logistic regression models. Osteoporosis was defined as femur neck BMD values equal to or less than 2.5 standard deviations (SDs) below the mean of the young adult reference group, and dietary intake data were obtained from two NHANES 24-h recall interviews. RESULTS: After multivariable adjustment, middle-aged and elderly populations with quintile 4 (OR: 0.54, 95% CI 0.34, 0.84; P = 0.007) and quintile 5 HEI-2015 total scores (OR: 0.43, 95% CI 0.26, 0.70; P = 0.001) were associated with reduced odds of osteoporosis compared with quintile 1. Higher intake of total vegetables, greens and beans, total fruits, whole fruits, and whole grains was associated with decreased odds of osteoporosis among elderly adults. Surprisingly, saturated fat intake can also protect against osteoporosis. CONCLUSION: Higher dietary quality estimated from HEI-2015 total and component food scores was significantly associated with a reduced risk of osteoporosis among the middle-aged and elderly Americans participating in NHANES included in this study.

Associations of Copper Intake with Bone Mineral Density and Osteoporosis in Adults: Data from the National Health and Nutrition Examination Survey.

Some studies have suggested an association between serum copper and bone density. Few studies have explored the association between copper intake and osteoporosis and bone mineral density (BMD). Our research aims to assess the associations of copper intake with the risk of osteoporosis in United States adults using the National Health and Nutritional Examination Surveys (NHANES). A total of 8224 individuals were included in our study. Osteoporosis was defined that BMD values surpass 2.5 standard deviations (SD) below the mean of the young adult reference group. Copper intake from diets and supplements was estimated by using two 24-h recall surveys. After adjustment for all the covariates of interest, the odds ratios (ORs) (95% confidence interval (CI)) between the risk of osteoporosis and total copper intake across quartiles 3 and 4 compared with quartile 1 were 0.48 (0.31-0.74) (P < 0.01) and 0.41 (0.26-0.65) (P < 0.01), respectively. The mean total femur BMD and total spine BMD of the highest dietary copper intake quartile (Cu 1.51 mg/d) was 0.03 g/cm2 and 0.02 g/cm2 greater than the lowest quartile. Our results indicate that dietary and total copper intake was positively associated with increasing BMD in US adults and negatively associated with the risk of osteoporosis in US adults.

Activation of vitamin D receptor inhibits Tau phosphorylation is associated with reduction of iron accumulation in APP/PS1 transgenic mice.

Vitamin D deficiency and iron accumulation are prevalent in the brains of Alzheimer's disease (AD) patients, however, whether Vitamin D has a role in the regulations of iron metabolism in the condition of AD remains unknown. Our previous studies revealed that vitamin D deficiency promotes ß-amyloid (Aß) deposition in the APP/PS1 mouse brains, while supplemented with a specific agonist of vitamin D receptor (VDR), paricalcitol (PAL), significantly reduced Aß production via promoting the lysosomal degradation of ß-site APP cleavage enzyme 1 (BACE1). In this study, our data suggested that activation of VDR by PAL significantly reduced the iron accumulation in the cortex and hippocampus of APP/PS1 mice through downregulation of Transferrin receptor (TFR) by reducing iron-regulatory protein 2 (IRP2) expression. Furthermore, activation of VDR effectively reduced the phosphorylations of Tau at Ser396 and Thr181 sites via inhibiting the GSK3ß phosphorylation (Tyr216). Taken together, our data suggest that activation of VDR could inhibit the phosphorylations of Tau possibly by repressing the iron accumulation-induced upregulation of GSK3ß activity in the brains of APP/PS1 mice. Thus, activation of VDR may be an effective strategy for treating AD.

Invaginated duct to mucosa pancreaticojejunostomy reduce postoperative pancreatic leakage: A matched case-controlled study.

ABSTRACT: Postoperative pancreatic leakage is an obstacle in pancreaticoduodenectomy, which always follows pancreaticojejunostomy (PJ) failure. Dozens of PJ procedures have been reported, and none have shown superiority over others. Therefore, the present study is conducted to assess the potential advantages of invaginated duct-to-mucosa (D-M) PJ.We retrospectively analyze the related data from patients who underwent pancreaticodedunostomy due to malignant tumors at the First Affiliated Hospital of Henan University of Science and Technology from January 2017 to August 2019. According to the different PJ procedures, the patients are divided into custom D-M group and invaginated D-M group. Matching by sex, age, pancreatic duct size, and pancreatic texture is performed. Pancreatic leakage and other complications are compared, and SPSS 16.0 is employed for analysis.A total of 48 pairs of patients are included. Patients in both groups has almost the same baseline characteristics in terms of sex (P = 1.000), age (P = .897), American Society of Anesthesiologists status (P = .575), body mass index (P = .873), pancreatic duct size (P = .932), pancreatic texture (P = 1.000) and tumor origin (P = .686). No significant difference is observed in operative outcomes, such as operative duration (P = .632), PJ duration (P = .748), blood loss (P = .617) and number of required transfusions (P = .523). Pancreatic leakage is significantly decreased in the invaginated D-M group (P = .005). The differences in other complications, such as bleeding (P = .617), biliary leakage (P = .646), pneumonia (P = .594) and thrombosis (P = .714), do not reach statistical significance. The postoperative hospitalization duration is almost the same for both groups (P = .764).Invaginated D-M PJ may reduce pancreatic leakage following pancreaticoduodenectomy.