Plakophilin 1 in carcinogenesis.

Plakophilin 1 (PKP1) belongs to the desmosome family as an anchoring junction protein in cellular junctions. It localizes at the interface of the cell membrane and cytoplasm. Although PKP1 is a non-transmembrane protein, it may become associated with the cell membrane via transmembrane proteins such as desmocollins and desmogleins. Homozygous deletion of PKP1 results in ectodermal dysplasia-skin fragility syndrome (EDSF) and complete knockout of PKP1 in mice produces comparable symptoms to EDSF in humans, although mice do not survive more than 24 h. PKP1 is not limited to expression in desmosomal structures, but is rather widely expressed in cytoplasm and nucleus, where it assumes important cellular functions. This review will summarize distinct roles of PKP1 in the cell membrane, cytoplasm, and nucleus with an overview of relevant studies on its function in diverse types of cancer.

Lanthanum hydroxide protects kidney through gut microbiota in a rat model of chronic kidney disease.

The progression of chronic kidney diseases (CKD) is complex, influenced by a myriad of factors including gut microbiota. While emerging evidence suggests that gut microbiota can have beneficial effects in managing CKD, it is also recognized that dysbiosis may contribute to the progression of CKD and associated uremic complications. Our previous research has demonstrated the efficacy of lanthanum hydroxide in delaying kidney failure and preserving renal function. However, the role of lanthanum hydroxide in modulating gut microbiota in this context remains unclear. In our study, we induced CKD in rats using adenine, leading to gut microbial dysbiosis, kidney pathology, and disturbances in amino acid metabolism. In this adenine-induced CKD model with hyperphosphatemia, treatment with lanthanum hydroxide improved renal function. This improvement was associated with the restoration of gut microbial balance and an increase in urine ammonium metabolism. These results suggest that the therapeutic potential of lanthanum hydroxide in CKD may be partly due to its ability to reshape gut microbiota composition. This study underscores the significance of lanthanum hydroxide in kidney protection, attributing its benefits to the modulation of gut microbiota in a rat model of CKD.

Brucine D restrains colorectal cancer tumorigenesis and autophagy by downregulating circ_0068464.

Bruceine D (BD) from Brucea javanica (L) exerts an antitumor effect in several human cancers. At present, it has not been reported whether BD inhibits the malignancy of colorectal cancer (CRC) cells. Therefore, investigating the role and regulatory mechanisms of BD in CRC is the main thrust of this study. Effect of BD on CRC cell viability, proliferation, apoptosis, invasion, and autophagy was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide, 5-ethynyl-2'-deoxyuridine, flow cytometry, transwell invasion, and western blotting assays. Expression changes of has_circ_0068464 (circ_0068464) were detected using real time quantitative polymerase chain reaction. The molecular mechanisms related to circ_0068464 were predicted through online prediction websites Starbase 2.0, circinteractome, and CircBank and validated using dual-luciferase reporter and RNA pull-down assays. The tumorigenic ability of BD and circ_0068464 on CRC was confirmed by xenograft experiments. The results showed that BD lessened CRC cell proliferation, invasion, autophagy, and prompted cell apoptosis. Circ_0068464 was overexpressed in CRC samples and cells. BD led to a significant reduction in circ_0068464 levels in cells of this carcinoma, but circ_0068464 overexpression partially rescued these effects urged by BD. Also, the combination of BD and circ_0068464 silencing decreased xenograft tumor growth compared to BD alone. Importantly, circ_0068464 could regulate ATG5 expression by functioning as a miR-520h molecular sponge. In conclusion, BD might suppress CRC growth by inhibiting the circ_0068464/miR-520h/ATG5 axis, providing a new perspective for the molecular pathogenesis of CRC and preliminarily indicating that BD may be a promising drug for CRC treatment.

Saliva Analysis Based on Microfluidics: Focusing the Wide Spectrum of Target Analyte.

Saliva is one of the most critical human body fluids that can reflect the state of the human body. The detection of saliva is of great significance for disease diagnosis and health monitoring. Microfluidics, characterized by microscale size and high integration, is an ideal platform for the development of rapid and low-cost disease diagnostic techniques and devices. Microfluidic-based saliva testing methods have aroused considerable interest due to the increasing need for noninvasive testing and frequent or long-term testing. This review briefly described the significance of saliva analysis and generally classified the targets in saliva detection into pathogenic microorganisms, inorganic substances, and organic substances. By using this classification as a benchmark, the state-of-the-art research results on microfluidic detection of various substances in saliva were summarized. This work also put forward the challenges and future development directions of microfluidic detection methods for saliva.

Advances in NIR-Responsive Natural Macromolecular Hydrogel Assembly Drugs for Cancer Treatment.

Cancer is a serious disease with an abnormal proliferation of organ tissues; it is characterized by malignant infiltration and growth that affects human life. Traditional cancer therapies such as resection, radiotherapy and chemotherapy have a low cure rate and often cause irreversible damage to the body. In recent years, since the traditional treatment of cancer is still very far from perfect, researchers have begun to focus on non-invasive near-infrared (NIR)-responsive natural macromolecular hydrogel assembly drugs (NIR-NMHADs). Due to their unique biocompatibility and extremely high drug encapsulation, coupling with the spatiotemporal controllability of NIR, synergistic photothermal therapy (PTT), photothermal therapy (PDT), chemotherapy (CT) and immunotherapy (IT) has created excellent effects and good prospects for cancer treatment. In addition, some emerging bioengineering technologies can also improve the effectiveness of drug delivery systems. This review will discuss the properties of NIR light, the NIR-functional hydrogels commonly used in current research, the cancer therapy corresponding to the materials encapsulated in them and the bioengineering technology that can assist drug delivery systems. The review provides a constructive reference for the optimization of NIR-NMHAD experimental ideas and its application to human body.

Lanthanum Hydroxide and Chronic Kidney Disease Mineral and Bone Disorder: A Rat Model.

OBJECTIVE: To investigate the pharmacological effects and molecular mechanisms of lanthanum hydroxide(LH) on ectopic mineralization of soft tissue and abnormal bone in rats with acute kidney injury(AKI). METHODS: Wistar rats were modeled by 5/6 nephrectomy. After the operation, the rats were divided into different groups, the biochemical indexes of serum collected at different times. Lanthanum hydroxide was administered by intragastric tube at doses of 0.4, 0.2, and 0.1g/kg, respectively. Rats were sacrificed in the 16th week after LH treatment. Observation of pathological changes in tissues were made by specific staining. Western Blot, Real-Time Quantitative PCR, and immunohistochemistry techniques were used to detect the impact on pathway-related proteins. RESULTS: Compared with the control group (no LH administered), the serum phosphate level of the LH group was significantly reduced (P<0.01), calcification of the thoracic aorta was reduced (P<0.05, P<0.01) (Serum biochemical tests before dosing and during drug treatment cycles), renal fibrosis was improved (P<0.01), nuclear entry of nuclear factor kappa-B (NF-κB) was reduced (P<0.01), and the expression of the smooth muscle protein 22α (SM22α) was significantly increased (P<0.01). The expression of osteogenic marker genes was decreased. In addition, compared with the controls, the receptor activator for nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) ratio of the femur in the model group was increased (P<0.05). CONCLUSION: LH can inhibit the occurrence and development of vascular calcification and bone abnormalities in AKI rats by inhibiting the NF-κB and RANKL/OPG signaling pathways.

S1PR2 Regulates Autophagy Through the AKT/mTOR Pathway to Promote Pathological Damage in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a fatal and debilitating neurodegenerative disease. Sphingosine-1-phosphate receptor 2 (S1PR2), one of the receptors of S1P, is a key regulatory factor for various diseases. OBJECTIVE: This study aimed to explore the role and possible mechanism of S1PR2 in AD. METHODS: S1PR2 expression in the AD mice was detected, and after intervening S1PR2 expression with sh-S1PR2 in AD mice, the behavioral changes, pathological lesions of the hippocampus, autophagy level, and AKT/mTOR pathway activation were analyzed. Furthermore, SH-SY5Y cells were induced by Aß25-35 to construct an AD cell model, and the effects of sh-S1PR2 on proliferation, apoptosis, autophagy, and AKT/mTOR pathway of AD cells were investigated. In addition, the effects of pathway inhibitor rapamycin on model cells were further analyzed. RESULTS: The expression of S1PR2 was significantly increased in AD mice, the sh-S1PR2 significantly improved behavioral dysfunction, alleviated pathological injury of the hippocampus, increased the number of neurons, and inhibited Aß production and p-tau expression, showing a positive effect on the AD pathology. In addition, silencing of S1PR2 expression significantly promoted the autophagy level and inhibited the activation of the AKT/mTOR pathway in AD model mice. In vitro experiments further confirmed that sh-S1PR2 promoted cell proliferation, inhibited apoptosis, relieved cytopathology, promoted autophagy, and inhibited the activation of the AKT/mTOR pathway in the cell model. The use of rapamycin further confirmed the role of AKT/mTOR pathway-mediated autophagy in the regulation of AD by S1PR2. CONCLUSION: S1PR2 promoted AD pathogenesis by inhibiting autophagy through the activation of AKT/mTOR pathway.

Nuclear GRP78 Promotes Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Ductal Adenocarcinoma.

PURPOSE: Stromal fibrosis limits nutritional supply and disarrays metabolism in pancreatic cancer (PDA, pancreatic ductal adenocarcinoma). Understanding of the molecular basis underlying metabolic cues would improve PDA management. The current study determined the interaction between glucose-regulated proteins 78 (GRP78) and hypoxia-inducible factor 1α (HIF-1α) and its mechanistic roles underlying PDA response to oxygen and glucose restrains. EXPERIMENTAL DESIGN: Gene expression and its association with clinicopathologic characteristics of patients with PDA and mouse models were analyzed using IHC. Protein expression and their regulation were measured by Western blot and immunoprecipitation analyses. Protein interactions were determined using gain- and loss-of-function assays and molecular methods, including chromatin immunoprecipitation, co-immunoprecipitation, and dual luciferase reporter. RESULTS: There was concomitant overexpression of both GRP78 and HIF-1α in human and mouse PDA tissues and cells. Glucose deprivation increased the expression of GRP78 and HIF-1α, particularly colocalization in nucleus. Induction of HIF-1α expression by glucose deprivation in PDA cells depended on the expression of and its own interaction with GRP78. Mechanistically, increased expression of both HIF-1α and LDHA under glucose deprivation was caused by the direct binding of GRP78 and HIF-1α protein complexes to the promoters of HIF-1α and LDHA genes and transactivation of their transcriptional activity. CONCLUSIONS: Protein complex of GRP78 and HIF-1α directly binds to HIF-1α own promoter and LDHA promoter, enhances the transcription of both HIF-1α and LDHA, whereas glucose deprivation increases GRP78 expression and further enhances HIF-1α and LDHA transcription. Therefore, crosstalk and integration of hypoxia- and hypoglycemia-responsive signaling critically impact PDA metabolic reprogramming and therapeutic resistance.

The effect of letrozole overlapped with gonadotropin on IVF outcomes in women with DOR or aged over 40 years old with repeated cycles.

BACKGROUND: Evaluating the efficacy of letrozole overlapped with gonadotropin-modified letrozole protocol (mLP) for diminished ovarian reserve (DOR) or advanced-age women with repeated cycles. METHODS: This is a retrospectively registered, paired-match study including 243 women with DOR and 249 women aged over 40 years old who received in vitro fertilization (IVF) treatment. 123 women received stimulation with mLP (mLP group). GnRH agonist (GnRH-a) long, GnRH antagonist (GnRH-anta), and mild stimulation protocol were used as controls with 123 women in each group. We further analyzed 50 of 123 patients in the mLP group who have experienced more than one failed cycles with other ovarian stimulation protocols (non-mLP group). Clinical pregnancy rate (CPR), cumulative clinical pregnancy rate (CCPR), and live birth rate (LBR) were main outcomes. RESULTS: The CPR in the mLP group (38.46%) was significantly higher than mild stimulation (17.11%), but not significantly different from GnRH-a long (26.13%) and GnRH-anta (29.17%) group. The CCPR showed an increasing trend in the mLP group (33.33%) although without significance when compared with controls. The CCRP of GnRH-a long, GnRH-anta, mild stimulation group were 21.68%, 29.03%, and 13.04%, respectively. In women with repeated cycles, mLP achieved the higher available embryo rate (P < 0.05), the top-quality embryo rate, the CPR (P < 0.001), and the LBR (P < 0.001). Further study showed a positive correlation between testosterone and the number of oocytes retrieved in the mLP group (r = 0.395, P < 0.01). CONCLUSION: The mLP may be effective for aged or DOR women who have experienced previous cycle failure by improving the quality of embryos, the CPR, and the LBR. An increasing serum testosterone level may reflect follicular growth during ovarian stimulation.

Structural characterization of an isocytosine-specific deaminase VCZ reveals its application potential in the anti-cancer therapy.

Non-natural nucleobase isocytosine (IC) is the isomer of cytosine; its chemical derivate 5-fluoroisocytosine (5-FIC) together with the isocytosine-specific deaminase (ICD) VCZ was suggested to be potential practical enzyme/prodrug pair for cancer therapy through gene-directed enzyme-prodrug therapy (GDEPT) method. In this study, we have determined the crystal structures of apo-VCZ and its complex with 5-FU. We identified the critical residues for substrate binding and catalytic reaction. We also captured the substrate-induced conformational changes of VCZ, then proposed the conjectural reaction procedures of VCZ for converting the IC into the uracil. Moreover, we evaluated the therapeutic effect of wildtype or the mutated VCZ protein in the colorectal cancer cell lines. Our studies will shed light on optimizing the ICD/5-FIC pairs by modifying either the enzyme or the prodrug based on the structural observations, thereby improving the possibility of applying the ICD/5-FIC pair in clinical trials.

Using proteomics and metabolomics to identify therapeutic targets for senescence mediated cancer: genetic complementarity method.

Background: Senescence have emerged as potential factors of lung cancer risk based on findings from many studies. However, the underlying pathogenesis of lung cancer caused by senescence is not clear. In this study, we try to explain the potential pathogenesis between senescence and lung cancer through proteomics and metabonomics. And try to find new potential therapeutic targets in lung cancer patients through network mendelian randomization (MR). Methods: The genome-wide association data of this study was mainly obtained from a meta-analysis and the Transdisciplinary Research in Cancer of the Lung Consortium (TRICL), respectively.And in this study, we mainly used genetic complementarity methods to explore the susceptibility of aging to lung cancer. Additionally, a mediation analysis was performed to explore the potential mediating role of proteomics and metabonomics, using a network MR design. Results: GNOVA analysis revealed a shared genetic structure between HannumAge and lung cancer with a significant genetic correlation estimated at 0.141 and 0.135, respectively. MR analysis showed a relationship between HannumAge and lung cancer, regardless of smoking status. Furthermore, genetically predicted HannumAge was consistently associated with the proteins C-type lectin domain family 4 member D (CLEC4D) and Retinoic acid receptor responder protein 1 (RARR-1), indicating their potential role as mediators in the causal pathway. Conclusion: HannumAge acceleration may increase the risk of lung cancer, some of which may be mediated by CLEC4D and RARR-1, suggestion that CLEC4D and RARR-1 may serve as potential drug targets for the treatment of lung cancer.

Senescence program and its reprogramming in pancreatic premalignancy.

Tumor is a representative of cell immortalization, while senescence irreversibly arrests cell proliferation. Although tumorigenesis and senescence seem contrary to each other, they have similar mechanisms in many aspects. Pancreatic ductal adenocarcinoma (PDA) is highly lethal disease, which occurs and progresses through a multi-step process. Senescence is prevalent in pancreatic premalignancy, as manifested by decreased cell proliferation and increased clearance of pre-malignant cells by immune system. However, the senescent microenvironment cooperates with multiple factors and significantly contributes to tumorigenesis. Evidently, PDA progression requires to evade the effects of cellular senescence. This review will focus on dual roles that senescence plays in PDA development and progression, the signaling effectors that critically regulate senescence in PDA, the identification and reactivation of molecular targets that control senescence program for the treatment of PDA.

Evaluation of soil quality in Inner Mongolia desert steppe-A case study of Siziwang Banner.

As a natural ecological fragile region, the vast desert steppe in the Inner Mongolia has a developed animal husbandry, and thus posed great impacts on soil quality. In order to accurately evaluate the current situation of soil quality in the desert steppe, it is therefore imperative to adopt a suitable method to effectively assess the soil quality in the region. In this study, the minimum data set (MDS) was established with the help of principal component analysis, Norm value calculation, and correlation analysis, and four indicators, including organic matter, sand grains, soil erosion degree, and pH, were established to evaluate the soil quality of the desert steppe in the Siziwang Banner, a county in the Inner Mongolia. The results from the minimum data set (MDS) method were validated based on the total data set (TDS) method, and the validation indicated that the MDS method can be representative of the soil quality of the study area. The results indicated: 1) the soil quality index (SQI) of 0-30 cm in more than 90% of the study area falls in the range of 0.4 and 0.6 (medium level), while the better level (SQI ≥0.6) only accounted less than 10% of the study area; 2) For the MDS indexes, soil organic matter content at all depths decreased in the southern mountains, central hills, and northern plateau, which is consistent with the changing trends of SQI; 3) The sand grain was the dominant particle in the study region, which was in accordance with the intense wind erosion; 4) The negative correlation was found between the soil pH value and SQI (the high value in pH corresponded to the low value in SQI), which reflected that soil pH has a more stressful effect on the local vegetation. Overall, the MDS indexes in this study can objectively and practically reflect the soil quality in the study area, which can provide a cost effective method for SQI assessment in the desert steppe, which is important for the further grassland ecological construction and grassland management to improve the soil quality in the desert steppes.

Sennoside A restrains TRAF6 level to modulate ferroptosis, inflammation and cognitive impairment in aging mice with Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disease and a momentous cause of dementia in the elderly. Sennoside A (SA) is an anthraquinone compound and possesses decisive protective functions in various human diseases. The purpose of this research was to elucidate the protective effect of SA against AD and investigate its mechanism. METHODS: Male APPswe/PS1dE9 (APP/PS1) transgenic mice with a C57BL/6J background were chosen as AD model. Age-matched nontransgenic littermates (C57BL/6 mice) were negative controls. SA's functions in AD in vivo were estimated by cognitive function analysis, Western blot, hematoxylin-eosin staining, TUNEL staining, Nissl staining, detection of Fe2+ levels, glutathione and malondialdehyde contents, and quantitative real-time PCR. Also, SA's functions in AD in LPS-induced BV2 cells were examined using Cell Counting Kit-8 assay, flow cytometry, quantitative real-time PCR, Western blot, enzyme-linked immunosorbent assay, and analysis of reactive oxygen species levels. Meanwhile, SA's mechanisms in AD were assessed by several molecular experiments. RESULTS: Functionally, SA mitigated cognitive function, hippocampal neuronal apoptosis, ferroptosis, oxidative stress, and inflammation in AD mice. Furthermore, SA reduced BV2 cell apoptosis, ferroptosis, oxidative stress, and inflammation induced by LPS. Rescue assay revealed that SA abolished the high expressions of TRAF6 and p-P65 (NF-κB pathway-related proteins) induced by AD, and this impact was reversed after TRAF6 overexpression. Conversely, this impact was further enhanced after TRAF6 knockdown. CONCLUSIONS: SA relieved ferroptosis, inflammation and cognitive impairment in aging mice with AD through decreasing TRAF6.

Mongolian medicine Wenguanmu ointment treats eczema by inhibiting the CKLF-1/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The main clinical manifestations of eczema include itching, erythema, swelling and pain. Currently, allergies and TH1/TH2 cytokine imbalances are significant causes of eczema. TCM believes that eczema is mainly caused by incongruity between dry and wet. Wenguanmu ointment is a classic Mongolian medicine, which mainly composed of Xanthoceras sorbifolia Bunge, Coptis chinensis Franch and Bezoar. These ingredients can clear heat and dampness, dispel wind and dehumidification, anti-inflammatoryad analgesic. In this study, it was found that Wenguanmu ointment can treat eczema with anti-inflammatory, analgesic and antipruritic. AIM OF THE STUDY: In this study, the content of main components in Wenguanmu ointment was tested. Moreover, the therapeutic effect and mechanism of Wenguanmu ointment on eczema model mice were studied. MATERIALS AND METHODS: Kunming mice (25 ± 2 g) were randomly divided into 6 groups: Control group; Model group; Vehicle group; Wenguanmu ointment group; Compound dexamethasone acetate cream group; Chushizhiyang ointment group. The eczema mouse model was established by DNCB. HPLC and TLC tests were used to determine the content of the main components in Wenguanmu ointment. HE staining was used to assess skin damage in mice. In order to detect the anti-inflammatory effect of Wenguanmu ointment on eczema, The levels of IgE, TNF-α, IFN-γ, COX-2 and IL-4 in serum was measured by ELISA. Genecards and Online Mendelian Inheritance in Man databases were used to analyze potential target gene predictions, and it was speculated that Wenguanmu ointment was associated with NF-κB signaling pathway and chemokine signaling pathway. To detect this inference, RT-qPCR and western blotting were used to detect protein and mRNA levels of CKLF-1, IκB-α, and NF-κB. RESULTS: Wenguanmu ointment can repress the symptoms of eczema caused by 2, 4-dinitrochlorobenzene, and inhibit the level of serum immunoglobulin E. Simultaneously it restrain the elevation of miscellaneous pro-inflammatory cytokines and chemokines, as well as reducing the expression of CKLF-1 and NF-κB protein in the nucleus, and increasing the protein expression of IκB to improve eczema. CONCLUSIONS: The ameliorating effect of Wenguanmu ointment on eczema lesions can play a importment role by inhibiting the CKLF-1/NF-κB pathway.

PC6 electroacupuncture reduces stress-induced autonomic and neuroendocrine responses in rats.

Stress can trigger cardiovascular disease. Both imbalance of autonomic nervous activity and increase of neurohormonal output are core aspects of stress responses and can lead to cardiovascular disease. PC6 as a very important acupoint is used to prevent and treat cardiovascular disease and to improve stress-related activities. We examined the influence of electroacupuncture (EA) at PC6 on stress-induced imbalance of autonomic nervous activity and increase of neurohormonal output. EA at PC6 relieved increased cardiac sympathetic nervous activity and decreased cardiac vagal nervous activity induced by immobilization stress. Also, EA at PC6 reduced immobilization stress-induced increases of plasma norepinephrine (NE) and adrenaline (E) released from sympatho-adrenal-medullary axis. Finally, EA at PC6 reduced immobilization stress-induced increases of corticotropin-releasing hormone (CRH) in paraventricular hypothalamic nucleus and plasma cortisol (CORT) released from hypothalamic-pituitary-adrenal axis. However, EA at tail had no significant effect on the stress-induced autonomic and neuroendocrine responses. The results demonstrate the role of EA at PC6 regulating the autonomic and neuroendocrine responses induced by stress and provide insight into the prevention and treatment of EA at PC6 for stress-induced cardiovascular disease by targeting autonomic and neuroendocrine systems.

Analysis of gene expression profiles in Alzheimer's disease patients with different lifespan: A bioinformatics study focusing on the disease heterogeneity.

Objective: Alzheimer's disease (AD) as the most frequent neurodegenerative disease is featured by gradual decline of cognition and social function in the elderly. However, there have been few studies focusing on AD heterogeneity which exists both genetically and clinically, leading to the difficulties of AD researches. As one major kind of clinical heterogeneity, the lifespan of AD patients varies significantly. Aiming to investigate the potential driving factors, the current research identified the differentially expressed genes (DEGs) between longer-lived AD patients and shorter-lived ones via bioinformatics analyses. Methods: Qualified datasets of gene expression profiles were identified in National Center of Biotechnology Information Gene Expression Omnibus (NCBI-GEO). The data of the temporal lobes of patients above 60 years old were used. Two groups were divided according to the lifespan: the group ≥85 years old and the group <85 years old. Then GEO2R online software and R package of Robust Rank Aggregation (RRA) were used to screen DEGs. Bioinformatic tools were adopted to identify possible pathways and construct protein-protein interaction network. Result: Sixty-seven AD cases from four qualified datasets (GSE28146, GSE5281, GSE48350, and GSE36980) were included in this study. 740 DEGs were identified with 361 upregulated and 379 downregulated when compared longer-lived AD patients with shorter-lived ones. These DEGs were primarily involved in the pathways directly or indirectly associated with the regulation of neuroinflammation and cancer pathogenesis, as shown by pathway enrichment analysis. Among the DEGs, the top 15 hub genes were identified from the PPI network. Notably, the same bioinformatic procedures were conducted in 62 non-AD individuals (serving as controls of AD patients in the four included studies) with distinctly different findings from AD patients, indicating different regulatory mechanisms of lifespan between non-AD controls and AD, reconfirming the necessity of the present study. Conclusion: These results shed some lights on lifespan-related regulatory mechanisms in AD patients, which also indicated that AD heterogeneity should be more taken into account in future investigations.

Anticoagulants Enhance Molecular and Cellular Immunotherapy of Cancer by Improving Tumor Microcirculation Structure and Function and Redistributing Tumor Infiltrates.

PURPOSE: Pancreatic ductal adenocarcinoma (PDA) resists immunotherapy of adoptive cell transfer (ACT) and immune checkpoint inhibitors. Understanding the mechanisms underlying this resistance will improve PDA immunotherapy. This study investigated therapeutic effects and underlying mechanisms of anticoagulants on immunotherapy in PDA. EXPERIMENTAL DESIGN: The antitumor activity of immunotherapy was evaluated in mouse models of desert, excluded, and inflamed tumors. The underlying mechanisms were investigated by analyzing immune cell infiltration by immunofluorescence imaging and tumor microcirculation by interstitial fluid pressure and coagulation status measurement. RESULTS: Combined use of heparin and ACT inhibited tumor growth and metastasis, whereas neither heparin nor ACT had any therapeutic effect. The combination of heparin and ACT significantly increased the intratumor infiltration of CD8+ T cells and M1 macrophages and reduced the infiltration of immunosuppressive M2 macrophages and FOXP3+/CD4+ regulatory T cells (Treg). Assessments of tumor microenvironment revealed that heparin promoted tumor vascular regression and normalized the remaining blood vessels, facilitating the extravasation and perivascular accumulation of activated CD8+ T cells in tumors. Mechanistically, tumor microvessel hemodynamic properties were significantly improved by heparin, which is consistent with its inhibitory effects on tumor angiogenesis. Similarly, the combination of heparin and anti-PD1 also produced a pronounced antitumor activity, whereas neither heparin nor anti-PD1 treatment had appreciable antitumor activity. CONCLUSIONS: Combined treatment of heparin and ACT or anti-PD1 produced synergistic antitumor effects, which were at least in part through tumor vascular normalization, hence increased antitumor T-cell responses due to reduced Treg infiltration and increased M1 macrophage polarization. This synergistic combination therapy warrants clinical evaluation. See related commentary by Korc, p. 2348.

Effects of the genetic knockout of the ß-1,3-galactosyltransferase 2 on spatial learning and neurons in the adult mouse hippocampus and somatosensory cortex.

OBJECTIVE: Glycosyltransferases contribute to the biosynthesis of glycoproteins, proteoglycans and glycolipids and play essential roles in various processes in the brain, such as learning and memory, brain development, neuronal survival and neurodegeneration. ß-1,3-galactosyltransferase 2 (B3galt2) belongs to the ß-1,3-galactosyltransferase gene family and is highly expressed in the brain. Recent studies have indicated that B3galt2 plays a vital role in ischemic stroke through several signaling pathways in a mouse model. However, the function of B3galt2 in the brain remains poorly understood. METHODS: The genotypes of mice were determined by PCR. To verify B3galt2 expression in an adult mouse brain, X-gal staining was performed in 6-month-old B3galt2 heterozygous (B3galt2+/-) mice. Using adult B3galt2 homozygous (B3galt2-/-), heterozygous and wild-type (WT) littermates, spatial learning and memory were determined by the Morris Water Maze test, and neurotoxicity and synaptic plasticity were examined by immunofluorescence. RESULTS: B3galt2 was highly expressed in the adult mouse hippocampus and cortex, especially in the hippocampal dentate gyrus. Compared to that of WT mice, the spatial learning ability of adult B3galt2-/- mice was impaired. B3galt2 mutations also caused neuronal loss and synaptic dysfunction in the hippocampus and somatosensory cortex, and these changes were more obvious in B3galt2-/- mice than in B3galt2+/- mice. CONCLUSIONS: The findings indicate that B3galt2 plays an important role in cognitive function, neuronal maintenance and synaptic plasticity in the adult mouse brain. This study suggests that genetic and/or pharmacological manipulation of glycosyltransferases may be a novel strategy for elucidating the mechanism of and managing various brain disorders.

Tibial nerve electrical stimulation for fecal incontinence: a systematic review and meta-analysis.

Tibial nerve stimulation (TNS) therapy is widely used to treat fecal incontinence (FI), but still, some controversy exists. This study aimed to determine whether TNS could improve FI from different evaluation angles. A systematic review and meta-analysis were conducted to provide indirect evidence of TNS treatment for FI. We searched for the original studies in PubMed, Embase, Web of Science, Ebsco Medline, Ovid Medline, and Cochrane Central Register of Controlled Trials published before November 31, 2021. The standardized mean difference was the efficacy analysis statistic, and the effect was expressed by the 95% confidence interval (CI). For the case series, we calculated the mean difference of the number of patients evaluated at baseline and last follow-up. Four randomized controlled trials (RCTs, four hundred and sixty participants) and eighteen case series (eight hundred and thirty-eight participants) were included in the study. The results of the RCTs showed that the number of weekly episodes of FI significantly reduced in the TNS group compared with the sham stimulation group. The results of the case series showed that TNS reduced the number of patients with FI per week. The Cleveland Clinic Florida FI Score significantly reduced. The post-treatment results of maximum squeeze pressure and maximum resting pressure were significantly different from baseline. This study showed that TNS to some extent reduced the number of patients with FI, reduced clinical symptoms, and improved anal physiological function. Despite the low quality of overall evidence, TNS still shows some potential as a safe treatment for FI.