B cell expansion hinders the stroma-epithelium regenerative cross talk during mucosal healing.

Therapeutic promotion of intestinal regeneration holds great promise, but defining the cellular mechanisms that influence tissue regeneration remains an unmet challenge. To gain insight into the process of mucosal healing, we longitudinally examined the immune cell composition during intestinal damage and regeneration. B cells were the dominant cell type in the healing colon, and single-cell RNA sequencing (scRNA-seq) revealed expansion of an IFN-induced B cell subset during experimental mucosal healing that predominantly located in damaged areas and associated with colitis severity. B cell depletion accelerated recovery upon injury, decreased epithelial ulceration, and enhanced gene expression programs associated with tissue remodeling. scRNA-seq from the epithelial and stromal compartments combined with spatial transcriptomics and multiplex immunostaining showed that B cells decreased interactions between stromal and epithelial cells during mucosal healing. Activated B cells disrupted the epithelial-stromal cross talk required for organoid survival. Thus, B cell expansion during injury impairs epithelial-stromal cell interactions required for mucosal healing, with implications for the treatment of IBD.

Causal relationship between depression and aging: a bidirectional two-sample Mendelian randomization study.

BACKGROUND: The causal relationship and the direction of the effect between depression and aging remain controversial. METHODS: We used a bidirectional two-sample Mendelian randomization analysis to examine the relationship between depression and age proxy indicators. We obtained pooled statistics from genome-wide association studies (GWAS) on depression and the age proxy indicators. We employed five MR analysis methods to address potential biases and ensure robustness of our results, with the inverse variance weighted (IVW) method being the primary outcome. We also conducted outlier exclusion using Radial MR, MRPRESSO, and MR Steiger filters. Additionally, sensitivity analyses were performed to assess heterogeneity and pleiotropy. RESULTS: Our MR analysis revealed that depression causally leads to shortened telomere length (ß = - 0.014; P = 0.038), increased frailty index (ß = 0.076; P = 0.000), and accelerated GrimAge (ß = 0.249; P = 0.024). Furthermore, our findings showed that the frailty index (OR = 1.679; P = 0.001) was causally associated with an increased risk of depression. Additionally, we found that appendicular lean mass (OR = 0.929; P = 0.000) and left-hand grip strength (OR = 0.836; P = 0.014) were causally associated with a reduced risk of depression. Sensitivity analyses demonstrated the robustness of our findings. CONCLUSIONS: Our study provides evidence that depression contributes to the accelerated aging process, resulting in decreased telomere length, increased frailty index, and accelerated GrimAge. Additionally, we found that the frailty index increases the risk of depression, while appendicular lean mass and left-handed grip strength reduce the risk of depression.

Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology.

X-box binding protein 1 (XBP1) is a member of the CREB/ATF basic region leucine zipper family transcribed as the unspliced isoform (XBP1-u), which, upon exposure to endoplasmic reticulum stress, is spliced into its spliced isoform (XBP1-s). XBP1-s interacts with the cAMP response element of major histocompatibility complex class II gene and plays critical role in unfolded protein response (UPR) by regulating the transcriptional activity of genes involved in UPR. XBP1-s is also involved in other physiological pathways, including lipid metabolism, insulin metabolism, and differentiation of immune cells. Its aberrant expression is closely related to inflammation, neurodegenerative disease, viral infection, and is crucial for promoting tumor progression and drug resistance. Meanwhile, recent studies reported that the function of XBP1-u has been underestimated, as it is not merely a precursor of XBP1-s. Instead, XBP-1u is a critical factor involved in various biological pathways including autophagy and tumorigenesis through post-translational regulation. Herein, we summarize recent research on the biological functions of both XBP1-u and XBP1-s, as well as their relation to diseases.

Microorganisms as Bio-SPE Materials for Extraction of Pharmaceutical Drugs: Mechanism of Extraction.

In solid-phase extraction (SPE), the extraction materials depend on the physicochemical interactions to obtain the target analytes from complex systems. However, many matrix interferences existing in real samples influence the extraction efficiency through these common interactions. Therefore, extraction materials based on more special interactions for biological systems need to be developed. In this work, live microorganisms including Escherichia coli and Staphylococcus aureus were considered as the potential biological SPE (bio-SPE) materials with their biological functions in the live state. To study the enrichment and selectivity of the bio-SPE, four antibacterial drugs and two non-antibacterial drugs were employed as the target analytes. The enrichment factor (EF) was used as the evaluation index. The results showed that when using chlorpheniramine (CPM) and ofloxacin (OFLO), the enrichment capacity of E. coli was better than that of S. aureus. When extracting a single analyte, the enrichment ability of E. coli for CPM was significantly higher than other analytes, and the EF was 8.5. In a mixture solution of antibacterial analytes, OFLO could be enriched mostly by E. coli. However, in the mixture solution of antibacterial and non-antibacterial analytes, CPM was enriched more than that of antibacterial analytes. In real rat plasma, bio-SPE using live E. coli could obviously extract CPM, while traditional liquid-liquid extraction could not. The confocal microscopy results showed that the extraction mechanism may not only depend on the surface adsorption of bacteria with analytes but also on the uptake into bacteria. This provides a valuable basis for the development of more biological separation materials based on biological interactions.

Type 2 immunity in intestinal homeostasis and inflammatory bowel disease.

Type 2 immune responses commonly emerge during allergic reactions or infections with helminth parasites. Most of the cytokines associated with type 2 immune responses are IL-4, IL-5, and IL13, which are mainly produced by T helper 2 cells (TH2), eosinophils, basophils, mast cells, and group 2 innate lymphoid cells (ILC2s). Over the course of evolution, humans have developed type 2 immune responses to fight infections and to protect tissues from the potential collateral damage caused by inflammation. For example, worm parasites induce potent type 2 immune responses, which are needed to simultaneously clear the pathogen and to promote tissue repair following injury. Due to the strong type 2 immune responses induced by helminths, which can promote tissue repair in the damaged epithelium, their use has been suggested as a possible treatment for inflammatory bowel disease (IBD); however, the role of type 2 immune responses in the initiation and progression of IBD is not fully understood. In this review, we discuss the molecular and cellular mechanisms that regulate type 2 immune responses during intestinal homeostasis, and we briefly discuss the scarce evidence linking type 2 immune responses with the aetiology of IBD.

[Puerariae Lobatae Radix elevated expression levels of OB-R, IRS2, GLUT1 and GLUT2 to regulate glucose metabolism in insulin-resistance HepG2 cells].

To observe the anti-hyperglycemic effect of Puerariae Lobatae Radix in hepatocyte insulin resistance(IR) models, and investigate its preliminary molecular mechanism. IR-HepG2 cell model was stably established with 1×10-9 mol•L⁻¹ insulin plus 3.75×10-6 mol•L-1 dexamethasone treatment for 48 h according to optimized protocol in our research group. After IR-HepG2 cells were treated with different concentrations(5%,10% and 15%) of Puerariae Lobatae Radix-containing serum, cell viability was detected by CCK-8 assay; the glucose consumptions in IR-HepG2 cells were separately detected at different time points (12, 15, 18, 21, 24, 30, 36 h) by using glucose oxidase method; intracellular glycogen content was detected by anthrone method; and the protein expression levels of leptin receptor (Ob-R), insulin receptor substrate-2 (IRS2), glucose transporter 1(GLUT1) and GLUT2 were detected by Western blot assay. The results showed that Puerariae Lobatae Radix-containing serum (5%, 10% and 15%) had no significant effect on IR-HepG2 cell viability; 5% and 10% Puerariae Lobatae Radix-containing serum significantly increased glucose consumption of IR-HepG2 cells (P<0.01) at 18, 21 and 24 h; 15% Puerariae Lobatae Radix-containing serum elevated the glucose consumption of IR-HepG2 cells at 15 h (P<0.05), and significantly elevated the glucose consumption at 18, 21, 24 and 30 h (P<0.01) in a dose-dependent manner. The optimized time of anti-hyperglycemic effect was defined as 24 h, and further study showed that Puerariae Lobatae Radix-containing serum could increase intracellular glycogen content after 24 h treatment (P<0.01), and up-regulate IRS2, Ob-R, GLUT1 and GLUT2 protein expression levels. Our results indicated that Puerariae Lobatae Radix-containing serum could achieve the anti-hyperglycemic effect through important PI3K/PDK signaling pathway partially by up-regulating the expression levels of Ob-R and IRS2, GLUT1 and GLUT2 in IR-HepG2 cells, accelerating the glucose transport into hepatocytes and increasing hepatic glycogen synthesis to enhance the anti-hyperglycemic effect of IR-HepG2 cells.

[Gegen Qinlian decoction activates PPARγ to ameliorate adipocytic insulin resistance in diabetic SD rats and IR-3T3-L1 adipocytes].

To investigate the effects of Gegen Qinlian decoction(GQD) in improving adipocytic insulin resistance(IR) and explore its related molecular mechanism. Diabetic rats models were induced by high glucose and high-fat diet with a small dose of streptozotocin, and after GQD treatment for 3 months, blood biochemical indexes such as fasting blood-glucose(FBG), insulin, glycosylated serum protein(GSP) and HOMA-IRI were detected and assessed. After the total RNA was extracted from the adipose tissue of diabetic SD rats, PPARγ, ADPN, GLUT4, GLUT2, ACACA and ACACB mRNA expression levels were separately detected by qPCR. Then, stable IR-3T3-L1 adipocyte model was built with 1 µmol•L⁻¹ dexamethasone. After the cell viability was detected by CCK-8 assay, 5%, 10% and 15% GQD-containing serum(GQD-CS) were respectively used to treat IR-3T-L1 adipocytes for 24 h. The contents of glucose, nonesterified fatty acid(NEFA) and adiponectin in cell culture supernatants were separately detected whereas the intracellular triglyceride(TG) contents of IR-3T3-L1 adipocytes were also measured. The ADPN, PPARγ and GLUT4 mRNA and protein expression levels were respectively detected by qPCR and Western blot in IR-3T3-L1 adipocytes. Results showed that GQD significantly decreased fasting blood glucose, insulin and GSP(P<0.01), and down-regulated HOMA-IRI(P<0.05) after the high-fat diet/streptozotocin-induced diabetic SD rats were treated for three months, with a good hypoglycemic effect. Moreover, PPARγ, ADPN, GLUT4, GLUT2, ACACA and ACACB mRNA expression levels were significantly elevated in the adipose tissue of GQD-treated diabetic SD rats. The 5%, 10% and 15% GQD-CS significantly increased glucose consumption of IR-3T3-L1 adipocytes at 24 h treatment(P<0.01), significantly decreased the intracellular TG content (P<0.01), and down-regulated NEFA to a certain extent but not significantly. Moreover, GQD-CS significantly up-regulated GLUT4 and ADPN expression. The results indicated that GQD could activate PPARγ to ameliorate adipocytic insulin resistance in the diabetic SD rats and IR-3T3-L1 adipocytes.

[Effects of berberine on mRNA expression levels of PPARγ and adipocytokines in insulin-resistant adipocytes].

Adipocytokines are closely associated with insulin resistance (IR) in adipose tissues, and they are more and more seriously taken in the study of the development of diabetes. This experiment was mainly to study the effect of berberine on mRNA expression levels of PPARγ and adipocytokines in insulin resistant adipocytes, and investigate the molecular mechanism of berberine in enhancing insulin sensitization and application advantages of droplet digital PCR (ddPCR). ddPCR absolute quantification analysis was taken in this experiment to simply and intuitively determine the appropriate reference genes. ddPCR and quantitative Real-time PCR (qPCR) were used to compare the effect of different doses of berberine (10, 20, 50, 100 µmol•L⁻¹) on mRNA expression levels of PPARγ, adiponectin, resistin and leptin in IR 3T3-L1adipocytes. Antagonist GW9662 was added to study the inherent correlation between PPARγ and adiponectin mRNA expression levels. ddPCR results showed that the expression level of ß-actin in adipocytes was stable, and suitable as reference gene for normalization of quantitative PCR data. Both of ddPCR and qPCR results showed that, as compared with IR models, the mRNA expression levels of adiponectin were decreased in the treatment with berberine (10, 20, 50, 100 µmol•L⁻¹) in a dose-dependent manner (P<0.01); the expression of PPARγ was decreased by 20, 50, 100 µmol•L⁻¹ berberine in a dose-dependent manner in qPCR assay (P<0.01) and decreased only by 50 and 100 µmol•L⁻¹ berberine in ddPCR assay (P<0.05). PPARγ specific antagonist GW9662 intervention experiment showed that adiponectin gene expression was directly relevant with PPARγ (P<0.05). ddPCR probe assay showed that various doses of berberine could significantly reduce mRNA expression levels of resistin and leptin (P<0.01) in a dose-dependent manner. In conclusion, berberine enhanced insulin sensitization effect not by up-regulating adiponect in expression of transcriptional level in PPARγ-dependent manner, but may by the elevated multimerization of adiponectin in the posttranslational regulation level. Berberine down-regulated the resistin and leptin expression levels, which could alleviate lipolysis and improve IR in adipocytes. ddPCR provided better sensitivity and linear range than qPCR, with obvious technical advantages for the detection of low abundance expression of target genes.

[Kudzu root (Ge-Gen) regulates on glucose and lipid metabolism to ameliorating insulin resistance on 3T3-L1 adipocytes].

This study aimed to explore the mechanism of Chinese traditional medicine, Kudzu root(Chinese name：Ge-Gen; Latin name： Puerariae Lobatae Radix) how to improving insulin resistance (IR) through the regulation of the glucose and lipid metabolism in the IR-3T3-L1 adipocytes. After the 3T3-L1 mouse preadipocytes were differentiated into mature adipocytes, IR model(IR-3T3-L1) was built with 1 µmol•L-1 dexamethasone treatment for 96 h. IR adipocytes were treated with different concentrations (5%,10% and 15%) of Ge-Gen containing serum (GG-CS)for 12 h or 24 h, whereas rosiglitazone group as positive control in this study. The glucose contents in cell culture supernatants were detected by glucose oxidase assay and the intracellular triglyceride (TG) contents were measured by glycerol phosphate oxidase assay respectively.The mRNA expression levels of PPARγ, ADPN, GLUT4, LPL, FABP4 and FASn gene were determined by real-time quantitative PCR(qPCR).Results showed that IR-3T3-L1 adipocytes significantly increased glucose consumption (P<0.01)and decreased TG contents (P<0.01) as compared with the normal control group, the glucose consumption significantly increased with the treatment of GG-CS (P<0.01) by dose-dependent and time-dependent manners,whereas the intracellular TG content was sigificantly decreased (P<0.01) by dose-dependent manner.qPCR analysis revealed that 10% and 15% GG-CS significantly up-regulated the mRNA expression level of PPARγ, ADPN and GLUT4 (P<0.01) with the same dose-dependent manner,whereas the GLUT4 mRNA expression was showed similar expression pattern with the treatment of 10% and 15% GG-CS (P<0.01).We also detected the mRNA expression levels of several important lipid-metabolizing enzymes such as LPL, FASn and FABP4 by PPARγ regulation. 15% GG-CS elevated LPL mRNA expression (P<0.05);10% and 15% GG-CS enhanced the FASn mRNA expression (P<0.01), whereas 5%,10% and 15% GG-CS down-regulated FABP4 mRNA expression (P<0.01). Together, our results indicated that GG could regulate the glucose and lipid metabolism to ameliorate IR with multi-target manners in 3T3-L1 adipocytes.

Causal relationship between metabolic syndrome and hidradenitis suppurativa: A two-sample bidirectional Mendelian randomization study.

Observational studies have suggested an association between metabolic syndrome (MetS) and hidradenitis suppurativa (HS), but whether this relationship is causal remains unclear. Elucidating the causal direction could provide insights into disease mechanisms and potential interventions. We performed bidirectional two-sample Mendelian randomization (MR) using summary statistics from genome-wide association studies (GWAS) of MetS and HS. For validation, we replicated the MetS analysis using data from an independent GWAS. We applied multiple MR methods, primarily inverse variance-weighted (IVW) regression, and conducted sensitivity analyses to assess heterogeneity and pleiotropy. The MR analysis demonstrated MetS causally increased HS risk (IVW odds ratio [OR], 1.428 [95% CI, 1.193-1.710]; p < 0.001), with consistent evidence from sensitivity analyses. However, HS did not appear to causally influence MetS risk (IVW OR, 1.008 [95% CI, 0.988-1.028]; p = 0.438). This study provides evidence that MetS causally increases the risk of developing HS. However, we found no evidence for a causal relationship in the reverse direction from HS to MetS. Further research is warranted to elucidate the mechanisms underlying the identified causal association between MetS and subsequent HS development.

Effectiveness of acupuncture in the governor vessel and Yangming meridian for the treatment of acute ischemic stroke: A systematic review and network meta-analysis.

BACKGROUND: Acupuncture of the governor vessel and Yangming meridian are widely used in the treatment of acute ischemic stroke (AIS). However, the optimal meridian for acupuncture in the treatment of AIS remains uncertain. PURPOSE: This network meta-analysis study aimed to compare the clinical effectiveness of acupuncture at governor vessel and Yangming meridian in the treatment of AIS. METHODS: All relevant studies published in CNKI, WANFANG, VIP, Sinomed, Cochrane Library, Web of Science, Pub Med, and Embase before January 13, 2024 were systematically retrieved. The two researchers independently screened the studies and extracted the data. Cochrane ROB tool was used to evaluate the quality of the studies, and Stata 14.0 software was used to conduct a network meta-analysis of neurological deficit score, activities of daily living (ADL), clinical effective rate and Fugl-meyer motor function evaluation (FMA). RESULTS: A total of 401 studies were obtained, and 17 studies met the inclusion criteria. The surface under the cumulative ranking curve (SUCRA) values of the four outcome indexes were all ranked by "Governor vessel acupuncture + Conventional neurology treatment(GVAc+CT) > Yangming meridian acupuncture + Conventional neurology treatment(YMAc+CT) > Conventional neurology treatment (CT)". Compared to YMAc+CT and CT, GVAc+CT had the best effect in reducing the degree of neurological deficit score (SMD = -0.72, 95%CI = [-1.22,-0.21] and SMD = -1.07,95%CI = [-1.45,-0.69], respectively) and promoting the recovery of ADL((SMD = 0.59,95%CI = [0.31,0.88] and SMD = 0.96,95%CI = [0.70,1.21], respectively). Compared to CT, GVAc+CT also had a better clinical effective rate in the treatment of AIS (RR = 1.14,95%CI = [1.04,1.25]). CONCLUSIONS: Governor vessel acupuncture combined with conventional neurology treatment has the best effect in reducing the degree of neurological deficit score and promoting the recovery of ADL in AIS patientscompared to YMAc+CT and CT. Governor Vessel acupuncture is the most preferable acupoint scheme for clinical acupuncture treatment of AIS.

Computed tomography-based contrast features for distinguishing extra-gastrointestinal stromal tumors from intra-abdominal fibromatosis.

PURPOSE: This study aims to define the computed tomography (CT) criteria that distinguish extra-gastrointestinal stromal tumors (eGISTs) from intra-abdominal fibromatosis (IAF). METHODS: Retrospective analysis was conducted on CT images obtained from 31 pathologically confirmed cases, including 17 cases of eGISTs and 14 of IAF. Various parameters [e.g., lesion location, contour characteristics, border delineation, enhancement patterns, presence of intralesional necrosis, vessels, air, fat, and hemorrhage, the long diameter (LD), LD/short diameter (SD) ratio, and volume (LD × SD × height diameter)] were meticulously evaluated. In addition, the degree of enhancement during arterial and portal venous phases and the lesion-to-aorta CT attenuation ratio during both phases were quantified. Statistical analysis was performed using Fisher's exact test, the Student's t-test, and the receiver operating characteristic curve to identify significant CT criteria. Sensitivity and specificity assessments were conducted for single and combined CT criteria. RESULTS: Significant differentiators between eGISTs and IAF include non-mesenteric localization, irregular contour, well-defined borders, heterogeneous enhancement, presence of intralesional necrosis and vessels, and absence of intralesional fat, with LD exceeding 9.6 cm, an LD/SD ratio >1.22, and volume surpassing 603.3 cm3 (P < 0.05). A combination of seven or more of these criteria yielded a specificity of 100%. CONCLUSION: Ten distinct CT criteria have been identified to distinguish eGISTs from IAF, notably encompassing non-mesenteric localization, irregular contour, well-defined borders, heterogeneous enhancement, presence of intralesional necrosis and vessels, absence of intralesional fat, LD >9.6 cm, an LD/SD ratio >1.22, and volume surpassing 603.3 cm3. CLINICAL SIGNIFICANCE: The current findings establish CT criteria to distinguish eGISTs from IAF in a clinical setting.

SARS-CoV-2 Neutralization by Cell Membrane-Coated Antifouling Nanoparticles.

The global outbreak of the COVID-19 pandemic has indisputably wreaked havoc on societies worldwide, compelling the scientific community to seek urgently needed therapeutic agents with low-cost and low-side effect profiles. Numerous approaches have been investigated in the quest to prevent or treat COVID-19, but many of them exhibit unwelcome side effects, such as dysfunctional viral immune responses and inflammation. Herein, we present the preparation of solid natural human pulmonary alveolar epithelial cell (ATII) membrane-coated PLGA NPs (PLGA NPs@ATII-M), which demonstrate remarkable affinity and competitiveness to neutralize the SARS-CoV-2 S1 protein-coated NPs (SCMMA NPs-S1), which are employed as a surrogate for coronavirus particles. In addition, we first considered the antifouling properties of these types of NPs, and we found that this membrane-coated NP formulation boasts excellent antifouling capabilities, which serve to protect their neutralization properties out of shielding by protein coronas in blood circulation. Moreover, this formulation is easily prepared and stored with a low-cost profile and exhibits good specificity, high targeting efficiency, and potentially side effect avoiding, thus making it a highly promising candidate for COVID-19 treatment.

Spiky tubular nanoparticles with low protein corona can realize efficient and non-destructive penetration through endothelial barrier.

Upon intravascular applications, i.e., cancer treatment, nanoparticles (NPs) are required to deliver through blood circulation, sustain serum protein interactions, before they penetrate the blood vessels and reach targeted sites for payload drug release. For a delivery process as such, it is elusive and difficult to comprehend the morphological change of NP surface and evaluate associated effects on its targeted delivery. Herein, we used silica NPs with different surface modifications to demonstrate the morphological impact of NPs during the application of the NP-blood protein interaction, vascular endothelial cell penetration, subsequent targeted delivery and photodynamic therapy efficacy, and pursue high drug-load NPs with surface designs. Compared to solid and mesoporous NPs, we found the spiky tubular NPs reserved the NPs' antifouling properties (or shedding of "protein corona"), promoted better endothelial penetration and less destruction in vitro and in vivo. Such effects could be attributed to their spiky surface structures, which can limit the NP-protein interaction area and promote the NP-protein steric hindrance. Further in molecular simulations, we determined that the spiky tubular morphological modification on NPs enhanced the interaction free energy and lowered the amino acids number and the subsequent frequency in contacting with VE-cadherin of vascular endothelia. As a result, the spiky tubular NPs demonstrated its advantages in mitigating damages to VE-cadherin stability and endothelial cell integrity. Exploiting such spiky tubular surface modification, we can improve the NP delivery efficiency and prohibit the leakiness of vascular endothelia, helping address challenges faced by tumor migration in nanomedicine applications for cancer therapy.

Cetuximab combined with chemotherapy for simultaneous esophageal squamous cell carcinoma and colon adenocarcinoma: A case report.

BACKGROUND: Multiple primary carcinomas (MPCs) are defined as two or more independent primary cancers that occur simultaneously or sequentially in the same individual. Synchronous MPCs are rarer than solitary cancers or metachronous MPCs. Accurate diagnoses of synchronous MPCs and the choice of treatment are critical for successful outcomes in these cases. CASE SUMMARY: A 64-year-old patient presented with dysphagia, without obvious cause. A diagnosis of synchronous esophageal squamous cell carcinoma and colon adenocarcinoma with liver metastasis was confirmed based on examination and laboratory results. After multi-disciplinary consultations, combination chemotherapy (a 3-wk cycle with oxaliplatin 212 mg administered on day 1 and capecitabine 1.5 g twice daily on days 1-14) and esophageal cancer radiotherapy were initiated. Based on the results of genetic testing, we switched to a regimen of leucovorin + fluorouracil + oxaliplatin and cetuximab regimen for 8 cycles. Subsequently, capecitabine and bevacizumab were administered until the most recent follow-up, at which the tumor remained stable. CONCLUSION: Successful cetuximab chemotherapy treatment provides a reference for the non-operative and homogeneous treatment of different pathological types of synchronous MCPs.

Nano-induced endothelial leakiness-reversing nanoparticles for targeting, penetration and restoration of endothelial cell barrier.

Nano-induced endothelial leakiness (NanoEL) can improve the ability of nanoparticles (NPs) to enter the tumor environment, nevertheless, it can inadvertently trigger adverse effects such as tumor metastasis. To overcome these concerns, it becomes important to develop a NPs design strategy that capitalizes on the NanoEL effect while averting unwanted side effects during the drug delivery process. Herein, we introduce the PLGA-ICG-PEI-Ang1@M NP which has a core comprising poly (lactic-co-glycolic acid) (PLGA) and the inner shell with a highly positively charged polyethyleneimine (PEI) and the anti-permeability growth factor Angiopoietin 1 (Ang1), while the outer shell is camouflaged with a Jurkat cell membrane. During the drug delivery process, our NPs exhibit their capability to selectively target and penetrate endothelial cell layers. Once the NPs penetrate the endothelial layer, the proton sponge effect triggered by PEI in the acidic environment surrounding the tumor site can rupture the cell membrane on the NPs' surface. This rupture, in turn, enables the positively charged Ang1 to be released due to the electrostatic repulsion from PEI and the disrupted endothelial layer can be restored. Consequently, the designed NPs can penetrate endothelial layers, promote the cell layer recovery, restrict the tumor metastasis, and facilitate efficient cancer therapy. STATEMENT OF SIGNIFICANCE.

Causal relationship between telomere length and epilepsy: A bidirectional Mendelian randomization study.

OBJECTIVE: Observational studies have suggested a link between telomere length (TL) and epilepsy, but the direction of the effect and whether it is causal or not is still being debated. The objective of this study was to investigate the causal relationship between TL and epilepsy using Mendelian randomization (MR) analysis. METHODS: We performed a bidirectional two-sample MR analysis using pooled statistics from genome-wide association studies (GWAS) of TL and epilepsy. Additionally, we conducted a replication analysis using data from another GWAS study on epilepsy to validate our findings. The final results were analyzed using five MR methods, with the inverse-variance weighted (IVW) method as the primary outcome. We applied methods such as radial MR, MR pleiotropy residual and outlier test and MR Steiger filters to exclude outliers. Sensitivity analyses were also conducted to assess heterogeneity and pleiotropy. RESULTS: Our analysis found no evidence of a causal relationship between epilepsy and TL (all p-values >0.05). The sensitivity analysis confirms the robustness of these results. SIGNIFICANCE: In summary, our study contradicts existing observational reports by not finding any evidence to support a causal relationship between epilepsy and TL. Further research is necessary to determine the underlying mechanism behind the association observed in observational studies.

The causal effect of serum 25-hydroxyvitamin D levels on epilepsy: A two-sample Mendelian randomization study.

OBJECTIVE: Observational studies have shown an association between 25-hydroxyvitamin D (25 (OH) D) and epilepsy, but it is unclear whether the association is causal. Therefore, we applied Mendelian randomization (MR) analysis to determine the causal relationship between serum 25 (OH) D levels and epilepsy. METHODS: We conducted a two-sample Mendelian randomization (TSMR) study to investigate the association between serum 25 (OH) D levels and epilepsy using pooled statistics from genome-wide association studies (GWAS). Data for 25 (OH) D came from a GWAS comprising 417,580 participants, and data for epilepsy were obtained from the International League Against Epilepsy (ILAE) consortium. Five methods were used to analyze TSMR, including the inverse variance weighting method, MR Egger method, weighted median method, simple model, and weighted model. In the sensitivity analysis, MR Egger and MR PRESSO methods were used to test for pleiotropy, inverse variance weighting and MR Egger in Cochran's Q statistics were used to test for heterogeneity. RESULTS: MR analyzed the relationship between 25 (OH) D and different types of epilepsy, and the results showed that a 1 standard deviation increase in natural log-transformed serum 25 (OH) D levels was associated with reduced risk for juvenile absence epilepsy (IVW OR = 0.985; 95% confidence interval [CI]: 0.971-0.999; P-value = 0.038). There was no apparent heterogeneity and horizontal gene pleiotropy. SIGNIFICANCE: Higher serum levels of 25 (OH) D were a protective factor for adolescent absence epilepsy, but had no effect on other types of epilepsy.

Effectiveness of acupuncture in migraine rats: A systematic review.

OBJECTIVE: To systematically evaluate the effectiveness and potential underlying mechanisms of acupuncture in the treatment of experimental model of migraine in rats. METHODS: Nine electronic databases, including CNKI (China National Knowledge Infrastructure), WanFang, VIP (Chinese Scientific Journals Database), Sinomed, PubMed, Cochrane Library, Web of Science and EBSCO, were searched for randomized experimental studies on migraine in rats involving acupuncture intervention. The search period ranged from inception to June 2022. The methodological quality was assessed using the SYRCLE's risk of bias tool for animal studies. Data were analyzed using the Revman 5.3 software. RESULTS: A total of 13 studies were included in this analysis. Findings from the available experimental studies documented that acupuncture significantly reduced behavior scores of rats with migraine (MD = -15.01, 95%CI = [-18.01, -12.01], P<0.00001) and downregulated the expression of calcitonin gene-related peptide (CGRP) (MD = -16.14, 95%CI = [-21.45, -10.83], P<0.00001), substance P (SP) (MD = -11.47, 95%CI = [-15.97, -6.98], P<0.00001) and nitric oxide (NO) (MD = -3.02, 95%CI = [-3.79, -2.26], P<0.00001) in serum, and stimulatory G protein (Gsa) (MD = -62.90, 95%CI = [-69.88, -55.92], P<0.00001) in brainstem. Acupuncture also significantly increased the content of inhibitory G protein (Gia) (MD = 24.01, 95%CI = [20.10, 27.92], P<0.00001) in brainstem and 50% paw withdrawal threshold (50%PWT) (MD = 1.96, 95%CI = [1.15, 2.77], P<0.00001). CONCLUSION: Acupuncture can effectively improve the behavioral performance of rates with migraine, and its mechanism of action might involve the inhibition of meningeal vasodilation and inflammatory factors, and the reduction of neurogenic inflammation.

PBX3 promotes pentose phosphate pathway and colorectal cancer progression by enhancing G6PD expression.

Metabolic reprogramming is a hallmark of cancers crucial for fulfilling the needs of energy, building blocks, and antioxidants to support tumor cells' rapid proliferation and to cope with the harsh microenvironment. Pre-B-cell leukemia transcription factor 3 (PBX3) is a member of the PBX family whose expression is up-regulated in various tumors, however, whether it is involved in tumor cell metabolic reprogramming remains unclear. Herein, we report that PBX3 is a positive regulator of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway (PPP). PBX3 promoted G6PD transcriptional activity in tumor cells by binding directly to its promoter, leading to PPP stimulation and enhancing the production of nucleotides and NADPH, a crucial reductant, thereby promoting nucleic acid and lipid biosynthesis while decreasing intracellular reactive oxygen species levels. The PBX3/G6PD axis also promoted tumorigenic potential in vitro and in vivo. Collectively, these findings reveal a novel function of PBX3 as a regulator of G6PD, linking its oncogenic activity with tumor cell metabolic reprogramming, especially PPP. Furthermore, our results suggested that PBX3 is a potential target for metabolic-based anti-tumor therapeutic strategies.