Magnetically Controlled Photothermal, Colorimetric, and Fluorescence Trimode Assay for Gastric Cancer Exosomes Based on Acid-Induced Decomposition of CP/Mn-PBA DSNBs.

The accurate quantification of cancer-derived exosomes, which are emerging as promising noninvasive biomarkers for liquid biopsies in the early diagnosis of cancer, is becoming increasingly imperative. In our work, we developed a magnetically controlled photothermal, colorimetric, and fluorescence trimode aptasensor for human gastric cancer cell (SGC-7901)-derived exosomes. This sensor relied on CP/Mn-PBA DSNBs nanocomposites, created by decorating copper peroxide (CP) nanodots on polyethyleneimine-modified manganese-containing Prussian blue analogues double-shelled nanoboxes (PEI-Mn-PBA DSNBs). Through self-assembly, we attached CD63 aptamer-labeled CP/Mn-PBA DSNBs (Apt-CP/Mn-PBA DSNBs) to complementary DNA-labeled magnetic beads (cDNA-MB). During exosome incubation, these aptamers preferentially formed complexes with exosomes, and we efficiently removed the released CP/Mn-PBA DSNBs by using magnetic separation. The CP/Mn-PBA DSNBs exhibited high photoreactivity and photothermal conversion efficiency under near-infrared (NIR) light, leading to temperature variations under 808 nm irradiation, correlating with different exosome concentrations. Additionally, colorimetric detection was achieved by monitoring the color change in a 3,3',5,5'-tetramethylbenzidine (TMB) system, facilitated by PEI modification, NIR-enhanced peroxidase-like activity of CP/Mn-PBA DSNBs and their capacity to generate Cu2+ and H2O2 under acidic conditions. Moreover, in the presence of Cu2+ and ascorbic acid (AA), DNA sequences could form dsDNA-templated copper nanoparticles (CuNPs), which emitted strong fluorescence at around 575 nm. Increasing exosome concentrations correlated with decreases in temperature, absorbance, and fluorescence intensity. This trimode biosensor demonstrated satisfactory ability in differentiating gastric cancer patients from healthy individuals using human serum samples.

Site-Specific Anchoring a Luminescent Tag in a Protein with Non-Emissive Iridium(III) Complex.

Site-specific modification of proteins with synthetic fluorescent tag effectively improves the resolution of imaging, and such a labeling method with negligible three-dimensional structural perturbations and minimal impact on the biological functions of proteins is of high interest to dissect the high-resolution activities of biomolecules in complex systems. To this end, several non-emissive iridium(III) complexes [Ir(C-N)2 (H2 O)2 ]+ OTF- (C-N denotes various cyclometalated ligands) were designed and synthesized. These complexes were tested for attaching a protein by coordinating to H/X (HisMet, HisHis, and HisCys) that are separated by i and i+4 in α-helix. Replacement of the two labile water ligands in the iridium(III) complex by a protein HisHis pair increases the luminescent intensity up to over 100 folds. This labeling approach has been demonstrated in a highly specific and efficient manner in a number of proteins, and it is also feasible for labeling target proteins in cell lysates.

Efficacy and safety of CD19-specific CAR T cell-based therapy in B-cell acute lymphoblastic leukemia patients with CNSL.

Few studies have described chimeric antigen receptor (CAR) T-cell therapy for patients with B-cell acute lymphoblastic leukemia (B-ALL) with central nervous system leukemia (CNSL) because of concerns regarding poor response and treatment-related neurotoxicity. Our study included 48 patients with relapsed/refractory B-ALL with CNSL to evaluate the efficacy and safety of CD19-specific CAR T cell-based therapy. The infusion resulted in an overall response rate of 87.5% (95% confidence interval [CI], 75.3-94.1) in bone marrow (BM) disease and remission rate of 85.4% (95% CI, 72.8-92.8) in CNSL. With a median follow-up of 11.5 months (range, 1.3-33.3), the median event-free survival was 8.7 months (95% CI, 3.7-18.8), and the median overall survival was 16.0 months (95% CI, 13.5-20.1). The cumulative incidences of relapse in BM and CNS diseases were 31.1% and 11.3%, respectively, at 12 months (P = .040). The treatment was generally well tolerated, with 9 patients (18.8%) experiencing grade ≥3 cytokine release syndrome. Grade 3 to 4 neurotoxic events, which developed in 11 patients (22.9%), were associated with a higher preinfusion disease burden in CNS and were effectively controlled under intensive management. Our results suggest that CD19-specific CAR T cell-based therapy can induce similar high response rates in both BM and CNS diseases. The duration of remission in CNSL was longer than that in BM disease. CD19 CAR T-cell therapy may provide a potential treatment option for previously excluded patients with CNSL, with manageable neurotoxicity. The clinical trials were registered at www.clinicaltrials.gov as #NCT02782351 and www.chictr.org.cn as #ChiCTR-OPN-16008526.

Visible-Light-Mediated [2+2] Photocycloadditions of Alkynes.

Visible-light-mediated [2+2] photocycloaddition reaction can be considered an ideal solution due to its green and sustainable properties, and is one of the most efficient methods to synthesize four-membered ring motifs. Although research on the [2+2] photocycloaddition of alkynes is challenging because of the diminished reactivity of alkynes, and the more significant ring strain of the products, remarkable achievements have been made in this field. In this article, we highlight the recent advances in visible-light-mediated [2+2] photocycloaddition reactions of alkynes, with focus on the reaction mechanism and the late-stage synthetic applications. Advances in obtaining cyclobutenes, azetines, and oxetene active intermediates continue to be breakthroughs in this fascinating field of research.

Clinical outcomes and microenvironment profiling in relapsed/refractory multiple myeloma patients with extramedullary disease receiving anti-BCMA CAR T-cell-based therapy.

Relapsed/refractory multiple myeloma patients with extramedullary disease (EMD) have unfavorable prognosis and lack effective therapy. Chimeric antigen receptor (CAR) T-cell activities in EMD have yet to be determined; how EMD-specific microenvironment influences the clinical outcomes of CAR T-cell therapy remains of great interest. In this prospective cohort study, patients with histologically confirmed extra-osseous EMD were enrolled and treated with combined anti-BCMA and anti-CD19 CAR T-cell therapy from May 2017 to September 2023. Thirty-one patients were included in the study. Overall response occurred in 90.3% of medullary disease and 64.5% of EMD (p = .031). Discrepancies in treatment response were noted between medullary and extramedullary diseases, with EMD exhibiting suboptimal and delayed response, as well as shortened response duration. With a median follow-up of 25.3 months, the median progression-free and overall survival were 5.0 and 9.7 months, respectively. Landmark analysis demonstrated that progression within 6 months post-infusion is strongly associated with an increased risk of death (HR = 4.58; p = .029). Compared with non-EMD patients, patients with EMD showed inferior survival outcomes. Unique CAR-associated local toxicities at EMD were seen in 22.6% patients and correlated with the occurrence and severity of systemic cytokine release syndrome. To the cutoff date, 65% treated patients experienced EMD progression, primarily in the form of BCMA+ progression. The pretherapy EMD immunosuppressive microenvironment, characterized by infiltration of exhausted CD8+ T cells, was associated with inferior clinical outcomes. CAR T cells have therapeutic activity in relapsed/refractory EMD, but the long-term survival benefits may be limited. EMD-specific microenvironment potentially impacts treatment. Further efforts are needed to extend EMD remission and improve long-term outcomes.

Photomediated Hydro(deutero)acylation of Olefins by Decarboxylative Addition of α-Oxocarboxylic Acids.

Acyl radicals have been generated from the decarboxylation of α-oxocarboxylic acids by using a readily accessible organic pyrimidopteridine photoredox catalyst under ultraviolet-A (UV-A) light irradiation. These reactive acyl radicals were smoothly added to olefins such as styrenes and diverse Michael acceptors, with the assistance of H2O/D2O as hydrogen donors, enabling easy access to a diverse range of ketones/ß-deuterio ketones. A wide range of α-oxocarboxylic acids are compatible with this reaction, which shows a reliable, atom-economical, and eco-friendly protocol. Furthermore, postsynthetic diversifications and applications are presented.

Structure-activity relationships of natural and synthetic lathyrane-based diterpenoids for suppression of NLRP3-driven inflammation and gouty arthritis.

Lathyrane-based diterpenoid is one of the critical bioactive elements of Euphorbia lathyris L., a widely used traditional Chinese medicine for the treatment of inflammation and infection. In this study, we introduced and evaluated seven synthetic or natural lathyrane-based diterpenoids with the same core structure but notable structural variations at specific positions, for their anti-inflammatory and gout-alleviating properties. There was no significant cytotoxicity below 10 µM among the initial test of the cell counting kit 8 of the seven candidate derivatives (compounds 13 to 19) in this work. Furthermore, maintaining the acyloxy group at 15-C position and the strongly hydrophobic aryl structure at 3-C and 5-C positions, compounds 15 (Euphorbia factor L3, EFL3) and 17 strikingly inhibited the production of IL-1ß related to the actuation of the inflammasome in our study. The ELISA assay indicated that the anti-inflammatory effects of EFL3 were better associated with MSU stimulation than other second-line pathways triggered by inflammasome. Further examinations on the acute paw gout model in C57BL/6 mice showed that EFL3 had a significantly inflammatory retarding effect by intraperitoneal injection. It decreased swelling volume as well as the cleavage and activation of local IL-1ß and casepas-1 in the paw. To conclude, our findings reveal several potential key structure-activity relationships that govern the anti-inflammatory effects of lathyrane-type diterpenoids, the dispensable acyl group at the 15-C position, the importance of maintaining the spatial structure of the B-ring, and the potential importance of hydrophobic substituents at the 3-C position. These insights may provide guidance for the structural design of lathyrane-type agents in the future; furthermore, we found that the lathyrane-based diterpenoid EFL3 is a potential agent for gout that is expected to provide a novel therapeutic strategy for inflammation intervention.

Nicotinamide improves the impaired extravillous trophoblast cell invasion induced by PM2.5 exposure-associated increase of TNFα secretion through the ROS/NF-κB/FLT1 pathway.

It has been well acknowledged that maternal exposure to fine particulate matters (PM2.5) might lead to poor pregnancy outcomes including the intrauterine growth restriction (IUGR) by interfering with the placental development. Our previous studies have demonstrated that maternal PM2.5 exposure induces IUGR, accompanied with increased maternal circulating TNFα level and impaired extravillous trophoblast cells (EVTs) invasion in mice. In this study, HTR8/SVneo cells, the immortalized human EVTs line, were used to assess effects and the underlying molecular mechanisms of nicotinamide on the impaired EVTs invasion. Our results showed that, the placental FLT1 protein level was significantly increased whereas maternal serum nicotinamide concentration was remarkably decreased in PM2.5-exposured pregnant mice at GD17.5 (vaginal plug day=GD0.5), compared to that in normal GD17.5 pregnant mice. FLT1 expression in HTR8/SVneo cells was significantly up-regulated by TNFα treatment, and the down-regulated FLT1 expression effectively abated the inhibitory effects of TNFα on HTR8/SVneo cells migration and invasion. Meanwhile, TNFα promoted reactive oxygen species (ROS) production and NF-κB signaling pathway activation in HTR8/SVneo cells in a dose-dependent manner. Nicotinamide treatment significantly reversed the effects of TNFα on cell migration and invasion, as well as the FLT1 expression, ROS production and NF-κB pathway activation. In summary, increased TNFα induced by PM2.5 exposure inhibits EVTs invasion by activating the ROS/NF-κB/FLT1 signaling pathway, and this adverse effect could be attenuated by nicotinamide treatment, suggesting a potential application in the clinical intervention of PM2.5-induced IUGR.

Effect of long-term serum sodium levels on the prognosis of patients on maintenance hemodialysis.

Abnormal serum Na (SNa) levels are common in patients with chronic kidney disease (CKD) which is associated with increased morbidity and mortality. There are relatively few studies on the effect of SNa indicators on the prognosis of patients undergoing maintenance hemodialysis (MHD). We aim to investigate the effect of long-term SNa levels on the survival and prognosis of patients undergoing hemodialysis (HD). Newly entered HD patients in the registration system of Zhejiang Provincial Dialysis Quality Control Center between January 1, 2010 and December 31, 2019 were included and followed up until December 31, 2020. Multiple sodium levels were collected from patients, defining long-term SNa as the mean of multiple SNa, according to which patients were grouped, with the prognostic differences between subgroups compared by Kaplan-Meier modeling and multifactorial Cox regression modeling. Finally, a total of 21,701 patients were included in this study and Cox regression showed that decreased SNa levels (Na < 135 mmol/L, HR = 1.704, 95% CI 1.408-2.063, p < 0.001; 135≦Na≦137.5 mmol/L, HR = 1.127,95% CI 1.016-1.250, p = 0.024) and elevated SNa levels (142.5 < Na≦145mmol/L, HR = 1.198, 95% CI 1.063-1.350, p = 0.003; Na > 145mmol/L, HR = 2.150, 95% CI 1.615-2.863, p < 0.001) were all independent risk factors for all-cause mortality in MHD patients.

[Effect of polymethoxylated flavonoids on glucose and lipid metabolism in rat model of obesity induced by a high-fat diet].

This study established a rat model of obesity by using a high-fat diet(HFD) to explore the effect of polymethoxylated flavonoids on glucose and lipid metabolism in the model rats and decipher the role and mechanism of polymethoxylated flavonoids in mitigating obesity. Thirty normal SD rats were selected and randomized into normal, model, ezetimibe(0.1 mg·kg~(-1)), and polymethoxylated flavonoids(62.5 mg·kg~(-1) and 125 mg·kg~(-1)) groups based on the body weight. Except the normal group receiving a conventional diet, the other groups received a HFD. Rats were administrated with corresponding doses of drugs by gavage. During the administration period, the body weight of each group of rats was regularly weighed, and the serum lipid and glucose levels were measured by a fully automated biochemical analyzer. Islet homeostasis and serum levels of obesity factors were measured by ELISA. The 16S rRNA high-throughput sequencing was employed to study the gut microbiota. Hematoxylin-eosin staining was employed to observe the histomorphology of white fat, brown fat, and pancreas. After the wet weights of white fat and brown fat were measured, the organ index was calculated. Immunohistochemistry and Western blot were employed to determine the protein levels. The results showed that polymethoxylated flavonoids reduced the body weight and Lee's index and improved blood lipid levels of the model rats. Polymethoxylated flavonoids reduced blood glucose and insulin secretion, increased insulin responsiveness, and alleviated insulin resistance. In addition, polymethoxylated flavonoids regulated the serum levels of obesity factors and reduced the weights and indexes of white fat and brown fat, the diameter of white adipocytes, and the number of fat vacuoles in brown fat and pancreatic islet cells. The intervention with polymethoxylated flavonoids increased the diversity of gut microbiota in the model rats, increasing the beneficial bacteria associated with glucose and lipid metabolism and reduced the harmful bacteria at the genus level. In addition, polymethoxylated flavonoids up-regulated the protein levels of glucose transporter 4(GLUT4), phosphorylated AMP-activated protein kinase(p-AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α), and uncoupling protein 1(UCP1). In summary, polymethoxylated flavonoids may increase the body utilization of glucose and lipids by regulating the homeostasis of insulin, the serum levels of obesity factors, the diversity of gut microbiota, and the expression of mitochondrial metabolism-related proteins in brown adipocytes, thereby mitigating obesity in rats.

Construction and application of artificial lipoproteins using adiposomes.

Lipoproteins are complex particles comprised of a neutral lipid core wrapped with a phospholipid monolayer membrane and apolipoproteins on the membrane, which is closely associated with metabolic diseases. To facilitate the elucidation of its formation and dynamics, as well as its applications, we developed an in vitro system in which adiposomes, consisting of a hydrophobic core encircled by a monolayer-phospholipid membrane, were engineered into artificial lipoproteins (ALPs) by recruiting one or more kinds of apolipoproteins, for example, apolipoprotein (Apo) A-I, ApoE, ApoA-IV, and ApoB. In vitro and in vivo studies demonstrated the stability and biological activity of ALPs derived from adiposomes, which resembles native lipoproteins. Of note, adiposomes bearing ApoE were internalized via clathrin-mediated endocytosis following LDLR binding and were delivered to lysosomes. On the other hand, adiposomes bearing ApoA-IV mimicked the existing form of endogenous ApoA-IV and exhibited significant improvement in glucose tolerance in mice. In addition, the construction process was simple, precise, reproducible, as well as easy to adjust for mass production. With this experimental system, different apolipoproteins can be recruited to build ALPs for some biological goals and potential applications in biomedicine.

A Bimetallic Polymerization Network for Effective Increase in Labile Iron Pool and Robust Activation of cGAS/STING Induces Ferroptosis-Based Tumor Immunotherapy.

Due to the inherent low immunogenicity and immunosuppressive tumor microenvironment (TME) of malignant cancers, the clinical efficacy and application of tumor immunotherapy have been limited. Herein, a bimetallic drug-gene co-loading network (Cu/ZIF-8@U-104@siNFS1-HA) is developed that increased the intracellular labile iron pool (LIP) and enhanced the weakly acidic TME by co-suppressing the dual enzymatic activities of carbonic anhydrase IX (CA IX) and cysteine desulfurylase (NFS1), inducing a safe and efficient initial tumor immunogenic ferroptosis. During this process, Cu2+ is responsively released to deplete glutathione (GSH) and reduce the enzyme activity of glutathione peroxidase 4 (GPX4), achieving the co-inhibition of the three enzymes and further inducing lipid peroxidation (LPO). Additionally, the reactive oxygen species (ROS) storm in target cells promoted the generation of large numbers of double-stranded DNA breaks. The presence of Zn2+ substantially increased the expression of cGAS/STING, which cooperated with ferroptosis to strengthen the immunogenic cell death (ICD) response and remodel the immunosuppressive TME. In brief, Cu/ZIF-8@U-104@siNFS1-HA linked ferroptosis with immunotherapy through multiple pathways, including the increase in LIP, regulation of pH, depletion of GSH/GPX4, and activation of STING, effectively inhibiting cancer growth and metastasis.

Heterocyclic Boron Acid Catalyzed Dehydrative Amidation of Aliphatic/Aromatic Carboxylic Acids with Amines.

A commercially available and versatile dehydrative amidation catalyst, featuring a thianthrene boron acid structure, has been developed. The catalyst shows high catalytic activity to both aliphatic and less reactive aromatic carboxylic acid substrates, including several bioactive or clinical molecules with a carboxylic acid group.

Photoinduced, Silver(I)-Mediated Synthesis of Ester-Substituted Fused Quinazolinones via Cascade Alkoxycarbonylation/Cyclization of Heterocycles Bearing Unactivated Alkenes.

A new cascade alkoxycarbonylation/cyclization reaction of heterocycle-bearing unactivated alkenes is disclosed. The transformation is mediated by silver carbonate under photoirradiation. This method provides efficient access to pharmaceutically valuable molecules and natural product analogues containing quinazolinone-fused esters. Furthermore, this protocol is compatible with a variety of quinazolinone-bearing unactivated alkenes and alkyloxalyl chlorides that are readily prepared from abundant alcohols and oxalyl chlorides.

The STING-IRF3 Signaling Pathway, Mediated by Endoplasmic Reticulum Stress, Contributes to Impaired Myocardial Autophagic Flux After Ischemia/Reperfusion.

ABSTRACT: This study aimed to determine whether endoplasmic reticulum (ER) stress is involved in impaired autophagy after myocardial ischemia/reperfusion (M-I/R) and elucidate the underlying mechanisms. The expression levels of stimulator of interferon gene (STING) and interferon regulatory transcription factor 3 (IRF3) phosphorylation increased in M-I/R heart tissues and hypoxia-treated/reoxygenation-treated H9c2 cells. The ER stress inhibitor 4-phenylbutyric acid (4-PBA) significantly suppressed the stimulation of STING-IRF3 transcription and alleviated cardiac dysfunction caused by M-I/R injury. In addition, 4-PBA reversed ischemia-induced/reperfusion-induced autophagic flux dysfunction, as demonstrated by a decrease in p 62 and LC3 levels. Similarly, the protective effect of STING deficiency on myocardial cell damage was achieved by the recovery of autophagic flux. Conversely, the protective effect of 4-PBA against hypoxia/reoxygenation injury in cardiomyocytes was offset by STING overexpression, wherein the activated STING-IRF3 pathway promoted the expression of Rubicon (a negatively-regulated autophagic molecule) by binding to the Rubicon promoter. Rubicon ablation effectively counteracts the adverse effects of STING overexpression in cardiomyocytes. The data showed that STING-IRF3 signaling of ER stress receptors is particularly important in the progression of physiological M-I/R caused by the inhibition of autophagic flow in vivo and in vitro.

Maternal exposure to ambient PM2.5 perturbs the metabolic homeostasis of maternal serum and placenta in mice.

Epidemiological and animal studies have shown that maternal fine particulate matters (PM2.5) exposure correlates with various adverse pregnancy outcomes such as low birth weight (LBW) of offspring. However, the underlying biological mechanisms have not been fully understood. In this study, female C57Bl/6 J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) during pregestational and gestational periods, and metabolomics was performed to analyze the metabolic features in maternal serum and placenta by liquid chromatography-mass spectrometry (LC-MS). The partial least squares discriminate analysis (PLS-DA) displayed evident clustering of FA- and CAP-exposed samples for both maternal serum and placenta. In addition, pathway analysis identified that vitamin digestion and absorption was perturbed in maternal serum, while metabolic pathways including arachidonic acid metabolism, serotonergic synapse, 2-oxocarboxylic acid metabolism and cAMP signaling pathway were perturbed in placenta. Further analysis indicated that CAP exposure influenced the nutrient transportation capacity of placenta, by not only changing the ratios of some critical metabolites in placenta to maternal serum but also significantly altering the expressions of nutrition transporters in placenta. These findings reaffirm the importance of protecting women from PM2.5 exposure, and also advance our understanding of the toxic actions of ambient PM2.5.

Formononetin improves the inflammatory response and bone destruction in knee joint lesions by regulating the NF-kB and MAPK signaling pathways.

Formononetin (FMN) is a phytoestrogen that belongs to the isoflavone family. It has antioxidant and anti-inflammatory effects, as well as, many other biological activities. Existing evidence has aroused interest in its ability to protect against osteoarthritis (OA) and promote bone remodeling. To date, research on this topic has not been thorough and many issues remain controversial. Therefore, the purpose of our study was to explore the protective effect of FMN against knee injury and clarify the possible molecular mechanisms. We found that FMN inhibited osteoclast formation induced by receptor activator of NF-κB ligand (RANKL). Inhibition of the phosphorylation and nuclear translocation of p65 in the NF-κB signaling pathway plays a role in this effect. Similarly, during the inflammatory response of primary knee cartilage cells activated by IL-1ß, FMN inhibited the NF-κB signaling pathway and the phosphorylation of the ERK and JNK proteins in the MAPK signaling pathway to suppress the inflammatory response. In addition, in vivo experiments showed that both low- and high-dose FMN had a clear protective effect against knee injury in the DMM (destabilization of the medial meniscus) model, and the therapeutic effect of high-dose FMN was stronger. In conclusion, these studies provide evidence of the protective effect of FMN against knee injury.

Dynamic Change of Endocannabinoid Signaling in the Medial Prefrontal Cortex Controls the Development of Depression After Neuropathic Pain.

Many patients with chronic pain conditions suffer from depression. The mechanisms underlying pain-induced depression are still unclear. There are critical links of medial prefrontal cortex (mPFC) synaptic function to depression, with signaling through the endocannabinoid (eCB) system as an important contributor. We hypothesized that afferent noxious inputs after injury compromise activity-dependent eCB signaling in the mPFC, resulting in depression. Depression-like behaviors were tested in male and female rats with traumatic neuropathy [spared nerve injury (SNI)], and neuronal activity in the mPFC was monitored using the immediate early gene c-fos and in vivo electrophysiological recordings. mPFC eCB Concentrations were determined using mass spectrometry, and behavioral and electrophysiological experiments were used to evaluate the role of alterations in eCB signaling in depression after pain. SNI-induced pain induced the development of depression phenotypes in both male and female rats. Pyramidal neurons in mPFC showed increased excitability followed by reduced excitability in the onset and prolonged phases of pain, respectively. Concentrations of the eCBs, 2-arachidonoylglycerol (2-AG) in the mPFC, were elevated initially after SNI, and our results indicate that this resulted in a loss of CB1R function on GABAergic interneurons in the mPFC. These data suggest that excessive release of 2-AG as a result of noxious stimuli triggers use-dependent loss of function of eCB signaling leading to excessive GABA release in the mPFC, with the final result being behavioral depression.SIGNIFICANCE STATEMENT Pain has both somatosensory and affective components, so the complexity of mechanisms underlying chronic pain is best represented by a biopsychosocial model that includes widespread CNS dysfunction. Many patients with chronic pain conditions develop depression. The mechanism by which pain causes depression is unclear. Although manipulation of the eCB signaling system as an avenue for providing analgesia per se has not shown much promise in previous studies. An important limitation of past research has been inadequate consideration of the dynamic nature of the connection between pain and depression as they develop. Here, we show that activity-dependent synthesis of eCBs during the initial onset of persistent pain is the critical link leading to depression when pain is persistent.

Prognostic Value of Long Noncoding RNA SNHG11 in Patients with Prostate Cancer.

The present study was aimed to explore the prognostic value of long noncoding RNA SNHG11 in prostate cancer, study its expression, and assess its effect on tumor progression. One hundred and twenty prostate cancer patients and 45 cases of benign prostate hyperplasia (BPH) patients were collected. RT-qPCR was used to test the expression of SNHG11 in prostate cancer and BPH tissues, as well as in cell lines. Kaplan-Meier survival analysis and Cox regression assays were introduced to evaluate the prognostic meaning of SNHG11 in prostate cancer. The CCK-8 assays were performed to explore the effect of SNHG11 on prostate cancer cell proliferation, and a Transwell assay was conducted to access the influence of SNHG11 on prostate cancer cell migration and invasion. SNHG11 expression level was upregulated both in prostate cancer tissues and cell lines. Overexpression of SNHG11 was significantly associated with Gleason score, clinical T stage, surgical margin status, and lymph node metastasis. Patients with high SNHG11 expression levels led to a shorter overall survival time and biochemical recurrence-free survival when compared with those of low expression levels. Multivariate Cox regression results suggested that SNHG11 has the potential to act as a prognostic marker for prostate cancer patients. Knockdown of SNHG11 suppressed 22RV1 cell proliferation, migration, and invasion. In conclusion, SNHG11 is upregulated in prostate cancer patients and predicts an unfavorable prognosis for prostate cancer patients. Its knockdown can weaken prostate cancer cell metastasis and growth in vitro.

An Oxidant- and Catalyst-Free Electrooxidative Cross-Coupling Approach to Synthesize meso-Substituted Porphyrin Derivatives.

The synthesis of porphyrin and chlorin derivatives has attracted significant attention due to their numerous applications. Herein, we report an environment friendly oxidant- and catalyst-free electrooxidative cross-coupling approach for multiple coupling reactions to synthesize meso C-N, C-O, and C-S substituted porphyrin and chlorin derivatives. For C-N cross-coupling reactions, diaminated porphyrins were obtained as the main products, while using 4-bromo-2,6-dimethyl aniline resulted in monoaminated product. Similarly, electrochemical catalysis of porphyrins with phenol and thiophene produced meso-disubstituted porphyrins in moderate yields under a smaller current. Chlorins were also applicable, and 20-substituted products were efficiently produced regioselectively. To the best of our knowledge, this work represents the first example of electrooxidative C-X cross-coupling of porphyrins and chlorins.