Comprehensive assessment on the association of dietary vitamins with all-cause and cardiovascular mortality among individuals with prediabetes: evidence from NHANES 1999-2018.

Background: Prediabetes has become a global health issue, and currently, the relationship between vitamin levels and mortality in prediabetes remains unclear. This study aims to investigate the association between the levels of eleven vitamins and all-cause and cardiovascular disease (CVD) mortality in prediabetes patients. Methods: This cross-sectional study included 14 634 prediabetes patients from 10 cycles of the National Health and Nutrition Examination Survey between 1999 and 2018. Mortality and underlying causes of death were determined by linking records from the National Death Index until December 31, 2019. Multivariable Cox proportional hazards regression models were established to assess hazard ratios and 95% confidence intervals for all-cause, CVD, cancer, and other mortalities. Restricted cubic splines were used to visualize non-linear associations between various vitamins and mortality risk. Results: During the follow-up period, 2316/14 634 prediabetes patients died (12.55%), with 722 deaths (3.68%) attributed to CVD. After multivariable adjustment, vitamin B1, niacin, folate, vitamin C, vitamin E, and vitamin K levels exhibited non-linear associations with all-cause mortality (all p < 0.05). Vitamin B1, niacin, and vitamin E levels showed non-linear associations with CVD mortality (p < 0.05). Vitamin B6 exhibited a linear negative association with all-cause, CVD, and other mortalities (p > 0.05). However, vitamins A and B2 levels were not significantly associated with mortality rates (all p > 0.05). Consistent results were observed in the subgroup analyses after complete adjustment for variables. Conclusions: Higher levels of dietary vitamins B1, B6, niacin, folate, vitamin C, vitamin E, and vitamin K were significantly associated with lower risk of all-cause mortality and CVD mortality in patients with prediabetes. There was no association between vitamin A and B2 levels and all-cause and CVD mortality among individuals with prediabetes. These findings suggest the importance of correcting vitamin deficiencies to prevent mortality in prediabetes patients.

Identification and experimental validation of genes associated with programmed cell death in dendritic cells of the thyroid tissue in Hashimoto's thyroiditis.

INTRODUCTION: Hashimoto's thyroiditis (HT) is a chronic autoimmune disorder. As antigen-presenting cells, dendritic cells(DCs) play a pivotal role in inducing programmed cell death (PCD) types, contributing to immune disorders. This study aimed to identify genes associated with multiple PCD pathways in dendritic cells within the thyroid tissue of patients with HT. METHODS: ce single-cell RNA-sequencing dataset HRA001684 was obtained from the National Genomics Data Center (NGDC) to calculate the area under the curve (AUC) scores for PCD-related genes. Additionally, mRNA sequencing datasets GSE138198 and HRA001684 were sourced from the Gene Expression Omnibus(GEO) and NGDC, respectively. Differentially expressed genes (DEGs) were identified by comparing normal and HT groups in GSE138198 and HRA001684. The intersection of these DEGs with PCD-related genes led to the identification of 17 PCD-related DEGs(PCDDEGs). RESULTS: AUC scores revealed that DCs in HT exhibited significantly elevated levels of necroptosis, ferroptosis, pyroptosis, autophagy, and PANoptosis, expressing six key PCDDEGs: TNFAIP3, CYBB, PTPN6, STAT1, TGFB1, and NLRP3. These genes displayed an AUC>0.8 for HT in the GSE29315, GSE138198, and HRA001684 datasets, confirming their diagnostic accuracy. Moreover, their expression was positively correlated with the serum levels of thyroid peroxidase and thyroglobulin antibodies, while the expression of all PCDDEGs was negatively correlated with the abundance of thyroid follicular epithelial cells. qRT-PCR, WB, IHC, and IF experiments further confirmed the differences in PCDDEGs gene and protein levels in HT patients. DISCUSSION: These findings highlight the crucial role of DCs in mediating PCD within the thyroid tissues of HT patients. The identified PCDDEGs-TNFAIP3, CYBB, PTPN6, STAT1, TGFB1, and NLRP3-may significantly contribute to HT pathogenesis through PCD pathways.

Relationship Between Serum Thyrotropin Levels and Metabolic Diseases in Older Adults.

CONTEXT: Subclinical hypothyroidism is associated with metabolic diseases; however, it remains controversial in older individuals. OBJECTIVE: This work aimed to investigate the relationship between thyrotropin (TSH) levels and metabolic diseases. METHODS: In this cross-sectional study, sampling was conducted from nationally representative general communities from 31 provinces in mainland China. A total of6791 older (aged ≥65 years) and 55 303 young participants (aged 18-64 years) were selected after excluding individuals with overt hyperthyroidism or overt hypothyroidism. According to the kit, TSH reference range (0.27-4.2 mU/L) and the age-specific TSH range previously formulated (an upper limit of 8.86 mU/L for older adults and 6.57 mU/L for young adults), the older adults and young adults were separately divided into 4 groups based on their TSH levels. Main outcome measures included anthropometric assessments, serum concentrations of thyroid functions, and various metabolic parameters. RESULTS: In contrast to young adults, there was no significant increase in the prevalence of any metabolic disorders assessed in the slightly elevated TSH group (TSH 4.21-8.86 mU/L) compared to the euthyroid group (TSH 0.27-4.2 mU/L) among older adults. After adjusting for interference factors, a TSH level higher than 8.86 mU/L was found to be an independent risk factor for low high-density lipoprotein cholesterol (OR, 1.84; 95% CI, 1.14-2.98) and dyslipidemia (OR, 1.49; 95% CI, 1.09-2.04) when compared to the euthyroid group in older adults. CONCLUSION: Slightly elevated TSH levels are not associated with an increased risk of metabolic diseases in older adults. Therefore, we recommend raising the upper limit of the TSH range for individuals aged 65 years and older.

Evaluation of significantly changed chemokine factors of idiopathic granulomatous mastitis in non-puerperal patients.

Idiopathic granulomatous mastitis (IGM), a recurrent inflammation disease of the non-lactating breast, has had an increasing clinical morbidity rate in recent years, and its complicated symptoms and unclear etiology make it challenging to treat. This rare benign inflammatory breast disease, centered on the lobules, represents the most challenging type of non-puerperal mastitis (NPM), also known as non-lactating mastitis. In this study, patients diagnosed with IGM (M, n = 23) were recruited as cases, and patients with benign control breast disease (C, n = 17) were enrolled as controls. Cytokine microarray detection measured and analyzed the differentially expressed cytokine factors between IGM and control patients. Then, we verified the mRNA and protein expression levels of the significantly changed cytokine factors using Q-RT-PCR, ELISA, western blot, and IHC experiments. The cytokine factor expression levels significantly changed compared to the control group. We observed a significant increase between IGM and control patients in cytokine factors expression, such as interleukin-1ß (IL-1ß), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1α, MIP-1ß, tumor necrosis factor receptor 2 (TNF RII). Then, we verified the expression of these top five dysregulated factors in both mRNA and protein levels. Our results demonstrated the cytokine map in IGM and indicated that several cytokines, especially chemokines, were associated with and significantly dysregulated in IGM tissues compared to the control group. The chemokine factors involved might be essential in developing and treating IGM. These findings would be helpful for a better understanding of IGM and offer valuable insights for devising novel diagnostic and therapeutic strategies.

NLRP3 inflammasome and its role in autoimmune diseases: A promising therapeutic target.

The NOD-like receptor protein 3 (NLRP3) inflammasome is a protein complex that regulates innate immune responses by activating caspase-1 and the inflammatory cytokines IL-1ß and IL-18. Numerous studies have highlighted its crucial role in the pathogenesis and development of inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, autoimmune thyroid diseases, and other autoimmune diseases. Therefore, investigating the underlying mechanisms of NLRP3 in disease and targeted drug therapies holds clinical significance. This review summarizes the structure, assembly, and activation mechanisms of the NLRP3 inflammasome, focusing on its role and involvement in various autoimmune diseases. This review also identifies studies where the involvement of the NLRP3 inflammasome in the disease mechanism within the same disease appears contradictory, as well as differences in NLRP3-related gene polymorphisms among different ethnic groups. Additionally, the latest therapeutic advances in targeting the NLRP3 inflammasome for autoimmune diseases are outlined, and novel clinical perspectives are discussed. Conclusively, this review provides a consolidated source of information on the NLRP3 inflammasome and may guide future research efforts that have the potential to positively impact patient outcomes.

Clinical features and risk factors of bilateral granulomatous lobular mastitis.

Granulomatous lobular mastitis (GLM) is an idiopathic inflammatory breast disease that tends to recur on the same side. With the accumulation of clinical cases, it has been observed that GLM can also occur contralaterally. Currently, most studies on GLM focus on treatment methods and risk factors for ipsilateral recurrence, and there are few reports on bilateral GLM. The study aimed to summarize the clinical characteristics of patients with bilateral GLM by reviewing their clinical data, and to discuss the risk factors affecting the occurrence of bilateral GLM. A retrospective study of the medical records database of patients with GLM admitted between May 2019 and August 2022 was performed. Patients were divided into bilateral GLM group (bilateral GLM group) and unilateral GLM patients (unilateral GLM group). Demographic and clinical characteristics, treatment, and follow-up were collected and analyzed. In this study, by reviewing the clinical data of 59 cases of bilateral GLM, we found that the median time between the onset of bilateral GLM on both sides was 6.63 (0-18) months. Additionally, because of the simultaneous or interval onset on both sides, the duration of the disease was longer compared to unilateral cases. Regarding the history of external hospital treatment, it was found that about 57.63% of patients with bilateral GLM received 2 or more treatment modalities, with a higher involvement of herbal medicine. Meanwhile, by counting the clinical data of the 2 groups of patients with bilateral GLM and unilateral GLM, it was shown by univariate analysis that fertility, nipple development, absolute CD4 value, and CD4/CD8 ratio were associated with contralateral onset of GLM in both groups, with inverted nipple being an independent risk factor.

The relationship between thyroid peroxidase antibody and differentiated thyroid cancer: a systematic review and meta-analysis.

Background: Thyroglobulin antibody (TgAb) has been found to be associated with the occurrence and development of differentiated thyroid cancer (DTC) for several years, but there is still controversy over whether thyroid peroxidase antibody (TPOAb) is related to differentiated thyroid cancer. Methods: We scrutinized relevant studies published up to July 2023 across four major databases including PubMed, Embase, Cochrane Library, and Web of Science, to examine the association between TPOAb and DTC. Clinical outcome measures include the incidence of DTC, tumor size, extrathyroidal invasion, lymph node metastasis, multifocality, recurrence and bilaterality. Results: 12 original studies were included, involving a total of 20,330 subjects. Our analysis of the included studies revealed that TPOAb+ individuals exhibited a higher risk of developing DTC (OR=1.57 [95% CI: 1.00-2.45], p=0.049) than TPOAb- individuals. Furthermore, TPOAb+ DTC patients were more prone to present with bilateral (OR=1.40 [95% CI: 1.21-1.62], p<0.00001) and multifocal (OR=1.40 [95% CI: 1.23-1.60], p<0.00001) tumors than TPOAb- patients. Sensitivity analysis indicated a high sensitivity for these three findings. No significant differences in the risk of extrathyroidal extension and lymph node metastasis, recurrence rate, tumor size, were observed between TPOAb+ and TPOAb- DTC patients. Conclusion: The presence of TPOAb is correlated with an increase prevalence of DTC. However, its effectiveness as a prognostic marker for DTC patients warrants further investigation. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023448824.

A new strategy for the treatment of heavily pretreated metastatic breast cancer: A case report and review of the literature.

BACKGROUND: Breast cancer is one of the most common type of cancers worldwide and remains a critical health issue. Although there are numerous treatment options for advanced metastatic breast cancer, the results are not satisfactory, particularly for triple-negative breast cancer. New treatment modalities need to be explored. CASE PRESENTATION: We present the case of a breast cancer patient with multiple metastases who achieved a good response and tolerance to the combination treatment of utidelone plus capecitabine. After being treated with 10 cycles of combined treatment, the patient is now in a good general condition with a progression-free survival time of 10 months. CONCLUSION: To our knowledge, this is the first report of utidelone plus capecitabine successfully treating a patient with heavily pretreated metastatic breast cancer. This combined treatment offers a new option for patients with multi-drug resistant breast cancer.

HMGB1 and Toll-like receptors: potential therapeutic targets in autoimmune diseases.

HMGB1, a nucleoprotein, is expressed in almost all eukaryotic cells. During cell activation and cell death, HMGB1 can function as an alarm protein (alarmin) or damage-associated molecular pattern (DAMP) and mediate early inflammatory and immune response when it is translocated to the extracellular space. The binding of extracellular HMGB1 to Toll-like receptors (TLRs), such as TLR2 and TLR4 transforms HMGB1 into a pro-inflammatory cytokine, contributing to the occurrence and development of autoimmune diseases. TLRs, which are members of a family of pattern recognition receptors, can bind to endogenous DAMPs and activate the innate immune response. Additionally, TLRs are key signaling molecules mediating the immune response and play a critical role in the host defense against pathogens and the maintenance of immune balance. HMGB1 and TLRs are reported to be upregulated in several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, and autoimmune thyroid disease. The expression levels of HMGB1 and some TLRs are upregulated in tissues of patients with autoimmune diseases and animal models of autoimmune diseases. The suppression of HMGB1 and TLRs inhibits the progression of inflammation in animal models. Thus, HMGB1 and TLRs are indispensable biomarkers and important therapeutic targets for autoimmune diseases. This review provides comprehensive strategies for treating or preventing autoimmune diseases discovered in recent years.

Dermis-retained breast dermo-glandular flap: a new surgical approach for granulomatous lobular mastitis.

Background: Granulomatous lobular mastitis (GLM) is characterized by nonspecific chronic inflammation concentrated in breast lobules. Surgical resection is one of the most common treatment options for GLM. On the basis of our previous use of Breast Dermo-Glandular Flap (BDGF), we designed a new surgical approach for GLM, especially for cases where the focus is close to the nipple. Here we describe this new treatment approach. Methods: In Peking Union Medical College Hospital (PUMCH) and Beijing Dangdai Hospital during January 2020-June 2021, we enrolled all 18 GLM patients who underwent surgery with the use of Dermis-Retained BDGF. All patients were women; most of the patients were 18-50 years old (88%); and the most common clinical manifestation of GLM was breast mass (60%). Then, we collected and analyzed data about the surgery and outcomes (drainage tubes moving time, relapse, patients' shape satisfaction). We regarded GLM recurrence on the same side as relapse. If there was no complication and the patient's satisfaction was excellent or good, we rated the surgery as successful. We recorded the occurrence of all common postsurgical complications of the breast. Results: The debridement area was 3-5.5 (4.3 ± 0.7) cm; surgery time was 78-119 (95.6 ± 11.6) min; and mean debridement time (27.8 ± 8.9 min) was shorter than the time to obtain and transplant the flap (47.5 ± 12.9 min). Blood loss was less than 139 ml. As for bacterial culture, two patients had positive results, but they had no symptoms. No surgery-related complications happened. In terms of the outcomes, all of the drainage tubes were removed in less than 5 days, and only one patient experienced relapse after 1 year of surgery during the follow-up. The patients' satisfaction with the breast shape was as follows: excellent (50%), good (22%), acceptable (22%), and poor (6%). Conclusion: For GLM patients refractory to conservative therapy or former unsatisfactory surgical management whose lesion is in the vicinity of the nipple and larger than 3 cm, Dermis-Retained BDGF is a suitable approach to fill the after-debridement defect below the nipple-areola and achieve a relatively satisfactory cosmetic outcome.

Calcium/calmodulin dependent protein kinase IV in trophoblast cells under insulin resistance: functional and metabolomic analyses.

BACKGROUND: Insulin resistance (IR) is an important determinant of glucose metabolic disturbance and placental dysplasia in gestational diabetes mellitus (GDM). Calcium/calmodulin dependent protein kinase IV (CAMK4) improves insulin IR induced by a high-fat diet (HFD). The current study sought to elucidate the role and potential mechanism of CAMK4 in GDM. METHODS: A GDM model was established in female C57BL/6J mice via HFD feeding for one week before mating and throughout gestation. The IR was elicited by 10-6 M insulin treatment for 48 h in HTR-8/SVneo cells and mouse primary trophoblast cells. The function of CAMK4 was investigated by transfection of overexpression plasmid in HTR-8/SVneo cells and infection of lentivirus loaded with CAMK4 encoding sequence in primary trophoblast cells. Real-time PCR, western blot, cell counting kit-8, transwell, wound healing, dual-luciferase reporter assay, and liquid chromatography/mass spectrometry-based untargeted metabolomics were performed to confirm the effects of CAMK4 on trophoblast cells. RESULTS: Decreased CAMK4 expression was found in the placenta of GDM mice. CAMK4 overexpression ameliorated IR-induced viability impairment, migratory and invasive capacity inhibition, autophagy blocking, insulin signaling inactivation and glucose uptake disorder in trophoblast cells. CAMK4 also transcriptionally activated orphan nuclear receptor NUR77, and the effects of CAMK4 were abrogated by silencing of NUR77. Metabolomics analysis revealed that CAMK4 overexpression caused alterations of amino acid, lipid and carbohydrate metabolism, which were important in GDM. CONCLUSION: Our results indicated that CAMK4/NUR77 axis may provide novel potential targets in GDM treatment.

Changing Iodine Status and the Incidence of Thyroid Disease in Mainland China: A Prospective 20-Year Follow-Up Study.

Background: We aimed to assess the long-term effects of the transition in iodine status on the incidence of thyroid disorders over 20 years of follow-up. Methods: The original prospective cohort study, started in 1999 (n = 3761), classified three regions in north China based on iodine status (insufficient iodine, more than adequate iodine, and excessive iodine, respectively) for 5 years. Subsequently, participants were followed for up to another 15 years to assess the long-term effects of shifts to adequate iodine on the incidence of thyroid disorders. Panshan transitioned from insufficient to adequate iodine, and Huanghua transitioned from excessive to more than adequate iodine. Both regions were compared with Zhangwu, in which iodine status changed from more than adequate to adequate iodine (from 214 to 167.2 µg/L). A cluster sampling method was used to select participants in the three regions. Participants completed questionnaires and underwent thyroid ultrasonography. Urinary iodine concentrations (UICs), serum thyroid hormone concentration, and thyroid antibodies were measured. Results: When the iodine status changed from insufficient to adequate (with the median UIC increasing from 88 to 141.9 µg/L), the incidence density of subclinical hyperthyroidism, positive thyroperoxidase antibody, positive thyroglobulin antibody (TgAb), and goiter decreased significantly (p < 0.05 for all). Additionally, the cumulative incidence of subclinical hypothyroidism was significantly lower compared with the region where the iodine status changed from being more than adequate to adequate (1.9% vs. 6.0%, p < 0.001). When the iodine status changed from excessive to more than adequate (median UIC from 634 to 266.7 µg/L), a significant decrease in the incidence density of subclinical hyperthyroidism, positive thyroid antibodies, positive TgAb, and goiter (p < 0.05 for all) were also found. However, an increase in thyroid nodule incidence density (17.26 vs. 28.25 per 1000 person-years, p < 0.001) was seen. Conclusions: The incidence of thyroid disorders (except for thyroid nodules) stabilized or decreased among adults in the three communities from year 5 to year 15 of follow-up. Appropriate iodine fortification is safe and effective over the long term. Restoring urinary iodine to appropriate levels reduces population risk for thyroid disorders.

Prevalence and risk factors of hypothyroidism after universal salt iodisation: a large cross-sectional study from 31 provinces of China.

OBJECTIVES: To investigate the prevalence and risk factors of hypothyroidism after universal salt iodisation for 20 years in mainland China. DESIGN: Nationwide, cross-sectional survey. SETTING AND PARTICIPANTS: The Thyroid Disorders, Iodine Status and Diabetes epidemiological study included adults from 31 provinces of China. Data included demographic, physical characteristics, urine, serum thyroid-stimulating hormone (TSH), thyroid-peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb) and thyroid ultrasonography. Subclinical hypothyroidism (SCH) was classified into severe SCH (TSH >10 mU/L) and mild SCH (TSH 4.2-9.9 mU/L). A total of 78 470 (38 182 men and 40 288 women) participants were included in the final analysis. RESULTS: The prevalence of hypothyroidism was 13.95%. The prevalence rates of overt hypothyroidism (OH) and SCH were 1.02% and 13.93%, which mild SCH was significantly higher than severe SCH (12.18% vs 0.75%). Prevalence was higher in women than in men, and this gender difference was noted among all age groups. The prevalence of mild SCH, severe SCH and OH increases by 1.16%, 1.40% and 1.29% for every 10 years older. TPOAb or/and TgAb positive were significantly associated with OH and severe SCH (OR 15.9, p<0.001). However, SCH was positively correlated with increased urine iodine concentration, but this correlation was only in antibody-negative female patients. In non-autoimmune and male populations, there was a U-shaped relationship between severe SCH and OH and urine iodine concentration. CONCLUSIONS: Mild SCH is the most common form of hypothyroidism, which is related to iodine intake. Severe SCH is more similar to OH which autoimmune is the main cause. The various effects of iodine on hypothyroidism depend on thyroid autoimmune and gender.

Bibliometric Analysis and Visualization of Research Progress in the Diabetic Nephropathy Field from 2001 to 2021.

Methods: The PubMed database was searched to identify all studies related to DN that were published from 2001 to 2021, with these studies being separated into four time-based groups. The characteristics of these studies were analyzed and extracted using BICOMB. Biclustering analyses for each of these groups were then performed using gCLUTO, with these results then being analyzed and GraphPad Prism 5 being used to construct strategy diagrams. The social network analyses (SNAs) for each group of studies were conducted using NetDraw and UCINET. Results: In total, 18,889 DN-associated studies published from 2001 to 2021 and included in the PubMed database were incorporated into the present bibliometric analysis. Biclustering analysis and strategy diagrams revealed that active areas of research interest in the DN field include studies of the drug-based treatment, diagnosis, etiology, pathology, physiopathology, and epidemiology of DN. The specific research topics associated with these individual areas, however, have evolved over time in a dynamic manner. Strategy diagrams and SNA results revealed podocyte metabolism as an emerging research hotspot in the DN research field from 2010 to 2015, while DN-related microRNAs, signal transduction, and mesangial cell metabolism have emerged as more recent research hotspots in the interval from 2016 to 2021. Conclusion: Through analyses of PubMed-indexed studies pertaining to DN published since 2001, the results of this bibliometric analysis offer a knowledge framework and insight into active and historical research hotspots in the DN research space, enabling investigators to readily understand the dynamic evolution of this field over the past two decades. Importantly, these analyses also enable the prediction of future DN-related research hotspots, thereby potentially guiding more focused and impactful research efforts.

Stromal Homeostasis-Restoring Nanomedicine Enhances Pancreatic Cancer Chemotherapy.

The desmoplastic stroma imposes a fatal physical delivery barrier in pancreatic ductal adenocarcinoma (PDAC) therapy. Deconstructing the stroma components hence predominates in stroma-targeting approaches, but conflicting outcomes have sometimes occurred due to the multifaceted nature of the stroma. Here, we constructed two sub-20-nm nanomedicines based on a so-called "next-wave" antifibrotic halofuginone (HF) and the tumoricidal paclitaxel (PTX) for enhanced PDAC chemotherapy. This was achieved by coassembling methoxy poly(ethylene glycol)-b-poly(caprolactone) with ketal-linked HF- and PTX-derived prodrugs. HF nanomedicine and PTX nanomedicine had excellent prodrug-nanocarrier compatibility and exhibited greatly improved pharmacokinetic profiles and high tumor accumulation. HF nanomedicine pretreatment restored stromal homeostasis and considerably facilitated the distribution of PTX nanomedicine and its penetration into carcinoma cells, leading to positive modulation of the infiltration of cytotoxic T cells and significant regression of tumor growth in two PDAC models. Our nanomedicine-based stromal remodeling strategy appears promising for treating desmoplastic malignancies.

Microcrystals of Ketal-Linked Paliperidone Prodrugs for Long-Acting Antipsychotics.

Intramuscularly injectable long-acting prodrug-based microcrystals (MCs) are of particular interest for chronic disease management. Nevertheless, current prevalently used linkers degraded by enzymes have the potential drawback of substantial differences in enzyme levels between individuals. Here, we reported the synthesis of a stearyl-modified paliperidone prodrug (SKP) with an acid-sensitive ketal linker for developing long-acting MC antipsychotics. SKP-MCs of three different sizes were prepared and systematically examined. We found that paliperidone exposure in SKP-MC-treated rats was prolonged compared with that in rats treated with the commercial antipsychotic Invega Sustenna and that the drug release rate decreased with increasing MC size. In inflammation-inhibition-model rats, paliperidone release from the SKP-MCs was considerably decreased, indicating that the immune-mediated foreign-body response after intramuscular administration boosted paliperidone release. Our findings will provide valuable insights into in vivo drug release from prodrug-based MC formulations. The ketal-linked prodrug strategy might be a new solution for developing long-acting prodrug formulations of hydroxyl-group-bearing drugs.

Evaluate the diagnostic and prognostic value of NUSAP1 in papillary thyroid carcinoma and identify the relationship with genes, proteins, and immune factors.

BACKGROUND: Nucleolar spindle-associated protein 1 (NUSAP1) is reported to be a useful diagnostic and prognostic marker for a variety of cancers, but relevant studies are lacking in papillary thyroid carcinoma (PTC). METHODS: The relationship between NUSAP1 expression and the overall survival (OS) of pan-cancer was examined by GEPIA and KMplot. We explored the relationship between NUSAP1 and clinical PTC data based on the THCA dataset of TCGA and the GEO dataset of NCBI; GO, KEGG analysis, and ceRNA networks were performed on co-expressed genes through LinkedOmics and Starbase. We assessed the relevance between NUSAP1 and the tumor microenvironment using ESTIMATE, correlations between NUSAP1 and immune cells with TIMER, the relationship between NUSAP1 and immunotherapy by TCIA, and small-molecule drugs targeting NUSAP1 that can be discovered using the CMap database. RESULTS: Higher expression of NUSAP1 in pan-cancer tissues was correlated with shorter OS. NUSAP1 was also significantly expressed in PTC tissues and was an independent prognostic risk factor. Compared to the NUSAP1 low expression group, the NUSAP1 high expression group was more likely to also have lymph node metastasis, pathological PTC type, shorter progression-free survival (PFS), and higher scores for immune checkpoint inhibitor treatment. The genes associated with NUSAP1 were mostly involved in the cell cycle, immune-related pathways, and AITD. Ten lncRNAs (GAS5, SNHG7, UCA1, SNHG1, HCP5, DLEU2, HOTAIR, TP53TG1, SNHG12, C9orf106), eleven miRNAs (hsa-miR-10a-5p, hsa-miR-10b-5p, hsa-miR-18a-5p, hsa-miR-18b-5p, hsa-miR-128-3p, hsa-miR-214-3p, hsa-miR-219a-2-3p, hsa-miR-339-5p, hsa-miR-494-3p, hsa-miR-545-3p, hsa-miR-769-5p), and one mRNA (NUSAP1) were constructed. NUSAP1 participated in the formation of the tumor microenvironment. CMap predicted the 10 most important small molecules about NUSAP1. CONCLUSIONS: In PTC, NUSAP1 shows good diagnostic value and prognostic value; NUSAP1 impacts the cell cycle, immune-related pathways, and AITD and has a complex effect on the tumor microenvironment in PTC.

Postoperative Ileus with the Topical Application of Tongfu Decoction Based on Network Pharmacology and Experimental Validation.

Objective: Postoperative gastrointestinal dysfunction is a common and important complication of surgery. This study aimed to explore the key pharmacological mechanisms of Tongfu decoction in treating postoperative ileus (POI). Methods: The active ingredients of Tongfu decoction and their targets were screened using the TCMSP database and STITCH and SwissTargetPrediction databases, respectively. The GeneCards and DisGeNET databases were used to obtain POI dysfunction-related therapeutic targets. After screening, a drug-active-ingredient-therapeutic target network was constructed and the key target functional enrichment analysis was carried out. The Sprague-Dawley rats with POI were used for in vivo experimental verification. The serum levels of IL-1ß, IL-6, IL-10, IFN-γ, and MCP-1 were measured after surgery using enzyme-linked immunosorbent assay. The Western blot analysis was used to determine the expression of key proteins of the PI3K-Akt signaling pathway in colon tissues. Results: An interaction network was constructed containing 7 Chinese medicine components, 36 compounds, and 85 target proteins. The functional enrichment analysis showed that the target proteins mainly acted on the POI through the PI3K-Akt signaling pathway. In in vivo experiments, Tongfu decoction had a promoting effect on the serum level of IL-10, an inhibitory effect on the serum levels of IL-1ß and CCL2, and an inhibitory effect on the local expression of PI3K, pAkt, and mTOR in colon tissue. In addition, the Tongfu decoction increased the intestinal ink advancing rate. Conclusion: Nonoral Tongfu decoction can also be used to treat POI; its mechanism is affected by IL-10 and IL-1ß.The inhibition of the PI3K-Akt signaling pathway affected the treatment with Tongfu decoction by inducing an immune-inflammatory storm in POI.

Iodine deficiency is associated with increased thyroid hormone sensitivity in individuals with elevated TSH.

Objective: Central sensitivity of thyroid hormone refers to the sensitivity of hypothalamic-pituitary-thyroid (HPT) axis to the change in circulating free thyroxine (fT4). A complex relationship exists between thyroxine levels and iodine nutritional status. To explore the relationship between thyroid hormone sensitivity and iodine nutritional status in elevated thyrotropin (TSH), we used national data to assess the relationship between thyroid hormone sensitivity and iodine nutritional status with contrasting demographic characteristics in China. Methods: We enrolled 12,197 participants with TSH > 4.2 mIU/L from China. Serum and urine samples were collected, and we measured serum fT4, TSH, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) levels and urinary iodine concentration (UIC). The thyroid hormone sensitivity indices were calculated based on fT4 and TSH. The thyroid feedback quantile-based index (TFQI) is a new index to reflect thyroid hormone sensitivity. Higher TFQI quartiles indicated lower thyroid hormone sensitivity. Results: The odds ratios (ORs) for the fourth versus first TFQI quartile were 0.84 (95% CI 0.72-0.99) for iodine deficiency, 1.24 (95% CI 1.05-1.47) for TPOAb+, and 0.44 (95% CI 0.40-0.50) for females. The OR of the fourth and first TFQI quartiles for age <30 years and >60 years was 2.09 (95% CI 1.82-2.41) and 1.19 (95% CI 1.05-1.36), respectively (P < 0.05). Other thyroid sensitivity indices also yielded similar results. Conclusion: Thyroid hormone sensitivity and age have a U-shaped association in individuals with elevated TSH. Increased thyroid hormone sensitivity is associated with iodine deficiency and the female gender. Decreased thyroid hormone sensitivity is associated with TPOAb+. These findings are interesting and potentially useful for understanding the interaction between iodine nutrition and the hypothalamic-pituitary-thyroid axis.