MILIP Binding to tRNAs Promotes Protein Synthesis to Drive Triple-Negative Breast Cancer.

Patients with triple-negative breast cancer (TNBC) have a poor prognosis due to the lack of effective molecular targets for therapeutic intervention. Here we found that the long noncoding RNA (lncRNA) MILIP supports TNBC cell survival, proliferation, and tumorigenicity by complexing with transfer RNAs (tRNA) to promote protein production, thus representing a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, and MILIP silencing suppressed TNBC cell viability and xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its established role in repressing p53 in other types of cancers. Mechanistic investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1α1) and formed an RNA-RNA duplex with the type II tRNAs tRNALeu and tRNASer through their variable loops, which facilitated the binding of eEF1α1 to these tRNAs. Disrupting the interaction between MILIP and eEF1α1 or tRNAs diminished protein synthesis and cell viability. Targeting MILIP inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identify MILIP as an RNA translation elongation factor that promotes protein production in TNBC cells and reveal the therapeutic potential of targeting MILIP, alone and in combination with other types of protein synthesis inhibitors, for TNBC treatment. SIGNIFICANCE: LncRNA MILIP plays a key role in supporting protein production in TNBC by forming complexes with tRNAs and eEF1α1, which confers sensitivity to combined MILIP targeting and protein synthesis inhibitors.

Actomyosin Activity and Piezo1 Activity Synergistically Drive Urinary System Fibroblast Activation.

Mechanical cues play a crucial role in activating myofibroblasts from quiescent fibroblasts during fibrosis, and the stiffness of the extracellular matrix is of significant importance in this process. While intracellular force mediated by myosin II and calcium influx regulated by Piezo1 are the primary mechanisms by which cells sense and respond to mechanical forces, their intercellular mechanical interaction remains to be elucidated. Here, hydrogels with tunable substrate are used to systematically investigate the crosstalk of myosin II and Piezo1 in fibroblast to myofibroblast transition (FMT). The findings reveal that the two distinct signaling pathways are integrated to convert mechanical stiffness signals into biochemical signals during bladder-specific FMT. Moreover, it is demonstrated that the crosstalk between myosin II and Piezo1 sensing mechanisms synergistically establishes a sustained feed-forward loop that contributes to chromatin remodeling, induces the expression of downstream target genes, and ultimately exacerbates FMT, in which the intracellular force activates Piezo1 by PI3K/PIP3 pathway-mediated membrane tension and the Piezo1-regulated calcium influx enhances intracellular force by the classical FAK/RhoA/ROCK pathway. Finally, the multifunctional Piezo1 in the complex feedback circuit of FMT drives to further identify that targeting Piezo1 as a therapeutic option for ameliorating bladder fibrosis and dysfunction.

A Large Genetic Causal Analysis of the Gut Microbiota and Urological Cancers: A Bidirectional Mendelian Randomization Study.

BACKGROUND: Several observational studies and clinical trials have shown that the gut microbiota is associated with urological cancers. However, the causal relationship between gut microbiota and urological cancers remains to be elucidated due to many confounding factors. METHODS: In this study, we used two thresholds to identify gut microbiota GWAS from the MiBioGen consortium and obtained data for five urological cancers from the UK biobank and Finngen consortium, respectively. We then performed a two-sample Mendelian randomization (MR) analysis with Wald ratio or inverse variance weighted as the main method. We also performed comprehensive sensitivity analyses to verify the robustness of the results. In addition, we performed a reverse MR analysis to examine the direction of causality. RESULTS: Our study found that family Rikenellaceae, genus Allisonella, genus Lachnospiraceae UCG001, genus Oscillibacter, genus Eubacterium coprostanoligenes group, genus Eubacterium ruminantium group, genus Ruminococcaceae UCG013, and genus Senegalimassilia were related to bladder cancer; genus Ruminococcus torques group, genus Oscillibacter, genus Barnesiella, genus Butyricicoccus, and genus Ruminococcaceae UCG005 were related to prostate cancer; class Alphaproteobacteria, class Bacilli, family Family XI, genus Coprococcus2, genus Intestinimonas, genus Lachnoclostridium, genus Lactococcus, genus Ruminococcus torques group, and genus Eubacterium brachy group were related to renal cell cancer; family Clostridiaceae 1, family Christensenellaceae, genus Eubacterium coprostanoligenes group, genus Clostridium sensu stricto 1, and genus Eubacterium eligens group were related to renal pelvis cancer; family Peptostreptococcaceae, genus Romboutsia, and genus Subdoligranulum were related to testicular cancer. Comprehensive sensitivity analyses proved that our results were reliable. CONCLUSIONS: Our study confirms the role of specific gut microbial taxa on urological cancers, explores the mechanism of gut microbiota on urological cancers from a macroscopic level, provides potential targets for the screening and treatment of urological cancers, and is dedicated to providing new ideas for clinical research.

CX3CL1/CX3CR1 axis alleviates inflammation and apoptosis in human nucleus pulpous cells via M2 macrophage polarization.

CX3C chemokine ligand 1 (CX3CL1) belongs to the CX3C chemokine family and is involved in various disease processes. However, its role in intervertebral disc degeneration (IDD) remains to be elucidated. In the present study, western blotting, reverse transcription-quantitative PCR and ELISA assays were used to assess target gene expression. In addition, immunofluorescence and TUNEL staining were used to assess macrophage infiltration, monocyte migration and apoptosis. The present study aimed to reveal if and how CX3CL1 regulates IDD progression by exploring its effect on macrophage polarization and apoptosis of human nucleus pulposus cells (HNPCs). The data showed that CX3CL1 bound to CX3C motif chemokine receptor 1 (CX3CR1) promoted the M2 phenotype polarization via JAK2/STAT3 signaling, followed by increasing the secretion of anti-inflammatory cytokines from HNPCs. In addition, HNPC-derived CX3CL1 promoted M2 macrophage-derived C-C motif chemokine ligand 17 release thereby reducing the apoptosis of HNPCs. In clinic, the reduction of mRNA and protein levels CX3CL1 in degenerative nucleus pulposus tissues (NPs) was measured. Increased M1 macrophages and pro-inflammatory cytokines were found in NPs of IDD patients with low CX3CL1 expression. Collectively, these findings suggested that the CX3CL1/CX3CR1 axis alleviates IDD by reducing inflammation and apoptosis of HNPCs via macrophages. Therefore, targeting CX3CL1/CX3CR1 axis is expected to produce a new therapeutic approach for IDD.

Anticancer activity of oleanolic acid and its derivatives modified at A-ring and C-28 position.

Oleanolic acid (OA) is a five-ring triterpenoid compound, which is widely present in plants. Due to a wide range of pharmacological activities, oleanolic acid has attracted more and more attention. However, oleanolic acid is insoluble in water and has low bioavailability, which limits its clinical application. In this review, we focus on summarizing the anti-cancer activity and mechanism of the A ring or C-28 carboxyl modified derivatives of OA since 2015, to determine the strength of its anti-cancer effectiveness and evaluate whether it could be used as a clinical anti-cancer drug.

The N-Myc-responsive lncRNA MILIP promotes DNA double-strand break repair through non-homologous end joining.

The protooncoprotein N-Myc, which is overexpressed in approximately 25% of neuroblastomas as the consequence of MYCN gene amplification, has long been postulated to regulate DNA double-strand break (DSB) repair in neuroblastoma cells, but experimental evidence of this function is presently scant. Here, we show that N-Myc transcriptionally activates the long noncoding RNA MILIP to promote nonhomologous end-joining (NHEJ) DNA repair through facilitating Ku70-Ku80 heterodimerization in neuroblastoma cells. High MILIP expression was associated with poor outcome and appeared as an independent prognostic factor in neuroblastoma patients. Knockdown of MILIP reduced neuroblastoma cell viability through the induction of apoptosis and inhibition of proliferation, retarded neuroblastoma xenograft growth, and sensitized neuroblastoma cells to DNA-damaging therapeutics. The effect of MILIP knockdown was associated with the accumulation of DNA DSBs in neuroblastoma cells largely due to decreased activity of the NHEJ DNA repair pathway. Mechanistical investigations revealed that binding of MILIP to Ku70 and Ku80 increased their heterodimerization, and this was required for MILIP-mediated promotion of NHEJ DNA repair. Disrupting the interaction between MILIP and Ku70 or Ku80 increased DNA DSBs and reduced cell viability with therapeutic potential revealed where targeting MILIP using Gapmers cooperated with the DNA-damaging drug cisplatin to inhibit neuroblastoma growth in vivo. Collectively, our findings identify MILIP as an N-Myc downstream effector critical for activation of the NHEJ DNA repair pathway in neuroblastoma cells, with practical implications of MILIP targeting, alone and in combination with DNA-damaging therapeutics, for neuroblastoma treatment.

Effect of Psychological Nursing Intervention on Abnormal-Induced Labor of Fetus during Puerperium: Study on the Effects of Anxiety, Depression, and Life Events.

Objective: To study the effects of psychological nursing intervention on anxiety, depression, and life events in puerperal women with fetal abnormalities. Methods: From January 2020 to January 2022, eighty women with abnormal fetal induction and puerperium-treated were selected in our hospital as the subjects. The research group (n = 40) and control group (n = 40) were arbitrarily selected from 80 women with abnormal fetal induction and puerperium. The research group was given psychological nursing intervention based on routine nursing, and the control cases were given routine nursing. The scores of Generalized Anxiety Scale (GAD-7), Patient Health Questionnaire (PHQ-9), Event Impact Scale (IES-R), Life Events Scale (LES), and Newcastle Nursing Satisfaction Scale (NSNS) were studied before nursing and 4 weeks after discharge. Results: Four weeks after discharge, the score of GAD-7 in the research group was lower, and the difference was statistically significant (P < 0.05). The score of PHQ-9 in the research group was lower, and the difference was statistically significant (P < 0.05). The IES-R score of the research group was lower, and the difference was statistically significant (P < 0.05). The LES score of the research group was lower, and the difference was statistically significant (P < 0.05). And the NSNS score of the research group was higher, and the difference was statistically significant (P < 0.05). Conclusion: The value of psychological care interventions in women with abnormally induced labor is more remarkable, contributing to the reduction of anxiety and depression and increasing the satisfaction of care for women with abnormally induced labor.

Serum ferritin levels in children with attention deficit hyperactivity disorder and tic disorder.

BACKGROUND: Iron plays an important role in neurodevelopmental functions in the brain. Serum ferritin levels are different in children with attention deficit hyperactivity disorder and tic disorder than in healthy children. AIM: To explore the current status of iron deficiency in children with neurodevelopmental disorders and its sex and age effects. METHODS: A total of 1565 children with attention deficit hyperactivity disorder (ADHD), 1694 children with tic disorder (TD), 93 children with ASD and 1997 healthy control children were included between January 1, 2020, and December 31, 2021 at Beijing Children's Hospital. We describe the differences in age levels and ferritin levels between different disease groups and their sex differences. The differences between the sexes in each disease were analyzed using the t test. The incidence rate of low serum ferritin was used to describe the differences between different diseases and different age groups. A chi-square test was used to analyze the difference in the incidence of low serum ferritin between the disease group and the control group. Analysis of variance was used for comparisons between subgroups, and regression analysis was used for confounding factor control. RESULTS: A total of 1565 ADHD patients aged 5-12 years were included in this study, and the average serum ferritin levels of male and female children were 36.82 ± 20.64 µg/L and 35.64 ± 18.56 µg/L, respectively. A total of 1694 TD patients aged 5-12 years were included in this study, and the average serum ferritin levels of male and female children were 35.72 ± 20.15 µg/L and 34.54 ± 22.12 µg/L, respectively. As age increased, the incidence of low serum ferritin in ADHD and TD first decreased and then increased, and 10 years old was the turning point of rising levels. The incidence of ADHD with low serum ferritin was 8.37%, the incidence of TD with low serum ferritin was 11.04%, and the incidence of the healthy control group with low serum ferritin was 8.61%, among which male children with TD accounted for 9.25% and female children with TD accounted for 11.62%. There was a significant difference among the three groups (P < 0.05). In addition, there were 93 children with ASD with an average serum ferritin level of 30.99 ± 18.11 µg/L and a serum ferritin incidence of 15.05%. CONCLUSION: In conclusion, low serum ferritin is not a risk factor for ADHD or TD. The incidence of low serum ferritin levels in children with ADHD and TD between 5 and 12 years old decreases first and then increases with age.

Capsaicin suppresses hepatocarcinogenesis by inhibiting the stemness of hepatic progenitor cells via SIRT1/SOX2 signaling pathway.

BACKGROUND & AIMS: Capsaicin, a functional component of chili pepper, possesses anti-inflammatory, analgesic, and anti-cancer properties. This study aimed to determine the property of capsaicin against hepatocarcinogenesis in vivo and investigate the role of the SIRT1/SOX2 pathway in the mode of action of capsaicin in hepatic progenitor cells (HPCs), which is related to hepatocarcinogenesis. MATERIALS & METHODS: We prepared a diethylnitrosamine-induced liver cancer model in rats to examine hepatocarcinogenesis, and delivered liposomal capsaicin through the subcutaneous transposition of the spleen to the liver. Liver sections from rats and hepatocarcinoma patients were stained for the markers of HPCs or SIRT1/SOX2 signaling. SIRT1/SOX2 signalling expression was measured using immunoprecipitation and western blot. RESULTS: We found that capsaicin significantly inhibited hepatocarcinogenesis. Notably, capsaicin inhibited HPCs activation in vivo but did not induce apoptosis in the normal hepatic progenitor cell line in rats in vitro. This suggests that capsaicin suppresses hepatocarcinogenesis by inhibiting the stemness of HPCs. Moreover, capsaicin can induce this inhibition by reducing the stability of SOX2. SIRT1 is overexpressed in liver cancer and acts as a tumor promoter via SOX2 deacetylation. Using immunoprecipitation, we identified direct binding between SIRT1 and SOX2. The capsaicin treatment resulted in SIRT1 downregulation which reduced deacetylation, and increased nuclear export as well as subsequent ubiquitous degradation of SOX2. CONCLUSIONS: Altogether, we report that capsaicin suppresses hepatocarcinogenesis by inhibiting the stemness of HPCs via SIRT1/SOX2 signaling. It may serve as a promising therapeutic candidate for liver cancer.

Current management strategy of treating patients with erectile dysfunction after radical prostatectomy: a systematic review and meta-analysis.

The aim of this study is to present a summary of current evidence concerning the various treatments in the management of penile rehabilitation after radical prostatectomy (RP) and provide recommendations for future research. Randomized controlled trials (RCTs) were identified from electronic databases including PubMed, the Cochrane Library, Embase, and Web of Science from inception through March 2020 with no limitation to language. Comparable data from each study were combined in a meta-analysis where possible, otherwise data were synthesized narratively. The data analysis was completed by Review Manager version 5.3. A total of 39 RCTs were included in this study. At present, phosphodiesterase type 5 inhibitors (PDE5is) remain the first-line treatment for patients with erectile dysfunction (ED) after RP. Compared with the placebo group, patients in regular PDE5is group (mean difference (MD): 0.76; 95% confidence interval (CI): 1.69-4.44; p < 0.0001) and on demand group (MD: 3.92; 95% CI: 2.95-4.88; p < 0.00001) had a significantly higher mean Erectile Function domain of the International Index of Erectile Function (IIEF-EF) scores within 3 months after RP. As for the proportion of IIEF-EF ≥ 22, patients in regular PDE5is group and on demand PDE5is group had significantly higher proportion than those in placebo group 6 months after RP, and the odds ratios were 1.87 (95% CI: 1.32-2.66; p = 0.0005) and 2.17 (95% CI: 1.20-3.93; p = 0.01), respectively. No significant difference was observed between regular PDE5is group and on demand group regardless of mean IIEF-EF score or the proportion of IIEF-EF ≥ 22. Intracorporeal injection therapy seemed to have similar efficacy to PDE5is. The International Index of Erectile Function-5 items (IIEF-5) scores were significantly higher in vacuum constriction devices group than control group at 6-9 months after RP (MD: 6.70, 95% CI: 2.30-11.10, p = 0.003) with great between-study heterogeneity (p = 0.06, I2 = 72%). The other therapeutics including low-intensity extracorporeal shockwave therapy, statin therapy, psychotherapy interventions, and pelvic floor muscle training plus electrical stimulation showed certain improvement on erectile function. We found that the combination therapy showed certain advantages over monotherapy. Currently, PDE5is-based combination therapy remains the mainstream treatment for ED after RP. Intracorporeal injection therapy and vacuum therapy could be served as alternative treatments if PDE5is are ineffective and contraindicated.

Anti-Allergic Rhinitis Mechanism of Bikangfu via Regulation of IL-35/STAT3， Inhibition of Eosinophil Activation and Improvement of Immune Function / 中国实验方剂学杂志

ObjectiveTo investigate the mechanism of interleukin-35（IL-35）/signal transducer and activator of transcription 3（STAT3）inhibition of eosinophil activation against allergic rhinitis（AR） by Bifukang. MethodOne hundred patients were randomly divided into a control group and a treatment group，50 cases in each group. The control group was given mometasone furoate nasal spray，and the treatment group was given Bifukang by nasal packing. The course of treatment was 28 days. The clinical efficacy，nasal classification and visual analogue scale（VAS） score of the two groups were observed before and after treatment. Enzyme linked immunosorbent assay（ELISA） was used to detect the expression levels of inflammatory factors ［interleukin（IL）-4，IL-10，IL-17，IL-35］ and Eotaxin and CC chemokine receptor-3（CCR3）in serum and nasal secretion of the two groups. The expression levels of STAT1，STAT3 and STAT4 were detected by real-time polymerase chain reaction（Real-time PCR）.The content of immunoglobulin G（IgG） and the ratio of CD4+/CD8+were detected by ELISA and flow cytometry. ResultAfter treatment， compared with before treatment， the levels of IL-4 and IL-17 in serum and nasal secretion in 2 groups were decreased， while the levels of IL-10 and IL-35 were increased （P<0.05， P<0.01）. The expression of STAT1， STAT2 and STAT3 in nasal secretions were significantly decreased （P<0.05）. IgG and CD4+/CD8+ were decreased， and the differences were statistically significant （P<0.05， P<0.01）.After treatment，compared with the control group，the levels of IL-4 and IL-17 in serum and nasal secretions of the treatment group were decreased，while the levels of IL-10 and IL-35 were increased （P<0.05）. The expression of STAT1，STAT3 and STAT4 in the treatment group was significantly inhibited compared with the control group after treatment （P<0.05）. In addition， the post-treatment serum CD4+/CD8+ and immunoglobulin G （IgG） levels were reduced in the treatment group compared with those of the control group （P<0.05， P<0.01）. During the treatment，there were no abnormal changes in heart，liver，kidney function and routine blood and urine tests in the two groups. ConclusionBifukang has a good effect on allergic rhinitis，and its mechanism may be related to the regulation of IL-35/STAT3 pathway，the inhibition of eosinophil activation and the improvement of related immune function.

Does Listening to Music Improve Pain Perception and Anxiety in Patients Undergoing Cystoscopy: A Meta-Analysis.

Objective: To identify the effect of music on outpatient-based cystoscopy. Methods: We systematically reviewed the effect of music on all reported outpatient for cystoscopy and extracted data from randomized trials from inception to February 3, 2021, with no language restrictions. The analysis was completed via STATA version 14.2. Results: A total of 27 studies were initially identified, and 6 articles containing 639 patients were included in the final analysis. In terms of post-procedural pain perception, a pooled analysis of 6 articles containing 639 patients showed that music seems to improve discomfort in patients who undergo cystoscopy (WMD: -1.72; 95%CI: -2.37 to -1.07). This improvement remained consistent in patients undergoing flexible cystoscopy (FC) (WMD: -1.18; 95% CI: -1.39 to -0.98) and rigid cystoscopy (RC) (WMD: -2.56; 95% CI: -3.64 to -1.48). The music group also had less post-procedural anxiety than those in no music group during cystoscopy (WMD: -13.33; 95% CI: -21.61 to -5.06), which was in accordance with the result of FC (WMD: -4.82; 95% CI: -6.38 to -3.26) than RC (WMD: -26.05; 95% CI: -56.13 to 4.04). Besides, we detected a significantly lower post-procedural heart rate (HR) in the music group than no music group during cystoscopy (WMD: -4.04; 95% CI: -5.38 to -2.71), which is similar to the results of subgroup analysis for FC (WMD: -3.77; 95% CI: -5.84 to -1.70) and RC (WMD: -4.24; 95% CI: -5.98 to -2.50). A pooled analysis of three trials indicated that patients in the music group had significantly higher post-operative satisfaction visual analog scale (VAS) scores than those in the no-music group during RC. However, there was no significant difference between the music group and no music group regarding post-procedural systolic pressures (SPs) during cystoscopy (WMD: -3.08; 95% CI: -8.64 to 2.49). For male patients undergoing cystoscopy, the music seemed to exert a similar effect on decreasing anxiety and pain, and it might serve as a useful adjunct to increase procedural satisfaction. Conclusions: These findings indicate that listening to music contributes to the improvement of pain perception, HR, and anxiety feeling during cystoscopy, especially for male patients undergoing RC. Music might serve as a simple, inexpensive, and effective adjunct to sedation during cystoscopy.

Trajectory patterns of blood pressure change up to six years and the risk of dementia: a nationwide cohort study.

The present study aimed to investigate the associations between the trajectory of blood pressure (BP) change and the risk of subsequent dementia and to explore the differences in age, gender, and hypertension subgroups. We included 10,660 participants aged ≥ 60 years from 1998 to 2018 waves of the Chinese Longitudinal Healthy Longevity Survey. Latent growth mixture models were used to estimate BP trajectories. Cox-proportional hazard models were used to analyze the effects of BP trajectories on the risk of dementia. According to the results, stabilized systolic BP (SBP) was found to be associated with a higher risk of dementia compared with normal SBP [adjusted hazard ratio (aHR): 1.62; 95% confidence interval (CI): 1.27-2.07] and elevated SBP (aHR: 2.22; 95% CI: 1.51-3.28) in and only in the subgroups of the oldest-old, women, and subjects without hypertension at baseline. Similarly, stabilized pulse pressure (PP) was associated with a higher risk of dementia compared with normal PP (aHR: 1.52; 95% CI: 1.24-1.88) and elevated PP (aHR: 2.12; 95% CI: 1.48-3.04) in and only in the subgroups of the oldest-old, women, and subjects with hypertension at baseline. These findings suggest that stabilized SBP and PP have predictive significance for the occurrence of dementia in late life, and the factors of age, gender, and late-life hypertension should be considered when estimating the risk of BP decline on dementia.

The pan-cancer lncRNA PLANE regulates an alternative splicing program to promote cancer pathogenesis.

Genomic amplification of the distal portion of chromosome 3q, which encodes a number of oncogenic proteins, is one of the most frequent chromosomal abnormalities in malignancy. Here we functionally characterise a non-protein product of the 3q region, the long noncoding RNA (lncRNA) PLANE, which is upregulated in diverse cancer types through copy number gain as well as E2F1-mediated transcriptional activation. PLANE forms an RNA-RNA duplex with the nuclear receptor co-repressor 2 (NCOR2) pre-mRNA at intron 45, binds to heterogeneous ribonucleoprotein M (hnRNPM) and facilitates the association of hnRNPM with the intron, thus leading to repression of the alternative splicing (AS) event generating NCOR2-202, a major protein-coding NCOR2 AS variant. This is, at least in part, responsible for PLANE-mediated promotion of cancer cell proliferation and tumorigenicity. These results uncover the function and regulation of PLANE and suggest that PLANE may constitute a therapeutic target in the pan-cancer context.

Effects of baicalin capsules combined with α-lipoic acid on nerve conduction velocity, oxidative stress and inflammatory injury in patients with diabetic peripheral neuropathy.

OBJECTIVE: To observe the effects of baicalin capsules combined with α-lipoic acid on nerve conduction velocity, oxidative stress and inflammatory injury in patients with diabetic peripheral neuropathy. METHODS: A total of 96 patients with diabetic peripheral neuropathy who received treatment in our hospital were divided into the control group (CG) and the research group (SG) by a randomized double-blind method, with 48 cases in each group. In the CG, patients were treated with α-lipoic acid. In the SG, patients were treated with baicalin capsules combined with α-lipoic acid. The clinical efficacy, symptoms (neuropathic subjective symptom questionnaire (TSS) score), nerve conduction velocity, oxidative stress indicators (superoxide dismutase (SOD) and malondialdehyde (MDA)), inflammatory injury indicators (hs-C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor (TNF-α)) and adverse reactions were compared between the two groups. RESULTS: The clinical efficacy in the SG was higher than that in the CG (P<0.05). After treatment, the TSS score and the levels of serum SOD, MDA, TNF-α, IL-6 and CRP decreased in both groups, and the SG was lower than the CG (P<0.05). After treatment, the motor conduction velocity (MCV) and sensory conduction velocity (SCV) velocities of the tibial nerve and common peroneal nerve increased in both groups, and the SG was higher than the CG (P<0.05). There was no statistical difference in adverse drug reactions between the two groups (P>0.05). CONCLUSION: Compared with α-lipoic acid monotherapy, baicalin capsules combined with α-lipoic acid are effective in treating patients with diabetic peripheral neuropathy, this treatment can obviously relieve the clinical symptoms of patients, improve nerve conduction velocity, reduce oxidative stress and inflammatory injury, and it does not increase adverse reactions. Therefore, it is worthy of promotion.

N-cadherin inhibitor creates a microenvironment that protect TILs from immune checkpoints and Treg cells.

BACKGROUND: Few patients with prostate cancer benefit from current immunotherapies. Therefore, we aimed to explore new strategies to change this paradigm. METHODS: Human tissues, cell lines and in vivo experiments were used to determine whether and how N-cadherin impacts the production of programmed death ligand-1 (PD-L1) and indole amine 2,3-dioxygenase (IDO-1) and whether N-cadherin can increase the production of effector (e)Treg cells. Then, we used PC3-bearing humanized non-obese diabetic/severe combined immunodeficiency IL2Rγnull (hNSG) mice with an intravenous injection of human CD34+ hematopoietic stem cells into the tail vein to evaluate whether the N-cadherin antagonist N-Ac-CHAVC-NH2 (designated ADH-1) could improve the therapeutic effect of tumor-infiltrating lymphocyte (TIL)-related treatment. RESULTS: N-cadherin dramatically upregulated the expression of PD-L1 and IDO-1 through IFN-γ (interferongamma) signaling and increasing the production of free fatty acids that could promote the generation of eTreg cells. In preclinical experiments, immune reconstitution mediated by TILs slowed tumor growth and extended the survival time; however, this effect disappeared after immune system suppression by PD-L1, IDO-1 and eTreg cells. Furthermore, ADH-1 effectively reduced immunosuppression and enhanced TIL-related therapy. CONCLUSIONS: These data show that the N-cadherin antagonist ADH-1 promotes TIL antitumor responses. This important hurdle must be overcome for tumors to respond to immunotherapy.