The participation of ferroptosis in fibrosis of the heart and kidney tissues in Dahl salt-sensitive hypertensive rats.

BACKGROUND: Salt-sensitive hypertension is often more prone to induce damage to target organs such as the heart and kidneys. Abundant recent studies have demonstrated a close association between ferroptosis and cardiovascular diseases.Therefore, we hypothesize that ferroptosis may be closely associated with organ damage in salt-sensitive hypertension. This study aimed to investigate whether ferroptosis is involved in the occurrence and development of myocardial fibrosis and renal fibrosis in salt-sensitive hypertensive rats. METHODS: Ten 7-week-old male Dahl salt-sensitive (Dahl-SS) rats were adaptively fed for 1 week, then randomly divided into two groups and fed either a normal diet (0.3% NaCl, NDS group) or a high-salt diet (8% NaCl, HDS group) for 8 weeks. Blood pressure of the rats was observed, and analysis of the hearts and kidneys of Dahl-SS rats was conducted via HE-staining, Masson-staining, Prussian-blue-staining, TEM, tissue iron content detection, MDA content detection, immunofluorescence, and Western blot. RESULTS: Compared to the NDS group, rats in the HDS group increases in systolic blood pressure(SBP) and diastolic blood pressure(DBP)(P<0.05);collagen fiber accumulation was observed in the heart and kidney tissues (P<0.01), accompanied by alterations in mitochondrial ultrastructure,reduced mitochondrial volume, and increased density of the mitochondrial double membrane. Additionally,there were significant increases in both iron content and MDA levels(P<0.05). Immunofluorescence and Western blot results both indicated significant downregulation (P<0.05) of xCT and GPX4 proteins associated with ferroptosis in the HDS group. CONCLUSION: Ferroptosis is involved in the damage and fibrosis of the heart and kidney tissues in salt-sensitive hypertensive rats.

Calcineurin and CK2 reciprocally regulate synaptic AMPA receptor phenotypes via α2δ-1 in spinal excitatory neurons.

Calcineurin inhibitors, such as cyclosporine and tacrolimus (FK506), are commonly used immunosuppressants for preserving transplanted organs and tissues. However, these drugs can cause severe and persistent pain. GluA2-lacking, calcium-permeable AMPA receptors (CP-AMPARs) are implicated in various neurological disorders, including neuropathic pain. It is unclear whether and how constitutive calcineurin, a Ca2+/calmodulin protein phosphatase, controls synaptic CP-AMPARs. In this study, we found that blocking CP-AMPARs with IEM-1460 markedly reduced the amplitude of AMPAR-EPSCs in excitatory neurons expressing vesicular glutamate transporter-2 (VGluT2), but not in inhibitory neurons expressing vesicular GABA transporter, in the spinal cord of FK506-treated male and female mice. FK506 treatment also caused an inward rectification in the current-voltage relationship of AMPAR-EPSCs specifically in VGluT2 neurons. Intrathecal injection of IEM-1460 rapidly alleviated pain hypersensitivity in FK506-treated mice. Furthermore, FK506 treatment substantially increased physical interaction of α2δ-1 with GluA1 and GluA2 in the spinal cord and reduced GluA1/GluA2 heteromers in endoplasmic reticulum-enriched fractions of spinal cords. Correspondingly, inhibiting α2δ-1 with pregabalin, Cacna2d1 genetic knockout, or disrupting α2δ-1-AMPAR interactions with an α2δ-1 C-terminus peptide reversed inward rectification of AMPAR-EPSCs in spinal VGluT2 neurons caused by FK506 treatment. In addition, CK2 inhibition reversed FK506 treatment-induced pain hypersensitivity, α2δ-1 interactions with GluA1 and GluA2, and inward rectification of AMPAR-EPSCs in spinal VGluT2 neurons. Thus, the increased prevalence of synaptic CP-AMPARs in spinal excitatory neurons plays a major role in calcineurin inhibitor-induced pain hypersensitivity. Calcineurin and CK2 antagonistically regulate postsynaptic CP-AMPARs through α2δ-1-mediated GluA1/GluA2 heteromeric assembly in the spinal dorsal horn.Significance Statement Clinically used calcineurin inhibitors can cause severe pain, known as calcineurin inhibitor-induced pain syndrome (CIPS). However, its underlying mechanisms remain elusive. This study shows for the first time that calcineurin inhibition caused cell type-specific expression of synaptic Ca2+-permeable AMPARs in spinal cord excitatory neurons. Blocking spinal Ca2+-permeable AMPARs reduced CIPS. Calcineurin inhibition potentiated the α2δ-1 (previously known as a calcium channel subunit) interaction with GluA1 and GluA2 subunits, disrupting their intracellular assembly in the spinal cord. Additionally, inhibiting spinal CK2 diminished α2δ-1-AMPAR interactions and synaptic Ca2+-permeable AMPARs augmented by calcineurin inhibitors. Thus, calcineurin and CK2 dynamically control AMPAR phenotypes in spinal excitatory neurons through α2δ-1-mediated GluA1/GluA2 assembly. Targeting α2δ-1 and CK2 are effective strategies for treating CIPS.

Bioactive prenylated c6-c3 derivatives from the roots of Illicium brevistylum.

Three new prenylated C6-C3 compounds (1-3), together with two known prenylated C6-C3 compounds (4-5) and one known C6-C3 derivative (6), were isolated from the roots of Illicium brevistylum A. C. Smith. The structures of 1-3 were elucidated by spectroscopic methods including 1D and 2D NMR, HRESIMS, CD experiments and ECD calculations. The structure of illibrefunone A (1) was confirmed by single-crystal X-ray diffraction analysis. All compounds were evaluated in terms of their anti-inflammatory potential on nitric oxide (NO) generation in lipopolysaccharide-stimulated murine RAW264.7 macrophages and murine BV2 microglial cells, antiviral activity against Coxsackievirus B3 (CVB3) and influenza virus A/Hanfang/359/95 (H3N2). Compounds 3 and 4 exhibited potent inhibitory effects on the production of NO in RAW 264.7 cells with IC50 values of 20.57 and 12.87 µM respectively, which were greater than those of dexamethasone (positive control). Compounds 1 and 4-6 exhibited weak activity against Coxsackievirus B3, with IC50 values ranging from 25.87 to 33.33 µM.

Mitochondrial endogenous substance transport-inspired nanomaterials for mitochondria-targeted gene delivery.

Mitochondrial genome (mtDNA) independent of nuclear gene is a set of double-stranded circular DNA that encodes 13 proteins, 2 ribosomal RNAs and 22 mitochondrial transfer RNAs, all of which play vital roles in functions as well as behaviors of mitochondria. Mutations in mtDNA result in various mitochondrial disorders without available cures. However, the manipulation of mtDNA via the mitochondria-targeted gene delivery faces formidable barriers, particularly owing to the mitochondrial double membrane. Given the fact that there are various transport channels on the mitochondrial membrane used to transfer a variety of endogenous substances to maintain the normal functions of mitochondria, mitochondrial endogenous substance transport-inspired nanomaterials have been proposed for mitochondria-targeted gene delivery. In this review, we summarize mitochondria-targeted gene delivery systems based on different mitochondrial endogenous substance transport pathways. These are categorized into mitochondrial steroid hormones import pathways-inspired nanomaterials, protein import pathways-inspired nanomaterials and other mitochondria-targeted gene delivery nanomaterials. We also review the applications and challenges involved in current mitochondrial gene editing systems. This review delves into the approaches of mitochondria-targeted gene delivery, providing details on the design of mitochondria-targeted delivery systems and the limitations regarding the various technologies. Despite the progress in this field is currently slow, the ongoing exploration of mitochondrial endogenous substance transport and mitochondrial biological phenomena may act as a crucial breakthrough in the targeted delivery of gene into mitochondria and even the manipulation of mtDNA.

Biomechanical analysis of adjacent segments after correction surgery for adult idiopathic scoliosis: a finite element analysis.

The biomechanical aspects of adjacent segment degeneration after Adult Idiopathic Scoliosis (AdIS) corrective surgery involving postoperative changes in motion and stress of adjacent segments have yet to be investigated. The objective of this study was to evaluate the biomechanical effects of corrective surgery on adjacent segments in adult idiopathic scoliosis by finite element analysis. Based on computed tomography data of the consecutive spine from T1-S1 of a 28-year-old male patient with adult idiopathic scoliosis, a three-dimensional finite element model was established to simulate the biomechanics. Two posterior long-segment fixation and fusion operations were designed: Strategy A, pedicle screws implanted in all segments of both sides, and Strategy B, alternate screws instrumentation on both sides. The range of motion (ROM), Maximum von Mises stress value of intervertebral disc (IVD), and Maximum von Mises stress of the facet joint (FJ) at the fixation adjacent segment were calculated and compared with data of the preoperative AdIS model. Corrective surgery decreased the IVD on the adjacent segments, increased the FJ on the adjacent segments, and decreased the ROM of the adjacent segments. A greater decrease of Maximum von Mises stress was observed on the distal adjacent segment compared with the proximal adjacent segment. The decrease of Maximum von Mises stress and increment of Maximum von Mises stress on adjacent FJ in strategy B was greater than that in strategy A. Under the six operation modes, the change of the Maximum von Mises stress on the adjacent IVD and FJ was significant. The decrease in ROM in the proximal adjacent segment was greater than that of the distal adjacent segment, and the decrease of ROM in strategy A was greater than that in strategy B. This study clarified the biomechanical characteristics of adjacent segments after AdIS corrective surgery, and further biomechanical analysis of two different posterior pedicle screw placement schemes by finite element method. Our study provides a theoretical basis for the pathogenesis, prevention, and treatment of adjacent segment degeneration after corrective surgery for AdIS.

Views of Hong Kong Chinese medicine practitioners on the application of the "Chinese Medicine Anti-epidemic Plans" prepared by the Chinese medicine expert group of central authorities: a focus group study.

BACKGROUND: Drawing on the extensive utilization of traditional Chinese medicine (TCM) to combat COVID-19 in Mainland China, experts designed a series of TCM anti-epidemic strategies. This study aims to understand Hong Kong CM practitioners' application of and opinions on the "Chinese Medicine Anti-epidemic Plans." METHODS: Online focus group interviews were conducted, and purposive sampling was employed to invite 22 CM practitioners to voluntarily participate in three interview sessions. The interviews were audio recorded, then transcribed verbatim. The transcripts were analyzed using template analysis. RESULTS: Three themes were derived: (1) facilitators of the "Chinese Medicine Anti-epidemic Plans," (2) barriers of the "Chinese Medicine Anti-epidemic Plans," and (3) expectations on improving the "Chinese Medicine Anti-epidemic Plans." The participants could obtain relevant information from various sources, which highlights the value of the plans for TCM medicinal cuisine and non-pharmacologic therapies and guiding junior CM practitioners, supplementing Western medicine interventions, and managing Chinese herb reserves in clinics. However, the barriers included the lack of a specialized platform for timely information release, defective plan content, limited reference value to experienced CM practitioners, and lack of applicability to Hong Kong. The expectations of the CM practitioners for improving the plans were identified based on the barriers. CONCLUSIONS: To enhance the implementation of the anti-epidemic plans, CM practitioners in Hong Kong expect to utilize a specific CM platform and refine the plans to ensure that they are realistic, focused, comprehensive, and tailored to the local context.

Nomogram prediction of vessels encapsulating tumor clusters in small hepatocellular carcinoma ≤ 3 cm based on enhanced magnetic resonance imaging.

BACKGROUND: Vessels encapsulating tumor clusters (VETC) represent a recently discovered vascular pattern associated with novel metastasis mechanisms in hepatocellular carcinoma (HCC). However, it seems that no one have focused on predicting VETC status in small HCC (sHCC). This study aimed to develop a new nomogram for predicting VETC positivity using preoperative clinical data and image features in sHCC (≤ 3 cm) patients. AIM: To construct a nomogram that combines preoperative clinical parameters and image features to predict patterns of VETC and evaluate the prognosis of sHCC patients. METHODS: A total of 309 patients with sHCC, who underwent segmental resection and had their VETC status confirmed, were included in the study. These patients were recruited from three different hospitals: Hospital 1 contributed 177 patients for the training set, Hospital 2 provided 78 patients for the test set, and Hospital 3 provided 54 patients for the validation set. Independent predictors of VETC were identified through univariate and multivariate logistic analyses. These independent predictors were then used to construct a VETC prediction model for sHCC. The model's performance was evaluated using the area under the curve (AUC), calibration curve, and clinical decision curve. Additionally, Kaplan-Meier survival analysis was performed to confirm whether the predicted VETC status by the model is associated with early recurrence, just as it is with the actual VETC status and early recurrence. RESULTS: Alpha-fetoprotein_lg10, carbohydrate antigen 199, irregular shape, non-smooth margin, and arterial peritumoral enhancement were identified as independent predictors of VETC. The model incorporating these predictors demonstrated strong predictive performance. The AUC was 0.811 for the training set, 0.800 for the test set, and 0.791 for the validation set. The calibration curve indicated that the predicted probability was consistent with the actual VETC status in all three sets. Furthermore, the decision curve analysis demonstrated the clinical benefits of our model for patients with sHCC. Finally, early recurrence was more likely to occur in the VETC-positive group compared to the VETC-negative group, regardless of whether considering the actual or predicted VETC status. CONCLUSION: Our novel prediction model demonstrates strong performance in predicting VETC positivity in sHCC (≤ 3 cm) patients, and it holds potential for predicting early recurrence. This model equips clinicians with valuable information to make informed clinical treatment decisions.

Whitening and antioxidant activities of Inonotus sanghuang Extract and development of primary whitening gel products.

Polysaccharides and flavonoids have excellent antioxidant properties and tyrosinase inhibitory effects. In this paper, the antioxidant capacity of Inonotus sanghuang extract and its inhibition kinetics on mushroom tyrosinase were investigated to determine the preparation process of Inonotus sanghuang primary whitening gel. By conducting experimental studies on the effects of water extract and alcohol extract of Inonotus sanghuang on antioxidant capacity and tyrosinase activity, their inhibitory ability and types of inhibitory effects were determined. The single factor experiment was used to determine the preparation process of Sanghuang primary whitening gel. This study has proven that the extract of Inonotus sanghuang possesses antioxidant and tyrosinase inhibitory capabilities. It also identified the preparation process for the primary whitening gel of Inonotus sanghuang, thereby providing a theoretical and experimental basis for the development of whitening products utilising Inonotus sanghuang.

Computed Tomography-Guided Radiofrequency Ablation for Glossopharyngeal Neuralgia: Comparison of Cervical Computed Tomography Angiography, Transverse Process of Atlas, and Styloid Process Localization to Styloid Process Localization Alone.

BACKGROUND: Glossopharyngeal neuralgia (GPN) is a condition that causes simultaneous headache and facial pain. The treatment for GPN is similar to the treatment for trigeminal neuralgia. Craniotomy microvascular decompression (MVD) or radiofrequency (RF) therapy is needed if conservative treatment with oral drugs fails. Therefore, the choice of radiofrequency therapy target is essential when treating GPN. However, finding the glossopharyngeal nerve simply by styloid process positioning is challenging. STUDY DESIGN: Prospective, clinical research study. SETTING: Department of Anesthesiology and Pain Medical Center, Jiaxing, China. OBJECTIVE: To compare the clinical effects of computed tomography (CT)-guided RF treatments on GPN when the triple localization of cervical CT, the transverse process of the atlas, and the styloid process is used to those achieved when the treatments are guided by the styloid process alone. METHODS: From August 2016 to December 2019, 19 cases of GPN neuralgia were treated by radiofrequency under the guidance of CT guided by the styloid process only. (These patients comprised the single localization (SL) of styloid process group, in whom the target of the RF treatments was the posterior medial side of half of the styloid process). From January 2020 to December 2022, 16 cases of GPN were treated by RF under the guidance of CT with cervical CTA (CT angiography), the transverse process of the atlas, and the styloid process. (These patients were placed in the TL group, in whom the target of RF therapy was the gap between the internal carotid artery and the internal jugular vein behind the horizontal styloid process at the lower edge of the transverse process of the atlas). Two percent lidocaine was injected subcutaneously at the needle insertion site, and a stylet with a 21-gauge blunt RF needle (model: 240100, manufacturer: Englander Medical Technology Co., Ltd.) was slowly advanced toward the target. After that, an RF probe was introduced, then low (2 Hz)- and high (50 Hz)-frequency currents of the RF instrument (model: PMG-230, Canada Baylis company) were applied to stimulate. A successful test was defined as a 0.5-1.0 mA current stimulation that could induce the original pain area in the pharynx, the inner ear, or both, without any abnormal irritation of the vagus or accessory nerves. If the first test was unsuccessful, then in the SL group, the needle tip's position was adjusted to the distal end of the styloid process, and in the triple localization (TL) group, the needle tip depth's was fine-tuned. A continuous RF treatment was given after a successful test. The RF temperature was 95ºC for 180 seconds. The time that the first puncture reached the target, the puncture paths, the success rate of the first test, the time that the glossopharyngeal nerve was found, the frequency of adjustments to the position of the RF needle, the incidence of intraoperative and postoperative complications, and the therapeutic effects were recorded. RESULTS: There were no significant differences in demographic data such as age, medical history, lateral classification, and pain score between the groups, but the TL group had a higher proportion of women than did the SL group. All patients' puncture targets were identified according to the designed puncture path before the operation. There was no difference between the 2 groups in the time of the first puncture to the target (5.05 ± 1.22 vs. 5.82 ± 1.51, P = 0.18), and the designed puncture depth (3.65 ± 0.39 vs. 4.04 ± 0.44). The difference in puncture angles (13.48 ± 3.56 vs. 17.84 ± 3.98, P < 0.01) was statistically significant, and in 8 cases in the SL group, the glossopharyngeal nerve could not be found after 60 minutes of testing, so the RF treatment was terminated. Meanwhile, this problem occurred in only 2 cases in the TL group. There were 3 cervical hematoma cases and 2 cases of transient hoarseness and cough in the SL group, whereas the TL group had, respectively, 0 and one cases of those issues. There was no death in either group. LIMITATIONS: More clinical data should be collected in future studies. CONCLUSION: When using RF as a treatment for GPN, the glossopharyngeal nerve is easier to find by using the triple positioning of the cervical CTA, the transverse process of the atlas and the styloid process as the target to determine the anterior medial edge of the internal carotid artery behind the styloid process at the level of the lower edge of the atlas transverse process. The glossopharyngeal nerve is more difficult to locate when only the posterior medial edge of the styloid process is targeted. The single-time effective rate of 180 seconds of RF ablation at 90ºC for GPN can reach 87.5% (14/16), suggesting the treatment's potential for clinical application.

The development of day surgery in China and the effectiveness and reflection of day surgery in ophthalmology-specialized hospitals.

This survey investigates the development of day surgery in China, and analyzes the national policy support, medical service management model, disease types of day surgery, medical insurance payment methods, and the medical service capacity, efficiency, quality and safety, health economics indicators, and patient satisfaction after the implementation of day surgery in a tertiary eye hospital. After more than 20 years of development, China's day surgery has shown a good development trend. The implementation of day surgery in eye hospitals accounts for more than 70% of elective surgery, and patients, medical institutions, and medical insurance institutions have all achieved good social benefits.

Disruption of the c-terminal serine protease domain of Fam111a does not alter calcium homeostasis in mice.

FAM111A gene mutations cause Kenney-Caffey syndrome (KCS) and Osteocraniostenosis (OCS), conditions characterized by short stature, low serum ionized calcium (Ca2+), low parathyroid hormone (PTH), and bony abnormalities. The molecular mechanism mediating this phenotype is unknown. The c-terminal domain of FAM111A harbors all the known disease-causing variations and encodes a domain with high homology to serine proteases. However, whether this serine protease domain contributes to the maintenance of Ca2+ homeostasis is not known. We hypothesized the disruption of the serine protease domain of FAM111A would disrupt Ca2+ homeostasis. To test this hypothesis, we generated with CRISPR/Cas9, mice with a frameshift insertion (c.1450insA) or large deletion (c.1253-1464del) mutation in the Fam111a serine protease domain. Serum-ionized Ca2+ and PTH levels were not significantly different between wild type, heterozygous, or homozygous Fam111a mutant mice. Additionally, there were no significant differences in fecal or urine Ca2+ excretion, intestinal Ca2+ absorption or overall Ca2+ balance. Only female homozygous (c.1450insA), but not heterozygous mice displayed differences in bone microarchitecture and mineral density compared to wild-type animals. We conclude that frameshift mutations that disrupt the c-terminal serine protease domain do not induce a KCS or OCS phenotype in mice nor alter Ca2+ homeostasis.

Acupoint Catgut Embedding for Treatment of Chronic Pelvic Pain due to the Sequelae of Pelvic Inflammatory Disease.

Chronic pelvic pain caused by the sequelae of inflammatory pelvic disease is a common clinical condition of pelvic pain in women. At present, the main challenges in its treatment are the limited effectiveness of pain relief and the frequent recurrence of symptoms, which significantly impact patients' quality of life and impose a considerable psychological burden on them. It is a clinically challenging disease. After summarizing years of treatment experience, the author's team discovered that acupoint catgut embedding demonstrated notable clinical efficacy in managing chronic pelvic pain stemming from pelvic inflammatory disease sequelae. Compared to existing Western medicine treatment methods, acupoint catgut embedding offers advantages such as a good analgesic effect, lower recurrence rate, economic benefits, and a relatively straightforward procedure. This article provides a comprehensive guide on embedding absorbable catgut into patients' acupoints for the treatment of chronic pelvic pain in females resulting from the sequelae of pelvic inflammatory disease.

[Effects of Vermicomposting on Compost Quality and Heavy Metals：A Meta-analysis].

In order to comprehensively evaluate the effects of vermicomposting on compost quality and the conversion of heavy metals under different control conditions, 109 studies were reviewed. The effects of earthworm species, pre-compost time, ventilation methods, initial C/N, initial pH, and initial moisture of the raw materials on compost quality and the heavy metal toxicity were quantitatively discussed during the vermicomposting process through Meta-analysis. The results showed that the six subgroups of factors all showed obvious influences on the compost quality and heavy metal toxicity. After vermicomposting, the contents of NO3--N (116.2%), TN (29.1%), TP (31.2%), and TK (15.0%) were significantly increased, whereas NH4+-N (-14.8%) and C/N (-36.3%) were significantly decreased. Meanwhile, the total amount of Cu and Cr of the final compost and their bioavailability were significantly reduced. Considering the influences of grouping factors on compost quality and heavy metals, it is recommended to adjust the initial moisture of pile materials to 70%-80%, C/N to 30-85, and pH to 6-7 and to conduct pre-composting for 0-15 d; additionally, vermicomposting should be naturally placed when the composting is aimed at promoting the compost quality. If the main purpose is to weaken the perniciousness of heavy metals in the raw material, it is recommended to adjust the initial moisture of the material to 50%-60%, C/N to less than 30, and pH to 7-8; to conduct no pre-compost; regularly turn the piles; and use the earthworm Eudrilus eugeniae for vermicomposting.

Nerve injury inhibits Oprd1 and Cnr1 transcription through REST in primary sensory neurons.

The transcription repressor REST in the dorsal root ganglion (DRG) is upregulated by peripheral nerve injury and promotes the development of chronic pain. However, the genes targeted by REST in neuropathic pain development remain unclear. The expression levels of 4 opioid receptor (Oprm1, Oprd1, Oprl1, Oprk1) and the cannabinoid CB1 receptor (Cnr1) genes in the DRG regulate nociception. In this study, we determined the role of REST in the control of their expression in the DRG induced by spared nerve injury (SNI) in both male and female mice. Transcriptomic analyses of male mouse DRGs followed by quantitative reverse transcription polymerase chain reaction analyses of both male and female mouse DRGs showed that SNI upregulated expression of Rest and downregulated mRNA levels of all 4 opioid receptor and Cnr1 genes, but Oprm1 was upregulated in female mice. Analysis of publicly available bioinformatic data suggested that REST binds to the promoter regions of Oprm1 and Cnr1. Chromatin immunoprecipitation analyses indicated differing levels of REST at these promoters in male and female mice. Full-length Rest conditional knockout in primary sensory neurons reduced SNI-induced pain hypersensitivity and rescued the SNI-induced reduction in the expression of Oprd1 and Cnr1 in the DRG in both male and female mice. Our results suggest that nerve injury represses the transcription of Oprd1 and Cnr1 via REST in primary sensory neurons and that REST is a potential therapeutic target for neuropathic pain.

Advancements of Macrophages Involvement in Pathological Progression of Colitis-Associated Colorectal Cancer and Associated Pharmacological Interventions.

Intestinal macrophages play crucial roles in both intestinal inflammation and immune homeostasis. They can adopt two distinct phenotypes, primarily determined by environmental cues. These phenotypes encompass the classically activated pro-inflammatory M1 phenotype, as well as the alternatively activated anti-inflammatory M2 phenotype. In regular conditions, intestinal macrophages serve to shield the gut from inflammatory harm. However, when a combination of genetic and environmental elements influences the polarization of these macrophages, it can result in an M1/M2 macrophage activation imbalance, subsequently leading to a loss of control over intestinal inflammation. This shift transforms normal inflammatory responses into pathological damage within the intestines. In patients with ulcerative colitis-associated colorectal cancer (UC-CRC), disorders related to intestinal inflammation are closely correlated with an imbalance in the polarization of intestinal M1/M2 macrophages. Therefore, reinstating the equilibrium in M1/M2 macrophage polarization could potentially serve as an effective approach to the prevention and treatment of UC-CRC. This paper aims to scrutinize the clinical evidence regarding Chinese medicine (CM) in the treatment of UC-CRC, the pivotal role of macrophage polarization in UC-CRC pathogenesis, and the potential mechanisms through which CM regulates macrophage polarization to address UC-CRC. Our objective is to offer fresh perspectives for clinical application, fundamental research, and pharmaceutical advancement in UC-CRC.

Calcineurin regulates synaptic Ca2+-permeable AMPA receptors in hypothalamic presympathetic neurons via α2δ-1-mediated GluA1/GluA2 assembly.

Hypertension is a major adverse effect of calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, used clinically as immunosuppressants. Calcineurin inhibitor-induced hypertension (CIH) is linked to augmented sympathetic output from the hypothalamic paraventricular nucleus (PVN). GluA2-lacking, Ca2+-permeable AMPA receptors (CP-AMPARs) are a key feature of glutamatergic synaptic plasticity, yet their role in CIH remains elusive. Here, we found that systemic administration of FK506 in rats significantly increased serine phosphorylation of GluA1 and GluA2 in PVN synaptosomes. Strikingly, FK506 treatment reduced GluA1/GluA2 heteromers in both synaptosomes and endoplasmic reticulum-enriched fractions from the PVN. Blocking CP-AMPARs with IEM-1460 induced a larger reduction of AMPAR-mediated excitatory postsynaptic current (AMPAR-EPSC) amplitudes in retrogradely labelled, spinally projecting PVN neurons in FK506-treated rats than in vehicle-treated rats. Furthermore, FK506 treatment shifted the current-voltage relationship of AMPAR-EPSCs from linear to inward rectification in labelled PVN neurons. FK506 treatment profoundly enhanced physical interactions of α2δ-1 with GluA1 and GluA2 in the PVN. Inhibiting α2δ-1 with gabapentin, α2δ-1 genetic knockout, or disrupting α2δ-1-AMPAR interactions with an α2δ-1 C terminus peptide restored GluA1/GluA2 heteromers in the PVN and diminished inward rectification of AMPAR-EPSCs in labelled PVN neurons induced by FK506 treatment. Additionally, microinjection of IEM-1460 or α2δ-1 C terminus peptide into the PVN reduced renal sympathetic nerve discharges and arterial blood pressure elevated in FK506-treated rats but not in vehicle-treated rats. Thus, calcineurin in the hypothalamus constitutively regulates AMPAR subunit composition and phenotypes by controlling GluA1/GluA2 interactions with α2δ-1. Synaptic CP-AMPARs in PVN presympathetic neurons contribute to augmented sympathetic outflow in CIH. KEY POINTS: Systemic treatment with the calcineurin inhibitor increases serine phosphorylation of synaptic GluA1 and GluA2 in the PVN. Calcineurin inhibition enhances the prevalence of postsynaptic Ca2+-permeable AMPARs in PVN presympathetic neurons. Calcineurin inhibition potentiates α2δ-1 interactions with GluA1 and GluA2, disrupting intracellular assembly of GluA1/GluA2 heterotetramers in the PVN. Blocking Ca2+-permeable AMPARs or α2δ-1-AMPAR interactions in the PVN attenuates sympathetic outflow augmented by the calcineurin inhibitor.

Association of circulating inflammatory proteins with type 2 diabetes mellitus and its complications: a bidirectional Mendelian randomization study.

Background: Increasing evidence indicates that immune response underlies the pathology of type 2 diabetes (T2D). Nevertheless, the specific inflammatory regulators involved in this pathogenesis remain unclear. Methods: We systematically explored circulating inflammatory proteins that are causally associated with T2D via a bidirectional Mendelian randomization (MR) study and further investigated them in prevalent complications of T2D. Genetic instruments for 91 circulating inflammatory proteins were derived from a genome-wide association study (GWAS) that enrolled 14,824 predominantly European participants. Regarding the summary-level GWASs of type 2 diabetes, we adopted the largest meta-analysis of European population (74,124 cases vs. 824,006 controls) and a prospective nested case-cohort study in Europe (9,978 cases vs. 12,348 controls). Summary statistics for five complications of T2D were acquired from the FinnGen R9 repository. The inverse variance-weighted method was applied as the primary method for causal inference. MR-Egger, weighted median and maximum likelihood methods were employed as supplementary analyses. Results from the two T2D studies were combined in a meta-analysis. Sensitivity analyses and phenotype-wide association studies (PheWAS) were performed to detect heterogeneity and potential horizontal pleiotropy in the study. Results: Genetic evidence indicated that elevated levels of TGF-α (OR = 1.16, 95% CI = 1.15-1.17) and CX3CL1 (OR = 1.30, 95% CI = 1.04-1.63) promoted the occurrence of T2D, and increased concentrations of FGF-21 (OR = 0.87, 95% CI = 0.81-0.93) and hGDNF (OR = 0.96, 95% CI = 0.95-0.98) mitigated the risk of developing T2D, while type 2 diabetes did not exert a significant influence on said proteins. Elevated levels of TGF-α were associated with an increased risk of ketoacidosis, neurological complications, and ocular complications in patients with T2D, and increased concentrations of FGF-21 were potentially correlated with a diminished risk of T2D with neurological complications. Higher levels of hGDNF were associated with an increased risk of T2D with peripheral vascular complications, while CX3CL1 did not demonstrate a significant association with T2D complications. Sensitivity analyses and PheWAS further ensure the robustness of our findings. Conclusion: This study determined four circulating inflammatory proteins that affected the occurrence of T2D, providing opportunities for the early prevention and innovative therapy of type 2 diabetes and its complications.