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.

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.

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.

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.

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.

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.

Elevated glucose metabolism driving pro-inflammatory response in B cells contributes to the progression of type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the immune system's failure to maintain self-tolerance, resulting in the autoimmune destruction of pancreatic beta cells. Although T1D has conventionally been viewed as a T-cell-dominant disease, recent research has emphasized the contribution of B cells in the onset of the disease. However, the mechanism underlying aberrant B cell responses remains unknown. B cell metabolism is a crucial prerequisite for B cell function and the development of adaptive immune responses. Here, we investigated the metabolic features of B cells, first in a cross-sectional cohort and subsequently in non-obese diabetic (NOD) mice, and revealed that there is an increased frequency of high-glucose-avidity (2-NBDGhigh) B cell population that may contribute to T1D progression. Further characterization of the metabolic, transcriptional and functional phenotype of B cells in NOD mice found that elevated glucose avidity is associated with a greater capacity for co-stimulation, proliferation and inflammatory cytokine production. Mechanistically, elevated Myc signaling orchestrated the glucose metabolism and the pro-inflammatory response of B cells in T1D. In vitro experiments demonstrated that pharmacological inhibition of glucose metabolism using metformin and 2-DG reduced pro-inflammatory cytokine production and B cell proliferation. Moreover, the combination of these inhibitors successfully delayed insulitis development, onset of diabetes, and improved high blood glucose levels in streptozotocin (STZ)-induced diabetic mice model. Taken together, our work has uncovered these high-glucose-avidity B cells as novel adjuvant diagnostic and therapeutic targets for T1D.

The miR-29 family members induce glioblastoma cell apoptosis by targeting cell division cycle 42 in a p53-dependent manner.

BACKGROUND: Emerging evidence has shown that miR-29 is a promising biomarker and therapeutic target for malignancies. The roles of miR-29a/b/c in glioma pathogenesis remain need further investigation. METHODS: The expression levels of miR-29a/b/c and CDC42 were systematically analysed, and prognostic significance was evaluated by Kaplan-Meier survival and Cox regression analyses. The roles of miR-29a/b/c in apoptosis and the underlying mechanisms were explored via an alkaline single-cell gel electrophoresis assay, caspase 3/7 activity assays and Western blotting. RESULTS: miR-29a/b/c expression decreased progressively with the elevation of the WHO grade in our 147 human glioma specimens, compared with 20 non-tumour control brain tissues, and decreased miR-29a/b/c expression was associated with more aggressive phenotypes. Kaplan-Meier and Cox regression analyses demonstrated that lower miR-29a/b/c expression was correlated with worse prognosis, which was confirmed by analysis of 198 glioma patients from the CGGA cohort. These all indicate that miR-29a/b/c were independent predictors of prognosis in glioma patients. miR-29a/b/c induced apoptosis in GBM cells by silencing CDC42. Further detailed mechanistic investigation revealed that miR-29a/b/c promoted apoptosis in a p53-dependent manner by suppressing the CDC42/PAK/AKT/MDM2 pathway. CONCLUSIONS: miR-29a/b/c are independent predictors of prognosis in glioma patients. They induce glioblastoma cell apoptosis via silencing of CDC42 and suppression of downstream PAK/AKT/MDM2 signalling in a p53-dependent manner.

AQP4 is an Emerging Regulator of Pathological Pain: A Narrative Review.

Pathological pain presents significant challenges in clinical practice and research. Aquaporin-4 (AQP4), which is primarily found in astrocytes, is being considered as a prospective modulator of pathological pain. This review examines the association between AQP4 and pain-related diseases, including cancer pain, neuropathic pain, and inflammatory pain. In cancer pain, upregulated AQP4 expression in tumor cells is linked to increased pain severity, potentially through tumor-induced inflammation and edema. Targeting AQP4 may offer therapeutic strategies for managing cancer pain. AQP4 has also been found to play a role in nerve damage. Changes in AQP4 expression have been detected in pain-related regions of the brain and spinal cord; thus, modulating AQP4 expression or function may provide new avenues for treating neuropathic pain. Of note, AQP4-deficient mice exhibit reduced chronic pain responses, suggesting potential involvement of AQP4 in chronic pain modulation, and AQP4 is involved in pain modulation during inflammation, so understanding AQP4-mediated pain modulation may lead to novel anti-inflammatory and analgesic therapies. Recent advancements in magnetic resonance imaging (MRI) techniques enable assessment of AQP4 expression and localization, contributing to our understanding of its involvement in brain edema and clearance pathways related to pathological pain. Furthermore, targeting AQP4 through gene therapies and small-molecule modulators shows promise as a potential therapeutic intervention. Future research should focus on utilizing advanced MRI techniques to observe glymphatic system changes and the exchange of cerebrospinal fluid and interstitial fluid. Additionally, investigating the regulation of AQP4 by non-coding RNAs and exploring novel small-molecule medicines are important directions for future research. This review shed light on AQP4-based innovative therapeutic strategies for the treatment of pathological pain. Dark blue cells represent astrocytes, green cells represent microglia, and red ones represent brain microvasculature.

Cobalt-Catalyzed Hypervalent Iodine(III) Promoted Cascade Annulation Reaction of Anilines with Formamides for 2-Aminobenzoxazoles Synthesis.

Herein, we disclose a practical and simple procedure to synthesize 2-aminobenzoxaoles. Simple anilines and formamides were used as substrates. The C-H bond ortho to the amino group in the anilines was directly functionalized under cobalt-catalyzed conditions with high levels of functional group tolerance. Hypervalent iodine(III) was both an oxidant and a Lewis acid for this reaction. The mechanism study showed that this transformation may involve a radical process.

Annulation of α-bromocinnamaldehydes to access 3-formyl-imidazo[1,2-α]pyridines and pyrimidines under transition metal-free conditions.

An environmentally friendly and transition metal-free method for the annulation of α-bromocinnamaldehydes was established. 3-Formyl-imidazo[1,2-α]pyridines and pyrimidines were obtained in moderate to excellent yields. This approach features easily available starting materials, transition metal-free conditions, good functional group tolerance and operational simplicity.

Synthesis of functionalized tetrahydrodibenzo[b,g][1,8]naphthyridin-1(2H)-ones through base-promoted annulation of quinoline-derived dipolarophiles and cyclic enaminones.

An eco-friendly and metal-free method for the synthesis of tetrahydrodibenzo[b,g][1,8]naphthyridin-1(2H)-ones was established. Quinoline-derived dipolarophiles and cyclic enaminones as starting materials undergo a 1,4-Michael addition/SNAr tandem annulation reaction affording the target products. This approach features transition metal-free conditions, good functional group tolerance and operational simplicity.

Chemodivergent Staudinger Reactions of Secondary Phosphine Oxides and Application to the Total Synthesis of LL-D05139ß Potassium Salt.

Unprecedented Staudinger reaction modes of secondary phosphine oxides (SPO) and organic azides are herein disclosed. By the application of various additives, selective nitrogen atom exclusion from the azide group has been achieved. Chlorotrimethylsilane mediates a stereoretentive Staudinger reaction with a 2-N exclusion which provides a valuable method for the synthesis of phosphinic amides and can be considered complementary to the stereoinvertive Atherton-Todd reaction. Alternatively, a 1-N exclusion pathway is promoted by acetic acid to provide the corresponding diazo compound. The effectiveness of this protocol has been further demonstrated by the total synthesis of the diazo-containing natural product LL-D05139ß, which was prepared as a potassium salt for the first time in 6 steps and 26.5 % overall yield.

Valence Disproportionation of GeS in the PbS Matrix Forms Pb5Ge5S12 Inclusions with Conduction Band Alignment Leading to High n-Type Thermoelectric Performance.

Converting waste heat into useful electricity using solid-state thermoelectrics has a potential for enormous global energy savings. Lead chalcogenides are among the most prominent thermoelectric materials, whose performance decreases with an increase in chalcogen amounts (e.g., PbTe > PbSe > PbS). Herein, we demonstrate the simultaneous optimization of the electrical and thermal transport properties of PbS-based compounds by alloying with GeS. The addition of GeS triggers a complex cascade of beneficial events as follows: Ge2+ substitution in Pb2+ and discordant off-center behavior; formation of Pb5Ge5S12 as stable second-phase inclusions through valence disproportionation of Ge2+ to Ge0 and Ge4+. PbS and Pb5Ge5S12 exhibit good conduction band energy alignment that preserves the high electron mobility; the formation of Pb5Ge5S12 increases the electron carrier concentration by introducing S vacancies. Sb doping as the electron donor produces a large power factor and low lattice thermal conductivity (κlat) of ∼0.61 W m-1 K-1. The highest performance was obtained for the 14% GeS-alloyed samples, which exhibited an increased room-temperature electron mobility of ∼121 cm2 V-1 s-1 for 3 × 1019 cm-3 carrier density and a ZT of 1.32 at 923 K. This is ∼55% greater than the corresponding Sb-doped PbS sample and is one of the highest reported for the n-type PbS system. Moreover, the average ZT (ZTavg) of ∼0.76 from 400 to 923 K is the highest for PbS-based systems.

Laparoscopic Complete Mesocolic Excision with Central Vascular Ligation (CME + CVL) for Right-Sided Colon Cancer: A New "Superior Mesenteric Artery First" Approach.

PURPOSE: It remains a technical challenge to perform "superior mesenteric artery (SMA) first" approach for laparoscopic right hemicolectomy with complete mesocolon excision (CME) as the vascular anatomy of the right colon varies a lot, which may cause difficulty in early location of SMA and the risk of vascular damage during central vascular ligation (CVL). The purpose of this study was to describe a new "SMA first" approach for laparoscopic CME with CVL in right hemicolectomy with Treitz's ligament and ileocolic vascular pedicle as the anatomical landmarks for early identification of and exposure of SMA. METHODS: This procedure was performed on 21 patients with right colon cancer between March 2020 and August 2021. To start, the transverse mesocolon was retracted to expose the ligament of Treitz, and the pedicle of ileocolic vessels was anteriorly grasped. Next, the peritoneum near the right border of the ligament of Treitz was divided along the left side of SMA until the peritoneum below the ileocolic vessels. Next, the mesenteric lymphatic adipose tissue outside of the sheath of SMA was dissected from medial to lateral. Then, laparoscopic right hemicolectomy with complete mesocolic excision (CME) was performed. Patients' preoperative baseline characteristics and intraoperative and postoperative complications were examined. RESULTS: The median operative time was 180 min, and the median intraoperative blood loss was 50 ml (interquartile range 40-90). Chylous leakage occurred in four patients, and all the patients resolved with percutaneous drainage. The total harvested lymph nodes was 21.0 (range 16-27). The median times to first flatus and liquid diet intake were both 3.0 days. The median number of postoperative hospital days was 10.0 days. No severe postoperative complications, such as abdominal infection, anastomotic leakage, or bleeding, were observed. CONCLUSIONS: This new "SMA first" approach is safe and technically feasible for laparoscopic CME with CVL in right hemicolectomy.

A Novel Technique With Ileal Mesentery to Reconstruct the Pelvic Peritoneum After Pelvic Dissection With End Colostomy for Rectal Cancer.

BACKGROUND: After abdominoperineal resection, low anterior resection, and end colostomy for lower rectal cancer, it is necessary to reconstruct the pelvic peritoneum to avoid small bowel obstruction, perineal hernia, and radiation enteritis in patients for whom postoperative radiotherapy is planned. However, pelvic peritoneal closure is technically difficult in patients who lack enough peritoneum to cover the defect or have received neoadjuvant radiation and have a rigid pelvis. IMPACT OF INNOVATION: The impact of this innovation is to reconstruct the pelvic peritoneum with the distal ileal mesentery laparoscopically. TECHNOLOGY, MATERIALS AND METHODS: After removal of the tumor, the distal ileal mesentery was selected to completely cover the defect. Subsequently, suturing of the ileal mesentery to the posterior wall of the urinary bladder and all sides of the pelvic cavity was performed. Finally, the patients were returned to the headfirst supine position to ensure that there was no small bowel falling into the pelvic dead space. PRELIMINARY RESULTS: All surgical procedures were successfully performed laparoscopically from January 2019 to April 2021. No perineal complications or intestinal obstructions occurred during the follow-up period. CONCLUSIONS AND FUTURE DIRECTIONS: This novel technique was found to be safe and effective. Moreover, it provided an economical method for the reconstruction of the pelvic peritoneum using autologous material, which could preserve the small intestine in the abdomen to avoid related complications. Additional larger series of patients with longer follow-up are needed to validate the safety and feasibility of this method.

Design of few-layer carbon nitride/BiFeO3 composites for efficient organic pollutant photodegradation.

Heterojunction-driven photocatalysis can degrade various organic pollutants, and developing carbon nitride-based composite photocatalysts is of great significance and gains growing interest. In this study, a two-dimensional graphitic carbon nitride nanosheets/BiFeO3 (GCNNs/BiFeO3) Z-scheme heterojunction has been synthesized through the electrostatic spinning and post-calcination The obtained GCNNs/BiFeO3 nanofibers show large surface contact between GCNNs the and BiFeO3 nanostructures. The Z-scheme heterojunction shows a remarkably enhanced photocatalytic performance, which could degrade 94% of tetracycline (TC) and 88% of Rhodamine B (RhB) under LED visible light irradiation in 150 min. Radical trapping experiments demonstrate the effective construction of Z-scheme heterojunctions, and •O2- and h+ are the main active species in the photocatalytic degradation process. This study realizes a novel nanostructured GCNNs/BiFeO3 heterojunction for photodegradation applications, which would guide the design of next-generation efficient photocatalysts.

Ortho-Phosphinoarenesulfonamide-Mediated Staudinger Reduction of Aryl and Alkyl Azides.

Conventional Staudinger reductions of organic azides are sluggish with aryl or bulky aliphatic azides. In addition, Staudinger reduction usually requires a large excess of water to promote the decomposition of the aza-ylide intermediate into phosphine oxide and amine products. To overcome the challenges above, we designed a novel triaryl phosphine reagent 2c with an ortho-SO2NH2 substituent. Herein, we report that such phosphine reagents are able to mediate the Staudinger reduction of both aryl and alkyl azides in either anhydrous or wet solvents. Good to excellent yields were obtained in all cases (even at a diluted concentration of 0.01 M). The formation of B-TAP, a cyclic aza-ylide, instead of phosphine oxide, eliminates the requirement of water in the Staudinger reduction. In addition, computational studies disclose that the intramolecular protonation of the aza-ylide by the ortho-SO2NH2 group is kinetically favorable and responsible for the acceleration of Staudinger reduction of the aryl azides.

Metal-Organic Framework Assembled on Oriented Nanofiber Arrays for Field-Effect Transistor and Gas Sensor-Based Applications.

Metal-organic framework (MOF) films are essential for numerous sensor and device applications. However, metal-organic framework materials have poor machinability due to their predominant powder-like nature, and their presence as the active layer in a device can seriously affect the performance and utility of the device. Herein, active layers of field-effect transistor (FETs) devices and chemiresistor gas sensors with high performance were constructed by loading Cu3(HITP)2 (HITP = 2,3,6,7,10,11-hexaiminotriphenylene) in situ-axial anchoring on oriented nanofiber arrays prepared via electrospinning. The strong interaction between polar groups on the polymer chains and metal ions promotes the nucleation of Cu3(HITP)2, steric hindrance makes particles of Cu3(HITP)2 with uniform size, morphology, and good crystallinity during nucleation by liquid phase epitaxial growth (LPE). Influences of differently-oriented Cu3(HITP)2 NFAs-based FETs on the electrical properties were studied, optimally oriented Cu3(HITP)2 NFAs-based FETs showed good mobility of 5.09 cm2/V·s and on/off ratio of 9.6 × 103. Moreover, excellent gas sensing response characteristics were exhibited in sensing volatile organic compounds (VOCs). Chemiresistor gas sensors with high response value, faster response and recovery are widely suited for VOCs. It brings new inspirations for the design and utilization of electrically conductive MOFs as an active layer for FETs and sensor units for chemiresistor gas sensors.

Synthesis of W-Phos Ligand and Its Application in the Copper-Catalyzed Enantioselective Addition of Linear Grignard Reagents to Ketones.

The asymmetric catalytic addition of linear Grignard reagents to ketones has been a long-standing challenge in organic synthesis. Herein, a novel family of PNP ligands (W-Phos) was designed and applied in copper-catalyzed asymmetric addition of linear Grignard reagents to aryl alkyl ketones, allowing facile access to versatile chiral tertiary alcohols in good to high yields with excellent enantioselectivities (up to 94 % yield, 96 % ee). The process can also be used to synthesize chiral allylic tertiary alcohols from more challenging α,ß-unsaturated ketones. Notably, the potential utility of this method is demonstrated in the gram-scale synthesis and modification of various densely functionalized medicinally relevant molecules.