Aberrant splicing of CaV1.2 calcium channel induced by decreased Rbfox1 enhances arterial constriction during diabetic hyperglycemia.

Diabetic hyperglycemia induces dysfunctions of arterial smooth muscle, leading to diabetic vascular complications. The CaV1.2 calcium channel is one primary pathway for Ca2+ influx, which initiates vasoconstriction. However, the long-term regulation mechanism(s) for vascular CaV1.2 functions under hyperglycemic condition remains unknown. Here, Sprague-Dawley rats fed with high-fat diet in combination with low dose streptozotocin and Goto-Kakizaki (GK) rats were used as diabetic models. Isolated mesenteric arteries (MAs) and vascular smooth muscle cells (VSMCs) from rat models were used to assess K+-induced arterial constriction and CaV1.2 channel functions using vascular myograph and whole-cell patch clamp, respectively. K+-induced vasoconstriction is persistently enhanced in the MAs from diabetic rats, and CaV1.2 alternative spliced exon 9* is increased, while exon 33 is decreased in rat diabetic arteries. Furthermore, CaV1.2 channels exhibit hyperpolarized current-voltage and activation curve in VSMCs from diabetic rats, which facilitates the channel function. Unexpectedly, the application of glycated serum (GS), mimicking advanced glycation end-products (AGEs), but not glucose, downregulates the expression of the splicing factor Rbfox1 in VSMCs. Moreover, GS application or Rbfox1 knockdown dynamically regulates alternative exons 9* and 33, leading to facilitated functions of CaV1.2 channels in VSMCs and MAs. Notably, GS increases K+-induced intracellular calcium concentration of VSMCs and the vasoconstriction of MAs. These results reveal that AGEs, not glucose, long-termly regulates CaV1.2 alternative splicing events by decreasing Rbfox1 expression, thereby enhancing channel functions and increasing vasoconstriction under diabetic hyperglycemia. This study identifies the specific molecular mechanism for enhanced vasoconstriction under hyperglycemia, providing a potential target for managing diabetic vascular complications.

Reducing greenhouse gas intensity using a mixture of controlled-release urea and common urea combining suitable maize varieties in a summer maize system.

The one-time application of common urea blended with controlled-release urea (CRU) is considered effective for improving nitrogen use efficiency and grain yield and reducing the greenhouse gas emissions of summer maize in intensive agricultural systems. However, the trade-off between the economic and environmental performances of different blended fertilizer treatments for different maize varieties remains unclear. Therefore, a consecutive two-year field experiment was conducted in the North China Plain to study the effects of different ratios of CRU and common urea on the yield, nitrous oxide (N2O) emissions, yield-scaled total N2O emissions, greenhouse gas intensity (GHGI), and net ecosystem economic benefit (NEEB) in 2021 and 2022. Four N fertilizer treatments with equal rate at 180 kg N ha-1 were applied as N180U (all Urea), N180C1(1/3CRU), N180C2(2/3CRU), and N180C (all CRU), and two maize varieties (JNK728-yellow ripe variety and ZD958-green ripe variety) were used. The N180C1 and N180C2 treatments produced the highest grain yield in varieties JNK728 and ZD958 (9.4-11.5 t ha-1 and 9.0-11.0 t ha-1), respectively. Compared to the N180U treatment (conventional method), the N180C1 treatment reduced the GHGI (24.8 %-25.9 %) and increased the NEEB (33.1 %-33.4 %) in the JNK728 variety, whereas the N180C2 treatment reduced the GHGI (16.9 %-28.8 %) and increased the NEEB (27.2 %-48.1 %) in the ZD958 variety. The study concludes that a one-time application of blended nitrogen fertilizer in suitable varieties can minimize the GHGI and maximize the NEEB, which is an effective strategy for balancing yield and nitrogen efficiency in the summer maize system in the North China Plain.

RADseq-based population genomic analysis and environmental adaptation of rare and endangered recretohalophyte Reaumuria trigyna.

Genetic diversity reflects the survival potential, history, and population dynamics of an organism. It underlies the adaptive potential of populations and their response to environmental change. Reaumuria trigyna is an endemic species in the Eastern Alxa and West Ordos desert regions in China. The species has been considered a good candidate to explore the unique survival strategies of plants that inhabit this area. In this study, we performed population genomic analyses based on restriction-site associated DNA sequencing to understand the genetic diversity, population genetic structure, and differentiation of the species. Analyses of 92,719 high-quality single-nucleotide polymorphisms (SNPs) indicated that overall genetic diversity of R. trigyna was low (HO = 0.249 and HE = 0.208). No significant genetic differentiation was observed among the investigated populations. However, a subtle population genetic structure was detected. We suggest that this might be explained by adaptive diversification reinforced by the geographical isolation of populations. Overall, 3513 outlier SNPs were located in 243 gene-coding sequences in the R. trigyna transcriptome. Potential sites under diversifying selection occurred in genes (e.g., AP2/EREBP, E3 ubiquitin-protein ligase, FLS, and 4CL) related to phytohormone regulation and synthesis of secondary metabolites which have roles in adaptation of species. Our genetic analyses provide scientific criteria for evaluating the evolutionary capacity of R. trigyna and the discovery of unique adaptions. Our findings extend knowledge of refugia, environmental adaption, and evolution of germplasm resources that survive in the Ordos area.

The phosphodiesterase DibA interacts with the c-di-GMP receptor LapD and specifically regulates biofilm in Pseudomonas putida.

The ubiquitous bacterial second messenger c-di-GMP is synthesized by diguanylate cyclase and degraded by c-di-GMP-specific phosphodiesterase. The genome of Pseudomonas putida contains dozens of genes encoding diguanylate cyclase/phosphodiesterase, but the phenotypical-genotypical correlation and functional mechanism of these genes are largely unknown. Herein, we characterize the function and mechanism of a P. putida phosphodiesterase named DibA. DibA consists of a PAS domain, a GGDEF domain, and an EAL domain. The EAL domain is active and confers DibA phosphodiesterase activity. The GGDEF domain is inactive, but it promotes the phosphodiesterase activity of the EAL domain via binding GTP. Regarding phenotypic regulation, DibA modulates the cell surface adhesin LapA level in a c-di-GMP receptor LapD-dependent manner, thereby inhibiting biofilm formation. Moreover, DibA interacts and colocalizes with LapD in the cell membrane, and the interaction between DibA and LapD promotes the PDE activity of DibA. Besides, except for interacting with DibA and LapD itself, LapD is found to interact with 11 different potential diguanylate cyclases/phosphodiesterases in P. putida, including the conserved phosphodiesterase BifA. Overall, our findings demonstrate the functional mechanism by which DibA regulates biofilm formation and expand the understanding of the LapD-mediated c-di-GMP signaling network in P. putida.

Preparation of an elderberry anthocyanin film and fresh-keeping effect of its application on fresh shrimps.

A smart packaging film was developed employing the pH-indicating activity of elderberry anthocyanins to solve the problem of refrigerated food freshness monitoring. The effect of elderberry anthocyanins on the properties of gellan gum, gelatin composite films and preservation of fresh shrimp as an indicator of freshness was investigated. The results showed that the elderberry anthocyanin-gellan gum/gelatin film had improved on film thickness (7.8×10-2 mm), TS (tensile strength) (14.57×103 MPa), WVP (water vapor permeability) (36.96×10-8 g/m·s·Pa), and a reduced EAB (elongation at break) (17.92%), and water solubility (water-soluble time of 60.5 s). SEM (scanning electron microscopy) and FTIR (infrared spectrum analysis) showed excellent compatibility between its components. Moreover, the elderberry anthocyanin film exhibited good mechanical properties and pH indication effects. Therefore, the film can be considered suitable for maintaining the quality of fresh shrimp. The results could provide a reference for research and development into new active intelligent packaging films.

Dysregulated Rbfox2 produces aberrant splicing of CaV1.2 calcium channel in diabetes-induced cardiac hypertrophy.

BACKGROUND: L-type Ca2+ channel CaV1.2 is essential for cardiomyocyte excitation, contraction and gene transcription in the heart, and abnormal functions of cardiac CaV1.2 channels are presented in diabetic cardiomyopathy. However, the underlying mechanisms are largely unclear. The functions of CaV1.2 channels are subtly modulated by splicing factor-mediated alternative splicing (AS), but whether and how CaV1.2 channels are alternatively spliced in diabetic heart remains unknown. METHODS: Diabetic rat models were established by using high-fat diet in combination with low dose streptozotocin. Cardiac function and morphology were assessed by echocardiography and HE staining, respectively. Isolated neonatal rat ventricular myocytes (NRVMs) were used as a cell-based model. Cardiac CaV1.2 channel functions were measured by whole-cell patch clamp, and intracellular Ca2+ concentration was monitored by using Fluo-4 AM. RESULTS: We find that diabetic rats develop diastolic dysfunction and cardiac hypertrophy accompanied by an increased CaV1.2 channel with alternative exon 9* (CaV1.2E9*), but unchanged that with alternative exon 8/8a or exon 33. The splicing factor Rbfox2 expression is also increased in diabetic heart, presumably because of dominate-negative (DN) isoform. Unexpectedly, high glucose cannot induce the aberrant expressions of CaV1.2 exon 9* and Rbfox2. But glycated serum (GS), the mimic of advanced glycation end-products (AGEs), upregulates CaV1.2E9* channels proportion and downregulates Rbfox2 expression in NRVMs. By whole-cell patch clamp, we find GS application hyperpolarizes the current-voltage curve and window currents of cardiac CaV1.2 channels. Moreover, GS treatment raises K+-triggered intracellular Ca2+ concentration ([Ca2+]i), enlarges cell surface area of NRVMs and induces hypertrophic genes transcription. Consistently, siRNA-mediated knockdown of Rbfox2 in NRVMs upregulates CaV1.2E9* channel, shifts CaV1.2 window currents to hyperpolarization, increases [Ca2+]i and induces cardiomyocyte hypertrophy. CONCLUSIONS: AGEs, not glucose, dysregulates Rbfox2 which thereby increases CaV1.2E9* channels and hyperpolarizes channel window currents. These make the channels open at greater negative potentials and lead to increased [Ca2+]i in cardiomyocytes, and finally induce cardiomyocyte hypertrophy in diabetes. Our work elucidates the underlying mechanisms for CaV1.2 channel regulation in diabetic heart, and targeting Rbfox2 to reset the aberrantly spliced CaV1.2 channel might be a promising therapeutic approach in diabetes-induced cardiac hypertrophy.

Epithelial TIPE1 Protein Guards against Colitis by Inhibiting TNF-α-Mediated Inflammation.

Intestinal epithelial cells (IECs) at the internal/external interface orchestrate the mucosal immune response, and IEC dysfunction has been linked to multiple inflammatory diseases, including inflammatory bowel disease. In this study, we found that a member of the TNF-α-induced protein 8 (TNFAIP8 or TIPE) family called TIPE1 is indispensable for maintaining epithelial cell barrier integrity and homeostasis under inflammatory conditions. TIPE1-deficient mice, or chimeric mice that were deficient in TIPE1 in their nonhematopoietic cells, were more sensitive to dextran sulfate sodium-induced experimental colitis; however, TIPE1 deficiency had no impact on the development of inflammation-associated and sporadic colorectal cancers. Mechanistically, TIPE1 prevented experimental colitis through modulation of TNF-α-dependent inflammatory response in IECs. Importantly, genetic deletion of both TIPE1 and its related protein TNFAIP8 in mice led to the development of spontaneous chronic colitis, indicating that both of these two TIPE family members play crucial roles in maintaining intestinal homeostasis. Collectively, our findings highlight an important mechanism by which TIPE family proteins maintain intestinal homeostasis and prevent inflammatory disorders in the gut.

Local anaesthetic procaine derivatives protect rat against diabetic nephropathy via inhibition of DPP-4, inflammation and oxidative stress.

Diabetic nephropathy (DN) is a serious devastating disease. However, the current clinical options to treat DN are not adequate. Thus, in the present study, we intend to develop novel series of procaine-embedded thiazole-pyrazoles as protective agent against DN. The compounds were tested for inhibition of dipeptidyl peptidase (DPP)-4, -8, and - 9 enzyme subtypes, where they selectively and potently inhibit DPP-4 as compared to other subtypes. The top three ranked DPP-4 inhibitors (8i, 8e and 8k) were further screened for inhibitory activity against NF-ĸB transcription. Among these three, compound 8i was identified as the most potent NF-ĸB inhibitor. The pharmacological benefit of compound 8i was further established in streptozotocin-induced diabetic nephropathy in rats. Compound 8i showed marked improvements in blood glucose, ALP, ALT, total protein, serum lipid profile such as total cholesterol, triglyceride, HDL levels and renal functions such as urine volume, urinary protein excretion, serum creatinine, blood urea nitrogen and creatinine clearance as compared to nontreated diabetic control group. It also reduces oxidative stress (MDA, SOD and GPx) and inflammation (TNF-α, IL-1ß and IL-6) in the rats as compared to disease control group rats. This study demonstrated the discovery of procaine-embedded thiazole-pyrazole compounds as a novel class of agent against diabetic nephropathy.

The Dynamics of Dopamine D2 Receptor-Expressing Striatal Neurons and the Downstream Circuit Underlying L-Dopa-Induced Dyskinesia in Rats.

L-dopa (l-3,4-dihydroxyphenylalanine)-induced dyskinesia (LID) is a debilitating complication of dopamine replacement therapy for Parkinson's disease. The potential contribution of striatal D2 receptor (D2R)-positive neurons and downstream circuits in the pathophysiology of LID remains unclear. In this study, we investigated the role of striatal D2R+ neurons and downstream globus pallidus externa (GPe) neurons in a rat model of LID. Intrastriatal administration of raclopride, a D2R antagonist, significantly inhibited dyskinetic behavior, while intrastriatal administration of pramipexole, a D2-like receptor agonist, yielded aggravation of dyskinesia in LID rats. Fiber photometry revealed the overinhibition of striatal D2R+ neurons and hyperactivity of downstream GPe neurons during the dyskinetic phase of LID rats. In contrast, the striatal D2R+ neurons showed intermittent synchronized overactivity in the decay phase of dyskinesia. Consistent with the above findings, optogenetic activation of striatal D2R+ neurons or their projections in the GPe was adequate to suppress most of the dyskinetic behaviors of LID rats. Our data demonstrate that the aberrant activity of striatal D2R+ neurons and downstream GPe neurons is a decisive mechanism mediating dyskinetic symptoms in LID rats.

Whole-exome sequencing and electrophysiological study reveal a novel loss-of-function mutation of KCNA10 in epinephrine provoked long QT syndrome with familial history of sudden cardiac death.

Congenital long QT syndrome (LQTS) is one type of inherited fatal cardiac arrhythmia that may lead to sudden cardiac death (SCD). Mutations in more than 16 genes have been reported to be associated with LQTS, whereas the genetic causes of about 20% of cases remain unknown. In the present study, we investigated a four-generation pedigree with familial history of syncope and SCD. The proband was a 33-year-old young woman who experienced 3 episodes of syncope when walking at night. The electrocardiogram revealed a markedly epinephrine-provoked prolonged QT interval (QT = 468 ms, QTc = 651 ms) but no obvious arrhythmia in the resting state. Three family members have died of suspected SCD. Whole-exome sequencing and bioinformatic analysis based on pedigree revealed that a novel missense mutation KCNA10 (c.1397G＞A/Arg466Gln) was the potential genetic lesion. Sanger sequencing was performed to confirm the whole-exome sequencing results. This mutation resulted in the KV1.8 channel amino acid residue 466 changing from arginine to glutamine, and the electrophysiological experiments verified it as a loss-of-function mutation of KV1.8, which reduced the K+ currents of KV1.8 and might result in the prolonged QT interval. These findings suggested that KCNA10 (c.1397G＞A) mutation was possibly pathogenic in this enrolled LQTS family, and may provide a new potential genetic target for diagnosis and counseling of stress-related LQTS families as well as the postmortem diagnosis of SCD.

Controlling Isomerization of Photoswitches to Modulate 2D Logic-in-Memory Devices by Organic-Inorganic Interfacial Strategy.

Logic-in-memory devices are a promising and powerful approach to realize data processing and storage driven by electrical bias. Here, an innovative strategy is reported to achieve the multistage photomodulation of 2D logic-in-memory devices, which is realized by controlling the photoisomerization of donor-acceptor Stenhouse adducts (DASAs) on the surface of graphene. Alkyl chains with various carbon spacer lengths (n = 1, 5, 11, and 17) are introduced onto DASAs to optimize the organic-inorganic interfaces: 1) Prolonging the carbon spacers weakens the intermolecular aggregation and promotes isomerization in the solid state. 2) Too long alkyl chains induce crystallization on the surface and hinder the photoisomerization. Density functional theory calculation indicates that the photoisomerization of DASAs on the graphene surface is thermodynamically promoted by increasing the carbon spacer lengths. The 2D logic-in-memory devices are fabricated by assembling DASAs onto the surface. Green light irradiation increases the drain-source current (Ids ) of the devices, while heat triggers a reversed transfer. The multistage photomodulation is achieved by well-controlling the irradiation time and intensity. The strategy based on the dynamic control of 2D electronics by light integrates molecular programmability into the next generation of nanoelectronics.

Th17/Treg imbalance in peripheral blood from patients with intracranial aneurysm.

BACKGROUND: Spontaneous subarachnoid hemorrhage (SAH) is highly associated with ruptured intracranial aneurysm (IA), which dramatically increases neurological disabilities or mortality in patients. The balance between T helper cells (Th17) and regulatory T cells (Treg) plays a crucial role in regulating immune-inflammatory response. In the current study, we aim to obtain a better understanding of the role of Th17 and Treg cells in patients with IA. METHODS: 138 patients total participated in this study, including ruptured aneurysms group (Ruptured IA, RIA, N.=70 cases) and unruptured aneurysms group (Unruptured IA, URIA, N.=68 cases). Additionally, 76 cases of healthy subjects were selected as control group. The frequencies of Th17 and Treg cells were determined using flow cytometry. The serum levels of cytokines including IL-17, IL-23, IL-10, and TGF-ß1 were determined using ELISA. mRNA was isolated from the whole blood. FOXP3 and RCRc mRNA expressions were detected using RT-qPCR. RESULTS: The percentage of Th17 cells in peripheral blood from RIA patients was higher than URIA patients (P<0.01), whereas the percentage of Treg cells in peripheral blood from RIA was significantly lower when compared with URIA patients (P<0.001). The serum levels of IL-17 (P<0.01) and IL-23 (P<0.05) were markedly increased while the levels of IL-10 (P<0.01) and TGF-ß1 (P<0.05) were decreased in RIA patients when compared with URIA patients. Lastly, the mRNA level of RCRc was significantly increased in RIA vs. URIA patients (P<0.001). By contrast, FOXP3 mRNA level was significantly decreased in RIA vs. URIA patients (P<0.001). CONCLUSIONS: In the current study, we demonstrated the imbalance of Th17/Treg in patients with IA, and the frequencies of Th17 cells were positively correlated with the severity of IA-induced SAH. These results provided data to support that targeting Th17/Treg could act as an effective approach for the management of IA.

Ultrasonic effects on molecular weight degradation, physicochemical and rheological properties of pectin extracted from Premna microphylla Turcz.

The high molecular weight and poor solubility of pectin extracted from Premna microphylla Turcz (PEP) limits its application. Therefore, in this paper, the degradation effects of PEP under ultrasound irradiation and the influences of ultrasonic on the PEP processing characteristics were investigated. The results indicated that the Mw of PEP decreased significantly with a narrow distribution after ultrasonic treatment. The degradation kinetics of PEP at different ultrasound intensities were sufficiently described by the 2nd-order kinetics eq. X-ray diffraction (XRD) and scanning electron microscopy (SEM) analysis suggested that ultrasonic treatment destroyed the ordered structure inside the PEP, resulting in a looser microscopic morphology. Compared with the control, the thermal stability of PEP was significantly boosted after ultrasonic treatment. Rheological analysis illustrated that the sonicated PEP presented lower apparent viscosities than the original PEP. While the elasticity and thermal reversibility of the degraded products was enhanced. Ultrasonic treatment prominently weakened its shear thinning fluid behavior and thixotropy, thus improved its processing quality. Therefore, desirable PEP can be prepared by ultrasonic irradiation. The results can provide a reference for the development and application of PEP.

Effects of ultrasonic on structure, chain conformation and morphology of pectin extracted from Premna microphylla Turcz.

In this study, ultrasonic effects on structure, chain conformation and morphology of pectin extracted from Premna microphylla Turcz (PEP) and its probable mechanism were investigated. In the process of ultrasonic treatments, the chains of PEP were fractured rapidly within the initial 10 min and then the degradation rate gradually slowed down. The primary structure of PEP nearly remained unchanged after ultrasonic degradation. The rigid semi-flexible chains of PEP were converted into flexible chains, flexible coils, even compact coils. Sonication at low intensity for short time made PEP molecular chains curly collapse and tighten up. Long duration sonication at high intensity generated excessive small rigidness segments that mutually aggregated because of hydrogen bonds and inhibited the self-coiling of PEP chains. Atomic force microscopy (AFM) analysis supported the conformation transition of PEP chains. The results provided a fundamental basis for orientation design and process control of PEP structure.

High-Concentration Metformin Reduces Oxidative Stress Injury and Inhibits the Growth and Migration of Clear Cell Renal Cell Carcinoma.

Objective: To explore the mechanism of metformin in treating CCRCC. Methods: Prospective cohort study was conducted. SOD and cyclin D in six CCRCC samples donated by volunteers were detected to compare the degree of oxidative stress injury and the status of cell proliferation. 786-0 CCRCC cells were cultured in vitro with different concentrations of metformin, and MTT assay and Transwell cell migration and wound healing assay were used to detect their proliferation and migration. After culture, SOD and cyclin D in 786-0 CCRCC cells were also detected. Results: In the edge tissue, SOD was lower than in the tumor nest and normal tissue, and cyclin D was highly expressed. In grade II CCRCC, SOD was higher than in grade IV CCRCC, but cyclin D was also highly expressed in grade IV CCRCC. The cell proliferation rate and density of the metformin group were lower than the control group, while in the high-concentration metformin group, it was lower than medium- and low-concentration groups. After culture, the migration of 786-0 cells in the metformin group was significantly lower than that in the control group, the wound healing rate was decreased, and the migration and wound healing rates in the high-concentration metformin group were significantly lower than those in the medium- and low-concentration groups. However, the SOD of the metformin group was higher than the control group, but the cyclin D was lower, while the SOD was higher than medium- and low-concentration groups in the high-concentration group, but the cyclin D was lower after cultured. Conclusion: High-concentration metformin can reduce oxidative stress injury, increase the expression of SOD in CCRCC, and reduce cyclin D in CCRCC to inhibit proliferation and migration, which has optimistic prospects and application value in controlling the progression of CCRCC.

Diminished Rbfox1 increases vascular constriction by dynamically regulating alternative splicing of CaV1.2 calcium channel in hypertension.

Calcium influx from depolarized CaV1.2 calcium channels triggers the contraction of vascular smooth muscle cells (VSMCs), which is important for maintaining vascular myogenic tone and blood pressure. The function of CaV1.2 channel can be subtly modulated by alternative splicing (AS), and its aberrant splicing involves in the pathogenesis of multiple cardiovascular diseases. The RNA-binding protein Rbfox1 is reported to regulate the AS events of CaV1.2 channel in the neuronal development, but its potential roles in vascular CaV1.2 channels and vasoconstriction remain undefined. Here, we detect Rbfox1 is expressed in rat vascular smooth muscles. Moreover, the protein level of Rbfox1 is dramatically decreased in the hypertensive small arteries from spontaneously hypertensive rats in comparison with normotensive ones from Wistar-Kyoto rats. In VSMCs, Rbfox1 could dynamically regulate the AS of CaV1.2 exons 9* and 33. By whole-cell patch clamp, we identify knockdown of Rbfox1 induces the hyperpolarization of CaV1.2 current-voltage relationship curve in VSMCs. Furthermore, siRNA-mediated knockdown of Rbfox1 increases the K+-induced constriction of rat mesenteric arteries. In summary, our results indicate Rbfox1 modulates vascular constriction by dynamically regulating CaV1.2 alternative exons 9* and 33. Therefore, our work elucidates the underlying mechanisms for CaV1.2 channels regulation and provides a potential therapeutic target for hypertension.

Clinical Observation of Ultrasound-Guided Nerve Block Anesthesia on Postoperative Pain Control of Fracture Patients.

To observe the postoperative pain control and clinical efficacy of ultrasound-guided nerve block anesthesia for patients with tibial fracture. A total of 128 patients with tibial fracture who received surgical treatment in our hospital from October 2020 to April 2021 were selected. The ultrasound guided anesthesia group and general anesthesia group were established by random number table method, with 64 patients in each group. Patients in the ultrasound-guided anesthesia group received ultrasound-guided nerve block anesthesia, and patients in the general anesthesia group received conventional general anesthesia. Observation times anesthetic effect in both groups, changes in hemodynamic parameters, digital pain scale (NRS) score as a result, compared two groups of patients with adverse reactions occur, change of the serum inflammatory factors indicators before and after operation, and USES the Pearson correlation coefficient analysis of the correlation between serum levels of inflammatory factor index and NRS score. The effect of anesthesia, postoperative recovery, directional force recovery, motor block and sensory block time of patients in ultrasound-guided anesthesia group decreased significantly than those in general anesthesia group (all P < 0.05). The comparison of MAP, HR and RR at T1 and T2 levels between the two groups was statistically significant (all P < 0.05). The changes of MAP, HR and RR in ultrasound guided anesthesia group were more stable than those in general anesthesia group.The NRS scores of patients in both groups showed an increasing trend with the extension of time. The 6 h, 12 h and 24 hNRS scores of patients in the ultrasound guided anesthesia group decreased significantly than those in the general anesthesia group (all P < 0.05). The total incidence of adverse reactions in ultrasound guided anesthesia group decreased significantly than that in general anesthesia group (P < 0.05).The serum levels of inflammatory factor interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in 2 groups increased significantly before surgery, and the levels of each index in ultrasound guided anesthesia group decreased significantly than that in general anesthesia group (ALL P < 0.05). Pearson correlation coefficient showed that serum IL-6 and TNF-α levels were positively correlated with NRS score (all P < 0.05). Ultrasound-guided nerve block anesthesia surgery can effectively improve the tibia fracture patients intraoperative anesthetic effect, improve patients with intraoperative and postoperative hemodynamic index of stability, the anesthesia surgery will exert positive effects on patients with postoperative pain control, can reduce the risk in patients with postoperative adverse reactions, reduce the postoperative patients with inflammatory factor activity. In addition, this paper found significant positive correlation between serum inflammatory factors IL-6 and TNF-α and NRF score, suggesting that serum IL-6 and TNF-α can be monitored for postoperative pain control in patients with tibial fracture, providing reference for improving postoperative treatment plan of patients.

Three-Dimensional Conformal Radiotherapy Combined with Gemcitabine and Docetaxel in the Treatment of Advanced Bladder Cancer and Its Effects on Inflammatory Factors and Immune Function.

Objective: To assess the efficacy of three-dimensional conformal radiotherapy (3D-CRT) combined with GT chemotherapy (gemcitabine+docetaxel) in the treatment of advanced bladder cancer and its influence on inflammatory factors and immune function. Methods: A total of 42 elderly patients with advanced bladder cancer who were admitted to our hospital from January 2019 to January 2020 were included and assigned to the GT group (21 cases) receiving GT chemotherapy and combination group (21 cases) given 3D-CRT combined with GT chemotherapy. The clinical efficacy, immune function, inflammatory factors, tumor markers, urinary angiogenesis molecules before and after treatment, 1-year survival rate, 2-year survival rate, and incidence of adverse reactions of the two groups were compared. SPSS 22.0 statistical software was used for data processing and analysis. Results: The combination group had 5 cases of CR, 12 cases of PR, 3 cases of SD, and 1 case of PD, with an ORR of 80.95% (17/21), which was remarkably higher than the ORR of 57.14% (12/21) in the GT group which had 3 cases of CR, 9 cases of PR, 5 cases of SD, and 4 cases of PD (P < 0.05). The 1-year survival rate of the combination group was 76.19% (16/21), and the 2-year survival rate was 47.62% (10/21), which were higher than the 1-year survival rate of 47.62% (10/21) and 2-year survival rate of 19.05% (4/21) in the GT group (P < 0.05). The two groups presented similar results in terms of adverse reactions rate (P > 0.05). After treatment, the combination group obtained significantly lower levels of urinary bladder cancer antigen (UBC), nuclear matrix protein-22 (NMP-22), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) than the GT group (P < 0.05). The CD3+, CD4+, and CD4+/CD8+ levels of the two groups of patients were lower than those before treatment (P < 0.05), but no statistical difference was observed between the two groups after treatment (P > 0.05). The levels of interleukin-6 (IL-6) and interferon-γ (IFN-γ) of the two groups witnessed a decline after treatment, with lower results in the combination group as compared to the control group (P < 0.05). Before treatment, no significant difference in the Generic Quality of Life Inventory-74 (GQOLI-74) score between the two groups was found (P > 0.05). After treatment, the combination group had higher GQOLI-74 scores than the GT group (P < 0.05). Conclusion: 3D-CRT combined with GT chemotherapy yields a significant effect on the treatment of elderly advanced bladder cancer by effectively protecting immune function, mitigating inflammation, inhibiting tumor marker levels and the expression of angiogenic molecules, and improving patients' survival.

TNFAIP8 protein functions as a tumor suppressor in inflammation-associated colorectal tumorigenesis.

Tumor necrosis factor-α-induced protein 8 (TNFAIP8 or TIPE) is a member of the TNFAIP8 family. While TIPE was broadly considered to be pro-cancerous, its precise roles in carcinogenesis especially those of the intestinal tract are not clear. Here, we show that genetic deletion of TIPE in mice exacerbated chemical-induced colitis and colitis-associated colon cancer. Loss of TIPE exacerbated inflammatory responses and inflammation-associated dysbiosis, leading to the activation of NF-κB and STAT3, and it also accelerated dysplasia, DNA damage and proliferation of intestinal epithelial cells. We further show that colon microbiota were essential for increased tumor growth and progression in Tipe-/- mice. The tumor suppressive function of TIPE originated primarily from the non-hematopoietic compartment. Importantly, TIPE was downregulated in human colorectal cancers, and patients with low levels of Tipe mRNA were associated with reduced survival. These results indicate that TIPE serves as an important modulator of colitis and colitis-associated colon cancer.

Tumor Necrosis Factor-α-Induced Protein 8-Like 2 Fosters Tumor-Associated Microbiota to Promote the Development of Colorectal Cancer.

Although increasing evidence links the gut microbiota with the development of colorectal cancer, the molecular mechanisms for microbiota regulation of tumorigenesis are not fully understood. Here, we found that a member of the TNFα-induced protein 8 (TNFAIP8) family called TIPE2 (TNFAIP8-like 2) was significantly upregulated in murine intestinal tumors and in human colorectal cancer, and colorectal cancer with high expression of Tipe2 mRNA associated with reduced survival time of patients. Consistent with these findings, TIPE2 deficiency significantly inhibited the development of colorectal cancer in mice treated with azoxymethane/dextran sodium sulfate and in Apcmin/+ mice. TIPE2 deficiency attenuated the severity of colitis by successfully resolving and restricting colonic inflammation and protected colonic myeloid cells from death during colitis. Transplantation of TIPE2-deficient bone marrow into wild-type mice successfully dampened the latter's tumorigenic phenotype, indicating a hematopoietic-specific role for TIPE2. Mechanistically, restricting the expansion of Enterobacteriaceae/Escherichia coli (E. coli) decreased intestinal inflammation and reduced the incidence of colonic tumors. Collectively, these data suggest that hematopoietic TIPE2 regulates intestinal antitumor immunity by regulation of gut microbiota. TIPE2 may represent a new therapeutic target for treating colorectal cancer.