siRNA nanoparticle targeting Usp20 lowers lipid levels and ameliorates metabolic syndrome in mice.

Atherosclerotic cardiovascular disease (ASCVD) is closely correlated with elevated low-density lipoprotein cholesterol (LDL-C). In feeding state, glucose and insulin activate mTORC1 that phosphorylates the deubiquitylase USP20. USP20 then stabilizes HMG-CoA reductase (HMGCR), thereby increasing lipid biosynthesis. In this study, we applied clinically approved lipid nanoparticles (LNPs) to encapsulate the siRNA targeting Usp20. We demonstrated that silencing of hepatic Usp20 by siRNA decreased body weight, improved insulin sensitivity and increased energy expenditure through elevating UCP1. In Ldlr-/- mice, silencing Usp20 by siRNA decreased lipid levels and prevented atherosclerosis. This study suggests that the RNAi-based therapy targeting hepatic Usp20 has a translational potential to treat metabolic disease.

Use of a Memokath™ 045 temperature-controlled memory alloy stent for treating upper renal calyx calyceal neck atresia: a case report.

Renal calyceal neck atresia is a rare disorder. There is no clear guidance for standard treatment of this condition. The Memokath™ 045 temperature-controlled memory alloy stent is commonly used in the treatment of urethral strictures, but it has not been used for treating calyceal neck atresia. We present a case of a 44-year-old female patient with left lumbar pain who underwent two stages of treatment to resolve calyceal neck atresia located at the upper calyx of her left kidney. The first procedure was transurethral ureteroscopy combined with percutaneous recanalization of the left upper calyx calyceal neck atresia. One 6 F internal stent and one 8 F internal stent were placed, and she was discharged with a left nephrostomy tube. After her urinary tract infection was fully resolved, the patient returned for the second procedure of percutaneous upper renal calyx calyceal neck metal stent implantation. The temporary stents and nephrostomy tube were successfully removed. Our findings suggest that the Memokath™ 045 temperature-controlled memory alloy stent is an effective choice for treating calyceal neck atresia.

A novel technique for NO.253 lymph node dissection and left colic artery preservation to avoid potential postoperative internal hernia in laparoscopic radical resection for rectal cancer.

BACKGROUND: The preservation of the left colic artery (LCA) has emerged as a preferred approach in laparoscopic radical resection for rectal cancer. However, preserving the LCA while simultaneously dissecting the NO.253 lymph node can create a mesenteric defect between the inferior mesenteric artery (IMA), the LCA, and the inferior mesenteric vein (IMV). This defect could act as a potential "hernia ring," increasing the risk of developing an internal hernia after surgery. The objective of this study was to introduce a novel technique designed to mitigate the risk of internal hernia by filling mesenteric defects with autologous tissue. METHODS: This new technique was performed on eighteen patients with rectal cancer between January 2022 and June 2022. First of all, dissected the lymphatic fatty tissue on the main trunk of IMA from its origin until the LCA and sigmoid artery (SA) or superior rectal artery (SRA) were exposed and then NO.253 lymph node was dissected between the IMA, LCA and IMV. Next, the SRA or SRA and IMV were sequentially ligated and cut off at an appropriate location away from the "hernia ring" to preserve the connective tissue between the "hernia ring" and retroperitoneum. Finally, after mobilization of distal sigmoid, on the lateral side of IMV, the descending colon was mobilized cephalad. Patients'preoperative baseline characteristics and intraoperative, postoperative complications were examined. RESULTS: All patients' potential "hernia rings" were closed successfully with our new technique. The median operative time was 195 min, and the median intraoperative blood loss was 55 ml (interquartile range 30-90). The total harvested lymph nodes was 13.0(range12-19). The median times to first flatus and liquid diet intake were both 3.0 days. The median number of postoperative hospital days was 8.0 days. One patient had an injury to marginal arterial arch, and after mobolization of splenic region, tension-free anastomosis was achieved. No other severe postoperative complications such as abdominal infection, anastomotic leakage, or bleeding were observed. CONCLUSIONS: This technique is both safe and effective for filling the mesenteric defect, potentially reducing the risk of internal hernia following laparoscopic NO.253 lymph node dissection and preservation of the left colic artery in rectal cancer surgeries.

Hypervalent Iodine Promoted Selective [2 + 2 + 1] Cycloaddition of Aromatic Ketones and Methylamines: A One-Pot Access to 1-Pyrrolines.

Herein, a versatile highly regioselective three-component annulation of simple aromatic ketones and methylamines using a hypervalent iodine reagent for polyarylated 1-pyrrolines has been described in good to excellent yields. Meanwhile, unsymmetrical 1-pyrroline isomers could be realized and synthesized. Such an intriguing one-pot two-step tandem assembly strategy with green conditions and high regioselectivity shows predictable inspiration in related annulation reactions.

Electro-scalp acupuncture regulates the expression of CYP27a1/b1, CYP24a and related inflammatory cytokines in ischemic cortex of rats with middle cerebral artery occlusion. / ç”µå¤´é’ˆè°ƒæŽ§å¤§è„‘ä¸­åŠ¨è„‰æ “å¡žå¤§é¼ ç¼ºè¡€å¤§è„‘çš®å±‚åŒºCYP27a1/b1、CYP24aåŠç›¸å ³ç‚Žæ€§ç»†èƒžå› å­è¡¨è¾¾çš„ç ”ç©¶.

OBJECTIVES: To observe the effect of electro-scalp acupuncture (ESA) on the expression of cytochrome P450a1/b1 (CYP27a1/b1), cytochrome P45024a (CYP24a), signal transducer and activator of transcription (STAT)4, STAT6, tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-4 in ischemic cerebral cortex of rats with acute ischemic stroke, so as to explore its mechanism in alleviating inflammatory reaction of ischemic stroke. METHODS: Sixty SD rats were randomly divided into sham-operation, model, vitamin D3 and ESA groups, with 15 rats in each group. The middle cerebral artery occlusion rat model was established with thread ligation according to Zea-Longa's method. Rats in the vitamin D3 group were given 1, 25-VitD3 solution (3 ng·100 g-1·d-1) by gavage, once daily for 7 days. Rats in the ESA group were treated at bilateral anterior parietotemporal slash (MS6) with ESA (2 Hz/100 Hz, 1 mA), 30 min a day for 7 days. Before and after interventions, the neurological deficit score and neurobehavioral score were evaluated. TTC staining was used to detect the volume of cerebral infarction in rats. The positive expressions of CYP24a, CYP27a1 and CYP27b1 in the cerebral cortex of ischemic area were detected by immunofluorescence. The mRNA expressions of STAT4 and STAT6 in the cerebral cortex of ischemic area were detected by quantitative real-time PCR. The protein expression levels of TNF-α, IL-1ß and IL-4 in the cerebral cortex of ischemic area were detected by Western blot. RESULTS: Compared with the sham-operation group, the neurological deficit score, neurobehavioral score, the percentage of cerebral infarction volume, the positive expression level of CYP24a and mRNA expression level of STAT4, protein expression levels of TNF-α and IL-1ß in cerebral cortex were increased (P<0.01), while the positive expression levels of CYP27a1/b1 and STAT6 mRNA, protein expression level of IL-4 were decreased (P<0.01) in the model group. After the treatment and compared with the model group, the neurological deficit score, neurobehavioral score, the percentage of cerebral infarction volume, the positive expression level of CYP24a and mRNA expression level of STAT4, protein expression levels of TNF-α and IL-1ß in cerebral cortex were decreased (P<0.01), while the positive expression levels of CYP27a1/b1 and STAT6 mRNA expression level, protein expression level of IL-4 were increased (P<0.01) in the ESA and vitamin D3 groups. CONCLUSIONS: ESA can alleviate the inflammatory response in ischemic stroke, which maybe related to its function in regulating the balance between CYP27a1/b1 and CYP24a, converting vitamin D into active vitamin D3, inhibiting vitamin D3 degradation, and regulating Th1/Th2 balance.

The prognostic value of prognostic nutritional index and renal function indicators for mortality prediction in severe COVID-19 elderly patients: A retrospective study.

Identifying prognostic factors in elderly patients with severe coronavirus disease 2019 (COVID-19) is crucial for clinical management. Recent evidence suggests malnutrition and renal dysfunction are associated with poor outcome. This study aimed to develop a prognostic model incorporating prognostic nutritional index (PNI), estimated glomerular filtration rate (eGFR), and other parameters to predict mortality risk. This retrospective analysis included 155 elderly patients with severe COVID-19. Clinical data and outcomes were collected. Logistic regression analyzed independent mortality predictors. A joint predictor "L" incorporating PNI, eGFR, D-dimer, and lactate dehydrogenase (LDH) was developed and internally validated using bootstrapping. Decreased PNI (OR = 1.103, 95% CI: 0.78-1.169), decreased eGFR (OR = 0.964, 95% CI: 0.937-0.992), elevated D-dimer (OR = 1.001, 95% CI: 1.000-1.004), and LDH (OR = 1.005, 95% CI: 1.001-1.008) were independent mortality risk factors (all P < .05). The joint predictor "L" showed good discrimination (area under the curve [AUC] = 0.863) and calibration. The bootstrapped area under the curve was 0.858, confirming model stability. A combination of PNI, eGFR, D-dimer, and LDH provides useful prognostic information to identify elderly patients with severe COVID-19 at highest mortality risk for early intervention. Further external validation is warranted.

Characteristics and mechanism of local scour reduction around spur dike using the collar in clear water.

To reduce the local scour around the spur dike, the U-shaped collar is proposed in this study. The influence of the collar's length, width, and porosity on the local scour reduction in clear water is studied by model tests and numerical simulations. Experimental studies show that the collar has a significant effect on reducing the local scour. The location of the maximum scour depth of the spur dike moves downstream. The width of the collar has the greatest impact on the reduction effect among the three selected factors, followed by the porosity and the length. Local scour reduction efficiency of the collar can reach 56.9%. Based on the regression analysis of the range and variety, a formula for predicting the reduction effect around the spur dike is put forward, and the deviation between the values by formula and that in experiments are within ± 4%. The characteristics of the flow field around the spur dike under constant conditions with a collar are studied via numerical simulation. The numerical simulation results show that compared to the case without collar, the flow velocities around the spur dike in cases with permeable collar and solid collar reduced by 45% and 25%, respectively, and the shear stresses reduced by 20% and 28.6%, respectively. The results of this study can provide a reference for local scour reduction using the solid collar or collar made of permeable materials such as gabions.

Photo-induced tungsten-catalyzed cascade synthesis of pyrrolo[2,1-a]isoquinoline-1,3-dicarboxylate and its reaction mechanism.

A pyrrolo[2,1-a]isoquinoline core structure is prevalent in marine and other natural products. This article describes a tungsten-catalyzed [3+2] cycloaddition aromatization of dihydroisoquinoline ester and maleic anhydride or an acrylate. The photochemical reaction tolerates a range of functional groups such as ester, cyano, ketone, bromide, and alkene. It is shown that the cycloaddition-aromatization of 2-substitued acrylate catalyzed by a tungsten photocatalyst can be used to evaluate the leaving ability of the leaving group. Experiments done to determine the reaction mechanism revealed that the formation of an ion-pair intermediate generated in situ from dihydroisoquinoline ester and (Z)-4-methoxy-4-oxobut-2-enoic acid via the solvolysis of maleic anhydride with methanol is crucial for the cascade process to occur. The key cycloadduct acid intermediate derived from [3+2] cycloaddition was isolated and determined by X-ray crystallography.

Unveiling the hidden: identification and management of overlooked blood vessels in laparoscopic left hemicolectomy for splenic flexure cancer.

BACKGROUND: During laparoscopic left hemicolectomy procedures, a previously overlooked consistently thick blood vessel within the gastrocolic ligament near the splenic hilum may contribute to post-operative bleeding complications. The purpose of this study was to investigate the identification and management of the previously overlooked blood vessel. METHODS: This is a retrospective descriptive study of patients undergoing laparoscopic left colectomy for splenic fexure cancer conducted at a national gastrointestinal surgery centre in China. Consecutive patients with splenic fexure cancer who underwent laparoscopic left colectomy using our"five-step process"(n = 34) between January 2021 and July 2023 were included. RESULTS: The vessels can be effectively exposed using the aforementioned "five-step process." It was observed that the overlooked vessels consistently present in all patients were identified as the omental branch of the left gastroepiploic artery and vein. CONCLUSION: We have identified the origin of previously overlooked blood vessels and recommended a safe method for their management. This may offer advantages to colorectal surgeons performing laparoscopic left colectomy for splenic flexure cancer.

MFN2 suppresses the accumulation of lipid droplets and the progression of clear cell renal cell carcinoma.

Dissolving the lipid droplets in tissue section with alcohol during a hematoxylin and eosin (H&E) stain causes the tumor cells to appear like clear soap bubbles under a microscope, which is a key pathological feature of clear cell renal cell carcinoma (ccRCC). Mitochondrial dynamics have been reported to be closely associated with lipid metabolism and tumor development. However, the relationship between mitochondrial dynamics and lipid metabolism reprogramming in ccRCC remains to be further explored. We conducted bioinformatics analysis to identify key genes regulating mitochondrial dynamics differentially expressed between tumor and normal tissues and immunohistochemistry and Western blot to confirm. After the target was identified, we created stable ccRCC cell lines to test the impact of the target gene on mitochondrial morphology, tumorigenesis in culture cells and xenograft models, and profiles of lipid metabolism. It was found that mitofusin 2 (MFN2) was downregulated in ccRCC tissues and associated with poor prognosis in patients with ccRCC. MFN2 suppressed mitochondrial fragmentation, proliferation, migration, and invasion of ccRCC cells and growth of xenograft tumors. Furthermore, MFN2 impacted lipid metabolism and reduced the accumulation of lipid droplets in ccRCC cells. MFN2 suppressed disease progression and improved prognosis for patients with ccRCC possibly by interrupting cellular lipid metabolism and reducing accumulation of lipid droplets.

A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened.

The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.

Difluoromethylated Difunctionalization of Alkenes under Visible Light.

Difluoromethylated compounds usually act as bioisosteres for alcohol functional groups and show unique physicochemical and biological properties. The cyano-difluoromethylation of alkenes using 5-((difluoromethyl)sulfonyl)-1-phenyl-1H-tetrazole as a CF2H radical difluoromethyl precursor was developed to afford nitriles including a CF2H group. A low-cost, stable, easily handled 5-((difluoromethyl)sulfonyl)-1-methyl-1H-tetrazole (DFSMT) was synthesized and applied as the radical CF2H reagent. Using DFSMT as the radical CF2H precursor, the oxyl-difluoromethylation of alkenes was developed to obtain difluoromethylated ether products. All of the reactions showed good functional group tolerability. Initial mechanistic experiments indicated that the CF2H radical was involved as the key active intermediate.

Visible Light Mediated Chemoselective Hydroxylation of Benzylic Methylenes.

We have developed a metal-free photocatalytic selective hydroxylation of benzylic methylenes to secondary alcohols. This approach utilizes low-cost eosin Y as photocatalyst, O2 as green oxidant, and inexpensive triethylamine as inhibitor for overoxidation. The mild reaction conditions enable the production of secondary alcohols with 56-95% yields, making it a promising and environmental-friendly method for the synthesis of secondary alcohols from benzylic methylenes.

Mitochondrial dynamics and mitochondrial autophagy: Molecular structure, orchestrating mechanism and related disorders.

Mitochondrial dynamics and autophagy play essential roles in normal cellular physiological activities, while abnormal mitochondrial dynamics and mitochondrial autophagy can cause cancer and related disorders. Abnormal mitochondrial dynamics usually occur in parallel with mitochondrial autophagy. Both have been reported to have a synergistic effect and can therefore complement or inhibit each other. Progress has been made in understanding the classical mitochondrial PINK1/Parkin pathway and mitochondrial dynamical abnormalities. Still, the mechanisms and regulatory pathways underlying the interaction between mitophagy and mitochondrial dynamics remain unexplored. Like other existing reviews, we review the molecular structure of proteins involved in mitochondrial dynamics and mitochondrial autophagy, and how their abnormalities can lead to the development of related diseases. We will also review the individual or synergistic effects of abnormal mitochondrial dynamics and mitophagy leading to cellular proliferation, differentiation and invasion. In addition, we explore the mechanisms underlying mitochondrial dynamics and mitochondrial autophagy to contribute to targeted and precise regulation of mitochondrial function. Through the study of abnormal mitochondrial dynamics and mitochondrial autophagy regulation mechanisms, as well as the role of early disease development, effective targets for mitochondrial function regulation can be proposed to enable accurate diagnosis and treatment of the associated disorders.

MMP-9 inhibition alleviates postoperative cognitive dysfunction by improving glymphatic function via regulating AQP4 polarity.

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, characterized by deficits in memory, attention and cognitive flexibility. However, the underlying mechanisms of POCD remain unclear. Neuroinflammation and blood-brain barrier disruption have been implicated as potential pathological processes. This study explores the neuroprotective effects and mechanisms of the matrix metalloproteinase（MMP-9）inhibitor GM6001 against POCD. We hypothesize GM6001 may reduce neuroinflammation and preserve blood-brain barrier integrity through direct inhibition of MMP-9. Moreover, GM6001 may stabilize aquaporin-4 polarity and glymphatic clearance function by modulating MMP-9-mediated cleavage of dystroglycan, a key protein for aquaporin-4 anchoring. Our results demonstrate GM6001 alleviates postoperative cognitive deficits and neuroinflammation. GM6001 also preserves blood-brain barrier integrity and rescues aquaporin-4 mislocalization after surgery. This study reveals a novel dual role for MMP-9 inhibition in cognitive protection through direct anti-neuroinflammatory effects and regulating aquaporin-4 membrane distribution. Targeting MMP-9 may represent a promising strategy to prevent postoperative cognitive dysfunction by integrating multiple protective mechanisms.

A potential role of human esophageal cancer-related gene-4 in cardiovascular homeostasis.

Human esophageal cancer related gene-4 (ECRG-4) encodes a 148-aminoacid pre-pro-peptide that can be processed tissue-dependently into multiple small peptides possessing multiple functions distinct from, similar to, or opposite to the tumor suppressor function of the full-length Ecrg4. Ecrg-4 is covalently bound to the cell surface through its signal peptide, colocalized with the innate immunity complex (TLR4-CD14-MD2), and functions as a 'sentinel' molecule in the maintenance of epithelium and leukocyte homeostasis, meaning that the presence of Ecrg-4 on the cell surface signals the maintained homeostasis, whereas the loss of Ecrg-4 due to tissue injury activates pro-inflammatory and tissue proliferative responses, and the level of Ecrg-4 gradually returns to its pre-injury level upon wound healing. Interestingly, Ecrg-4 is also highly expressed in the heart and its conduction system, endothelial cells, and vascular smooth muscle cells. Accumulating evidence has shown that Ecrg-4 is involved in cardiac rate/rhythm control, the development of atrial fibrillation, doxorubicin-induced cardiotoxicity, the ischemic response of the heart and hypoxic response in the carotid body, the pathogenesis of atherosclerosis, and likely the endemic incidence of idiopathic dilated cardiomyopathy. These preliminary discoveries suggest that Ecrg-4 may function as a 'sentinel' molecule in cardiovascular system as well. Here, we briefly review the basic characteristics of ECRG-4 as a tumor suppressor gene and its regulatory functions on inflammation and apoptosis; summarize the discoveries about its distribution in cardiovascular system and involvement in the development of CVDs, and discuss its potential as a novel therapeutic target for the maintenance of cardiovascular system homeostasis.

Synthesis of Bench-stable Polycyclic Organophosphorus Heterocycles via Staudinger-type Annulations of ortho-Azidophenols.

The formation of a five- or six-membered ring is known to stabilize unstable molecular structures such as hemiacetals. This idea can also be extended to stabilize other high-coordinated p-block element species. Herein, we synthesized two novel polycyclic organophosphorus heterocycles via Staudinger-type annulations. Reactions of either ortho-phosphinoarenesulfonyl fluorides 1 or ortho-phosphinobenzoic acid methyl esters 4 with ortho-azidophenols 2 gave rise to penta-coordinated P(V) heterocycles, benzo-benzo-1,2,3-thiazaphospholo-1,3,2-oxazaphosphole (B-B-TAP-OAP) 3 and benzo-benzo-1,2-azaphospholo-1,3,2-oxazaphosphol-12-one (B-B-AP-OAP) 5 in satisfactory yields. It is remarkable that heterocycles 3 and 5 are both bench-stable and exhibit considerable stability in a 10 % aqueous tetrahydrofuran solution. Preliminary computational studies disclosed that the formation of nitrogen gas is the key driving force for the annulations. In addition, the formation of a strong Si-F bond is another contributor to the annulation of 1 and 2.

Identification of SRSF10 as a promising prognostic biomarker with functional significance among SRSFs for glioma.

AIMS: The serine/arginine-rich splicing factor (SRSF) protein family members are essential mediators of the alternative splicing (AS) regulatory network, which is tightly implicated in cancer progression. However, the expression, clinical correlation, immune infiltration, and prognostic value of SRSFs in gliomas remain unclear. MATERIALS AND METHODS: Glioma samples were extracted from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets. Several databases, such as HPA, DAVID, UALCAN were used to comprehensively explore the roles of SRSFs. In addition, experimental validation of SRSF10 was also conducted. KEY FINDINGS: Here, we found the expression alterations of the SRSF family in glioma samples using data from the TCGA and CGGA_325 datasets. Among the 12 genes, most were found to be closely associated with glioma clinical features, which linked to poor prognosis in glioma patients. Interestingly, survival analysis identified only SRSF10 as a potential independent risk prognostic biomarker for glioma patients. Immune analysis indicated that glioma patients with high SRSF10 expression may respond well to immunotherapies targeting immune checkpoint (ICP) genes. Finally, knocking down SRSF10 reduced glioma cell viability, induced G1 cell cycle arrest, and induced the exclusion of bcl-2-associated transcription factor 1 (BCLAF1) exon 5a. SIGNIFICANCE: Overall, this study uncovers the oncogenic roles of most SRSF family members in glioma, with the exception of SRSF5, while highlighting SRSF10 as a potential novel independent prognostic biomarker for glioma.

Potential window alignment regulating ion transfer in faradaic junctions for efficient photoelectrocatalysis.

In the past decades, a band alignment theory has become a basis for designing different high-performance semiconductor devices, such as photocatalysis, photoelectrocatalysis, photoelectrostorage and third-generation photovoltaics. Recently, a faradaic junction model (coupled electron and ion transfer) has been proposed to explain charge transfer phenomena in these semiconductor heterojunctions. However, the classic band alignment theory cannot explain coupled electron and ion transfer processes because it only regulates electron transfer. Therefore, it is very significant to explore a suitable design concept for regulating coupled electron and ion transfer in order to improve the performance of semiconductor heterojunctions. Herein, we propose a potential window alignment theory for regulating ion transfer and remarkably improving the photoelectrocatalytic performance of a MoS2/Cd-Cu2ZnSnS4 heterojunction photocathode. Moreover, we find that a faradaic potential window, rather than the band position of the intermediate layer, is a criterion for identifying interface charge transfer direction. This finding can offer different perspectives for designing high-performance semiconductor heterojunctions with suitable potential windows for solar energy conversion and storage.