Dapagliflozin attenuates fat accumulation and insulin resistance in obese mice with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), a common endocrine disorder affecting premenopausal women, is associated with various metabolic consequences such as insulin resistance, hyperlipidemia, obesity, and type 2 diabetes mellitus (T2DM). Insulin sensitizers, such as metformin and pioglitazone, though effective, often leads to significant gastrointestinal adverse effects or weight gain, limiting its suitability for women with PCOS. There is an urgent need for safe, effective and affordable agents. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, enhances glucose elimination through urine, thereby reducing body weight and improving glucose and lipid metabolism. Nevertheless, it is not currently recommended as a therapeutic option for PCOS in clinical guidelines. In this study, we systematically examined the impact of dapagliflozin on an obese PCOS mouse model, focusing on alterations in glucose metabolism, adipose tissue morphology, and plasma lipid profile. Obese PCOS was induced in mice by continuous dihydrotestosterone (DHEA) injections over 21 days and high-fat diet (HFD) feeding. PCOS mice were then orally gavaged with dapagliflozin (1 mg/kg), metformin (50 mg/kg), or vehicle daily for 8 weeks, respectively. Our results demonstrated that dapagliflozin significantly prevented body weight gain and reduced fat mass in obese PCOS mice. Meanwhile, dapagliflozin treatment improved glucose tolerance and increased insulin sensitivity compared to the control PCOS mice. Furthermore, dapagliflozin significantly improved adipocyte accumulation and morphology in white adipose tissue, resulting in a normalized plasma lipid profile in PCOS mice. In conclusion, our results suggest that dapagliflozin is an effective agent in managing glucose and lipid metabolism disorders in obese PCOS mice.

Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma.

Nur77 modulators have emerged as a promising therapeutic approach for hepatocellular carcinoma. In this study, a structure-based rational drug design approach was used to design and synthesise a series of 4-((8-hydroxy-2-methylquinolin-4-yl)amino)benzoylhydrazone derivatives based on the binding characteristics of our previously reported 10g and the native ligand 3NB at the binding Site C of Nur77. Cell-based cytotoxicity assays revealed that compound TMHA37 demonstrated the highest cytotoxicity against all tested cancer cells. The induced fit docking and binding pose metadynamics simulation suggested that TMHA37 was the most promising Nur77 binder at Site C. Molecular dynamics simulation validated the stable binding of TMHA37 to Nur77's Site C but not to Sites A or B. Specifically, TMHA37 bound strongly to Nur77-LBD (KD = 445.3 nM) and could activate Nur77's transcriptional activity. Furthermore, TMHA37 exhibited antitumor effects by blocking the cell cycle at G2/M phase and inducing cell apoptosis in a Nur77-dependent manner.

Identification of potential ATP-competitive cyclin-dependent kinase 1 inhibitors: De novo drug generation, molecular docking, and molecular dynamics simulation.

Cyclin-dependent kinases 1 (CDK1) has been identified as a potential target for the search for new antitumor drugs. However, no clinically effective CDK1 inhibitors are now available for cancer treatment. Therefore, this study aimed to offer potential CDK1 inhibitors using de novo drug generation, molecular docking, and molecular dynamics (MD) simulation studies. We first utilized the BREED algorithm (a de novo drug generation approach) to produce a novel library of small molecules targeting CDK1. To initially obtain novel potential CDK1 inhibitors with favorable physicochemical properties and excellent druggability, we performed a virtual rule-based rational drug screening on our generated library and found ten initial hits. Then, the molecular interactions and dynamic stability of these ten initial hits and CDK1 complexes during their all-atom MD simulations (total 18 µs) and binding pose metadynamics simulations were investigated, resulting in five final hits. Furthermore, another MD simulation (total 2.1 µs) with different force fields demonstrated the binding ability of the five hits to CDK1. It was found that these five hits, CBMA001 (ΔG = -29.88 kcal/mol), CBMA002 (ΔG = -34.89 kcal/mol), CBMA004 (ΔG = -32.47 kcal/mol), CBMA007 (ΔG = -31.16 kcal/mol), and CBMA008 (ΔG = -34.78 kcal/mol) possessed much greater binding affinity to CDK1 than positive compound Flavopiridol (FLP, ΔG = -25.38 kcal/mol). Finally, CBMA002 and CBMA004 were identified as excellent selective CDK1 inhibitors in silico. Together, this study provides a workflow for rational drug design and two promising selective CDK1 inhibitors that deserve further investigation.

Sunitinib versus imatinib dose escalation after failure of imatinib standard dose in patients with advanced Gastrointestinal stromal tumors - a real-world multi-center study.

BACKGROUND: Whether to escalate imatinib dosage or directly switch to sunitinib in gastrointestinal stromal tumors (GISTs) failing on standard dose 400 mg/d of imatinib is still controversial. METHODS: We evaluated progression-free survival (PFS), overall survival (OS), and time to sunitinib failure (TTSF) of patients selecting imatinib dose escalation or directly switching to sunitinib after the failure of imatinib 400 mg/d therapy from 3 tertery referring centers between January 2008 to December 2016. RESULTS: A total of 240 patients receiving sunitinib (37.5 mg continuous daily dose or 50 mg 4 weeks on with 2 weeks off) for at least 8 weeks were examined. After failure on imatinib 400 mg/d, 100 (49.3%) patients had dose escalation to 600 mg or 800 mg per day (IM group, imatinib group), and 103 (50.7%) directly switched to sunitinib (SU group, sunitinib group). The PFS in the SU and IM groups was 12 months and 5.0 months (P < 0.001), respectively. TTSF or OS in both groups was not statistically significantly different. CONCLUSIONS: After the progression of imatinib standard-dose treatment in recurrent/metastatic GISTs, the PFS of patients directly switching to sunitinib was significantly longer compared with the PFS of patients with imatinib dose escalation. However, when the patients continued with sunitinib therapy after the failure of IM dose escalation, TTSF and OS in the IM group were similar to those in the SU group. Further exploration of the characteristics of the population benefiting from imatinib dose escalation are warranted.

Combination of Type I and II tyrosine kinase inhibitors-avapritinib and sunitinib-in refractory gastrointestinal stromal tumor after failure to multi-line therapy: a case report.

Background: Tyrosine kinase inhibitors (TKIs) are currently the main treatment choice for gastrointestinal stromal tumors (GISTs). However, the long-term use of TKIs can lead to drug resistance. There is no study or clinical report of combination therapies of TKIs that have been approved for marketing. Combination pharmacotherapy is a new approach for patients who do not respond to monotherapy. This case provides a reference value for selective combination of TKIs in treating advanced GIST. Case Description: In this article, we report the case of a 55-year-old female who was diagnosed with duodenal GIST in April 2018 and underwent R0 resection. KIT exon 9 mutation was detected. The patient had disease recurrence with multiple abdominal metastases during imatinib adjuvant therapy after 27 months, and failure to 2nd-line sunitinib treatment after 6 months. She underwent a cytoreductive surgery (R1), and the postoperative mutation analysis suggested KIT exon 9 mutation, with newly found secondary KIT_exon16_p. L783V mutation and other mutations on TP53, POT1, and SETD2, etc. The patient experienced short-term tumor control of standard 3rd-line therapy of regorafenib and the rapid progression of the 4th-line of ripretinib afterwards. Different TKI combination therapies (i.e., ripretinib plus sunitinib, ripretinib plus avapritinib and avapritinib plus sunitinib) were administered to the patient sequentially. Ripretinib plus sunitinib led to stable disease but was discontinued due to intolerable adverse effects. Finally, the patient received a combination regimen of avapritinib plus sunitinib. The patient's tumor showed continuous shrinking in 2 consecutive computed tomography scan evaluations within 4 months with acceptable side effects. Conclusions: Combined type I and type II TKIs of avapritinib combined with sunitinib therapy achieved tumor regression for a heavily multi-line treated patient. Our case provides a reference for a savage treatment choice in refractory GISTs after failure to all standard treatment.

Efficacy of immune checkpoint inhibitors in EGFR-Mutant NSCLC patients with EGFR-TKI resistance: A systematic review and meta-analysis.

Background: Epidermal growth factor receptor (EGFR) mutations are common in patients with non-small-cell lung cancer (NSCLC), particularly in Asian populations. Tyrosine kinase inhibitors (TKIs) are a first-line treatment in patients with mutant EGFR, but their use is often accompanied by drug resistance, which leads to disease progression. Chemotherapy and immunotherapy are the main treatment options after progression. The efficacy of immune checkpoint inhibitors (ICIs) and their combination therapy in patients with EGFR-TKI resistant is not clear. It is thus necessary to evaluate the efficacy of ICIs and ICI-based combination therapies in patients with EGFR-TKI-resistant NSCLC. Methods: We searched for randomized controlled trials (RCTs) comparing ICI therapy alone or in combination versus other therapies using PubMed, the Cochrane Library, Web of Science, EMBASE, MEDLINE, ClinicalTrials.gov, and several international conference databases, from database inception to 10 March 2022. The hazard ratio (HR) and 95% confidence interval (95% CI) for median overall survival (OS) and median progression-free survival (PFS) were evaluated. Odds ratio (OR), risk ratio (RR), and 95% CI were used as effect indicators for objective response rate (ORR) and safety data. Results: Seven eligible RCTs were included in the present meta-analysis. The results showed that neither ICIs nor combination therapy prolonged median OS in EGFR-TKI resistant NSCLC patients (HR = 1.04, 95% CI: 0.84-1.29, p = 0.73). However, compared with the control group, the patients treated with ICI-based combination therapy had better PFS (HR = 0.62, 95% CI: 0.45-0.86, p = 0.004) and ORR (OR = 1.84, 95% CI: 1.28-2.66, p = 0.001). Conclusion: ICI monotherapy did not improve the OS or PFS of NSCLC patients previously treated with EGFR-TKIs, whereas patients treated with ICI-based combination therapy had better PFS compared with those receiving conventional chemotherapy, indicating that this therapy could be offered to patients with EGFR-mutant NSCLC after progression following TKI treatment. There was no significant difference in all-grade treatment-related adverse events (TRAEs) between the combination therapy group and the control group. However, a higher incidence of discontinuation due to TRAEs was observed; this requires attention in future studies. The results of this meta-analysis provide a reference for clinical practice and future trial design. PROSPERO registration number: CRD42021282207.

Genotyping guided ripretinib directly after the progression of first-line imatinib therapy in advanced gastrointestinal stromal tumor: a case report.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Surgery and tyrosine kinase inhibitor (TKI) therapy are the main choices of treatment. However, the long-term use of TKIs is prone to drug resistance. Herein, we report the case of a 47-year-old female with primary gastric GIST with liver metastases since June 2015. The patient achieved disease control under imatinib therapy and underwent primary lesion resection. She took postoperative imatinib maintenance therapy, but discontinued imatinib for 10 months about 2 years after surgery. The patient suffered from disease progression in May 2019, with recurrence of liver metastases and new abdominal metastases. From then on, imatinib was resumed and partial response (PR) persisted for another 2 years. The patient subsequently experienced tumor progression due to secondary KIT exon 17 mutation confirmed by tissue biopsy and circulating tumor DNA (ctDNA) detection. After multidisciplinary team discussion, the patient received ripretinib as a second-line therapy, and ctDNA monitoring demonstrated that the KIT mutations turned negative. After disease control from ripretinib for 2+ months, she underwent cytoreductive surgery (R0/1) and received ripretinib maintenance treatment postoperatively. We believe that this case provides a reference value for individualized ripretinib precise therapy according to mutational analysis after the progression of first-line GIST treatment, and ctDNA can predict effectiveness to guide treatment.

Pentosan polysulfate ameliorates fibrosis and inflammation markers in SV40 MES13 cells by suppressing activation of PI3K/AKT pathway via miR-446a-3p.

BACKGROUND: Renal fibrosis is a common outcome of various renal damage, including diabetic nephropathy (DN), the leading cause of end-stage renal disease. Currently, there are no effective therapies for renal fibrosis. The present study aimed to determine whether pentosan polysulphate sodium (PPS), a FDA approved medication for interstitial cystitis, protects diabetic renal fibrosis. METHODS: Cell viability and apoptosis were evaluated in mouse mesangial cells (SV40-MES13) after incubating with the advanced glycation end products (AGEs), which play important roles in the pathogenesis of DN. Western blot and ELISA were performed to determine the expression of transforming growth factor-beta1 (TGF-ß1) and fibronectin (FN), two biomarkers of renal fibrosis, as well as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), two biomarkers of inflammation. The miRNA-mRNA regulatory network involved in the phosphatidylinositol 3-kinase (PI3K)/Ser and Thr Kinase (AKT) signalling was investigated by miRNA deep sequencing and validated by RT-PCR and miRNA transfection. RESULTS: AGEs significantly inhibited cell proliferation and promoted cell apoptosis, which was associated with the overexpression of TGF-ß1, FN, IL-6, and TNFα. PPS almost completely reversed AGEs-induced biomarkers of fibrosis and inflammation, and significantly altered the miRNA expression profile in AGEs-treated cells. Notably, the PI3K/AKT signalling was one of the most significantly enriched pathways targeted by PPS-related differentially expressed miRNAs. PPS significantly up-regulated miR-466a-3p, which was shown to target PIK3CA, and mediated the inhibitory effect of PPS on AGEs-induced activation of PI3K/AKT pathway. CONCLUSIONS: The treatment of PPS protected against AGEs-induced toxicity in SV40 MES13 cells via miR-466a-3p-mediated inhibition of PI3K/AKT pathway.

Hypertension Induced by Combination Therapy of Cancer: A Systematic Review and Meta-Analysis of Global Clinical Trials.

Background: Nowadays, due to the limitation of single therapy, combination therapy for cancer treatments has become important strategy. With the advancement of research on cardiotoxicities induced by anti-cancer treatment, among which cancer treatment-induced hypertension is the most frequent case. However, due to the small sample size and the absence of comparison (single-arm study alone), these studies have limitations to produce a feasible conclusion. Therefore, it is necessary to carry out a meta-analysis focusing on hypertension caused by cancer combination therapy. Methods: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and CNKI, from database inception to November 31, 2020, with randomized controlled trials (RCTs) associated with hypertension induced by cancer combination drugs. The main endpoint of which was to assess the difference in the incidence of hypertension in cancer patients with monotherapy or combination therapy. We calculated the corresponding 95% confidence interval (95% CIs) according to the random effect model and evaluated the heterogeneity between different groups. Results: According to the preset specific inclusion and exclusion criteria, a total of 23 eligible RCTs have been included in the present meta-analysis, including 6,241 patients (Among them, 2872 patients were the control group and 3369 patients were the experimental group). The results showed that cancer patients with combination therapy led to a higher risk of hypertension (All-grade: RR 2.85, 95% CI 2.52∼3.22; 1∼2 grade: RR 2.43, 95% CI 2.10∼2.81; 3∼4 grade: RR 4.37, 95% CI 3.33∼5.72). Furthermore, compared with the control group who received or did not receive a placebo, there was a higher risk of grade 3-4 hypertension caused by cancer combination treatment. Conclusion: The present meta-analysis carries out a comprehensive analysis on the risk of patients suffering from hypertension in the process of multiple cancer combination therapies. Findings in our study support that the risk of hypertension may increase significantly in cancer patients with multiple cancer combination therapies. The outcomes of this meta-analysis may provide a reference value for clinical practice and may supply insights in reducing the incidence of hypertension caused by cancer combined treatment.

FOXCUT Promotes the Proliferation and Invasion by Activating FOXC1/PI3K/AKT Pathway in Colorectal Cancer.

INTRODUCTION: Colorectal cancer (CRC) is the third most commonly diagnosed world cancer. Long noncoding RNAs (lncRNAs) serve important regulatory roles in tumorigenesis. However, the contributions of lncRNAs to human CRC remain largely unknown. MATERIAL AND METHODS: FOXC1 and FOXCUT lncRNA expression levels were detected in a panel of paired specimens obtained from 48 patients' tissues and cell lines with CRC using RT-qPCR. RNA interference was used to investigate potential correlations between FOXC1 and FOXCUT expression in HT29. Cell proliferation was assessed by MTT assay and EdU incorporation assay. The migration and invasion of CRC cells were detected by transwell assay. Western blot was applied to assess the protein expression and PI3K/AKT signaling pathway. RESULTS: In this study, a novel long noncoding RNA (FOXCUT) was frequently overexpressed in CRC tissues and cell lines. In addition, the expressions of FOXCUT and FOXC1 were positively correlated. When the expression of FOXCUT was downregulated by small interfering RNA (siRNA), the expression of FOXC1 was also decreased. Moreover, knockdown of FOXCUT significantly inhibited proliferation and invasion of CRC cell lines and resulted in downregulated expression of the matrix metalloproteinase 1 (MMP-1). Mechanistically, FOXCUT promotes the expression of FOXC1 to activate PI3K/AKT signaling pathway for its regulation of cell growth and proliferation. CONCLUSION: In summary, our findings indicate that FOXCUT plays an important oncogenic role and may serve as a novel biomarker and therapeutic target in CRC progression.

miR-877-5p antagonizes the promoting effect of SP on the gastric cancer progression.

Gastric cancer is one of the four major tumors in the world and the second leading cause of cancer-related death. It was reported that Substance P (SP), as an oncogenic factor, could regulate the expression of miRNAs in gastric cancer progression. Here, we focused on the role of miR-877-5p in gastric cancer development and the miR-877-5p involvement in the SP-mediated gastric cancer development. The mRNA expression level and cell proliferation were assessed by quantitative real-time PCR and cell counting kit-8 assay, respectively. Flow cytometry was conducted to detect apoptosis, followed by assessing the expression of related apoptosis factors. Dual-luciferase reporter assay was performed to validate the interaction between miR-877-5p and Forkhead cassette M1 (FOXM1). Our results showed that SP treatment significantly increased cell proliferation in gastric cancer. Moreover, the miR-877-5p expression was dose-dependently decreased by SP, whereas FOXM1 expression was markedly increased by SP in gastric cancer cells. miR-877-5p negatively regulated gastric cancer development via inhibiting cell proliferation and promoting apoptosis accompanied by increased cleaved caspase-3, cleaved caspase-9, and Bax protein levels and decreased Bcl-2 level. We confirmed that miR-877-5p could target FOXM1 and negatively regulate its expression. Furthermore, we demonstrated that SP could promote cell proliferation and inhibit apoptosis, while miR-877-5p overexpression reversed the effect of SP on cell proliferation and apoptosis. These results suggest that miR-877-5p overexpression can antagonize the promoting effect of SP on the development of gastric cancer, indicating that miR-877-5p may serve as a promising therapeutic target for gastric cancer.

A Novel Perineal Nerve Block Approach for Transperineal Prostate Biopsy: An Anatomical Analysis-based Randomized Single-blind Controlled Trial.

OBJECTIVE: To develop and validate a novel perineal nerve block approach for transperineal prostate biopsy. PATIENTS AND METHODS: Five adult male cadavers were dissected to delineate the superficial and deep branches of the perineal nerve. Afterwards, 90 out of 115 patients were selected and randomly assigned to receive periprostatic, periapical triangle, or branches of perineal nerve (BPN) block. The primary outcome was the maximal pain intensity associated with transperineal prostate biopsy, which was assessed by the 10-point visual analog scale. The secondary outcomes included the number of biopsy with visual analog scale of ≥4 in each biopsy procedure, and the incidences of complications. RESULTS: On the horizontal line of the upper anal border, the locations of the superficial branch of perineal nerve on the left and right sides were 1.87 ± 0.05 cm and 1.86 ± 0.06 cm, respectively; and the deep branch were 2.15 ± 0.07 cm and 2.16 ± 0.06 cm, respectively, from the midline, and lied between the deep layer of superficial fascia and prostate capsule. The number of cases finally enrolled in data analysis in periprostatic block, periapical triangle block, and BPN block groups were 26, 27, and 30, respectively. The maximal pain intensities were 3.4 (3.1-3.7), 3.3 (3.0-3.6), and 1.8 (1.5-2.2) in the 3 groups, respectively, and the numbers of biopsy with the pain intensity of ≥4 were 4.0 (3.2-4.9), 4.2 (3.3-5.2), and 0.7 (0.1-1.2), respectively. There were 4, 3 and 4 cases developing hematuria, and 1, 1 and 2 burdened with urine retention after biopsy in the 3 groups, respectively. CONCLUSION: Collectively, BPN block is a safe, effective and repeatable local anesthesia approach for transperineal prostate biopsy.

The deubiquitylase OTUD3 stabilizes GRP78 and promotes lung tumorigenesis.

The deubiquitylase OTUD3 plays a suppressive role in breast tumorigenesis through stabilizing PTEN protein, but its role in lung cancer remains unclear. Here, we demonstrate that in vivo deletion of OTUD3 indeed promotes breast cancer development in mice, but by contrast, it slows down KrasG12D-driven lung adenocarcinoma (ADC) initiation and progression and markedly increases survival in mice. Moreover, OTUD3 is highly expressed in human lung cancer tissues and its higher expression correlates with poorer survival of patients. Further mechanistic studies reveal that OTUD3 interacts with, deubiquitylates and stabilizes the glucose-regulated protein GRP78. Knockdown of OTUD3 results in a decrease in the level of GRP78 protein, suppression of cell growth and migration, and tumorigenesis in lung cancer. Collectively, our results reveal a previously unappreciated pro-oncogenic role of OTUD3 in lung cancer and indicate that deubiquitylases could elicit tumor-suppressing or tumor-promoting activities in a cell- and tissue-dependent context.

What causes growth of global greenhouse gas emissions? Evidence from 40 countries.

With the growing attention on global warming, understanding the main drivers of greenhouse gas (GHG) emissions is important. This paper investigated the contribution of intrinsic reasons for consumption-based GHG emissions growth using structural decomposition analysis based on world input-output database from 1995 to 2009. The drivers are decomposed into five sub-effects at both country-level and industry-level. The results are as follows: (1) The rapid global economic growth is the dominating driving force. However, a decreasing emission intensity caused by the improvement of energy efficiency and technology innovation can contribute significantly to emission reduction; (2) Key factors contributing to GHG emissions vary in different country groups. The investment effects in developing countries are overwhelming those in developed countries. Instead, the net export effects in developed countries are greater than them in developing countries, which means that developing countries are becoming pollution haven; (3) China and India are still the key contributors of CO2 growth and CH4 growth. In developing countries, the total effects of N2O emissions changes are positive, which is mainly because agriculture plays an important role in these countries; (4) Cluster analysis depicts the relationship between growth of GHG emissions and gross domestic outputs in different countries.

Design, synthesis and biological evaluation of LX2343 derivatives as neuroprotective agents for the treatment of Alzheimer's disease.

A series of LX2343 derivatives were designed, synthesized and evaluated as neuroprotective agents for Alzheimer's disease (AD) in vitro. Most of the compounds displayed potent neuroprotective activities. Especially for compound A6, exhibited a remarkable EC50 value of 0.22 µM. Further investigation demonstrated that compound A6 can significantly reduce Aß production and increase Aß clearance, and alleviate Tau hyperphosphorylation. Most importantly, compound A6 could ameliorate learning and memory impairments in APP/PS1 transgenic mice. The present study evidently showed that compound A6 is a potent neuroprotective agent and might serve as a promising lead candidate for the treatment of Alzheimer's disease.

Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy.

Alzheimer's disease (AD) is a progressively neurodegenerative disease with typical hallmarks of amyloid ß (Aß) plaque accumulation, neurofibrillary tangle (NFT) formation and neuronal death extension. Aggressive Aß accumulation promotes senile plaque formation and perturbs endoplasmic reticulum (ER) function to trigger the unfolded protein response (UPR) leading to neuronal apoptosis. The stress-dependent activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) increases the phosphorylation of eukaryotic translation initiation factor-2α (eIF2α) to promote the preferential synthesis of ß-site APP cleavage enzyme 1 (BACE1) and Aß generation in turn. Additionally, dysfunction in autophagy has been reported to contribute to several neurodegenerative diseases including AD, and impairment in autophagy-mediated pathway may constitutively stimulate the generation of Aß in AD. Here we discovered that protopanaxadiol derivative 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopanaxadiol-3ß-yl)-urea (DDPU) effectively improved the activity of daily living (ADL) and cognitive deficits in APP/PS1 transgenic mice. The crosstalk between Aß and ER stress has been intensively investigated by using DDPU as a probe. DDPU reduced Aß production mainly by inhibiting the PERK/eIF2α signaling-mediated BACE1 translation and stimulated Aß clearance by promoting autophagy as a PI3K inhibitor through PI3K/AKT/mTOR signaling pathway, while exhibited neuroprotective effect involving attenuation of ER stress. DDPU might be the first reported ginsenoside derivative with dual effects on both autophagy promotion and ER stress amelioration. Our results have highlighted the potential of DDPU in the treatment of AD.

A giant and extensive solitary Peutz-Jeghers-type polyp in the antrum of stomach: Case report.

RATIONALE: A solitary Peutz-Jeghers-type polyp is a hamartomatous polyp which without either mucocutaneous pigmentation or a family history of Peutz-Jeghers syndrome (PJS). It can occur in all of the gastrointestinal tract, but it is extremely rare in the stomach. PATIENT CONCERNS: A 53-year-old man was admitted to the local hospital with left upper abdominal pain lasting 2 weeks. A gastroscopy showed a giant and extensive bulging lesion on the greater curvature and posterior and anterior walls of the gastric antrum, involving three-quarters of the gastric wall. Endoscopic ultrasonography showed a muscularis mucosa lesion. DIAGNOSES: A solitary Peutz-Jeghers-type polyp in the antrum of stomach. INTERVENTIONS: The patient underwent an endoscopic submucosal dissection (ESD). OUTCOMES: The patient recovered quickly, without any complications. LESSONS: This is the second largest gastric solitary Peutz-Jeghers-polyp reported until now, and the largest gastric solitary Peutz-Jeghers type-polyp treated by endoscope.

DMT efficiently inhibits hepatic gluconeogenesis by regulating the Gαq signaling pathway.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with complicated pathogenesis and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. G protein-coupled receptors (GPCRs) are classified as distinct families by heterotrimeric G proteins, primarily including Gαs, Gαi and Gαq. Gαs-coupled GPCRs function potently in the regulation of hepatic gluconeogenesis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and Gαi-coupled GPCRs exhibit inhibitory effect on adenylyl cyclase and reduce intracellular cAMP level. However, little is known about the regulation of Gαq-coupled GPCRs in hepatic gluconeogenesis. Here, small-molecule 2-(2,4-dimethoxy-3-methylphenyl)-7-(thiophen-2-yl)-9-(trifluoromethyl)-2,3-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(1H)-one (DMT) was determined to suppress hepatic glucose production and reduce mRNA levels of gluconeogenic genes. Treatment of DMT in db/db mice decreased fasting blood glucose and hemoglobin A1C (HbA1c) levels, while improved glucose tolerance and pyruvate tolerance. Mechanism study demonstrated that DMT-inhibited gluconeogenesis by regulating the Gαq/phospholipase C (PLC)/inositol-1,4,5-triphosphate receptor (IP3R)-mediated calcium (Ca2+)/calmodulin (CaM)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/forkhead box protein O1 (FOXO1) signaling pathway. To our knowledge, DMT might be the first reported small molecule able to suppress hepatic gluconeogenesis by regulating Gαq signaling, and our current work has also highlighted the potential of DMT in the treatment of T2DM.

The anatomy for retroperitoneal laparoscopic splanchnicectomy / La anatomía de la esplacnicectomía laparoscópica retroperitoneal

Greater splanchnic nerves (GSNs) and lesser splanchnic nerves (LSNs) are the dominant nerves in the pain of advanced cancer patients, which provides the base of retroperitoneal laparoscopic splanchnicectomy. We dissected 25 cadavers to provide anatomic basis for the surgery. Most GSNs entered the abdominal cavity close to the medial crus of the diaphragm while most LSNs the middle one. The number of the branch varies from 1 (which was 80 %) ­ 3. The abdominal segment length of LSNs and GSNs was 26 mm and 20 mm respectively. The mean diameter of the nerves was about 2 mm. The laparoscope was put through abdominal wall beneath the 12th rib at the posterior axillary line, best angles and distances for the surgery were 50 ° and 80-110 mm respectively. The anatomic parameters of splanchnic nerves in the abdominal cavity as well as the angle and distance for the retroperitoneal laparoscopic splanchnicectomy and the anatomic landmarks were presented by the study. Besides the advantages of small incision, less pain and quick recovery, the anatomic parameters provided a practicable approach for the retroperitoneal laparoscopic splanchnicectomy.

Los nervios esplácnicos mayores (NEM) y los nervios esplácnicos menores (NEm) son los nervios dominantes en el dolor de los pacientes con cáncer avanzado, que proporciona la base de la esplacnicectomía laparoscópica retroperitoneal. Se disecaron 25 cadáveres para proporcionar base anatómica para la cirugía. La mayoría de los NEM entraron en la cavidad abdominal cerca del pilar medial del diafragma, mientras que la mayoría de los Nem lo hicieron cerca del pilar medio. El número de ramas varía de 1 (que era del 80 %) - 3. La longitud del segmento abdominal de NEm y NEM fue de 26 mm y 20 mm, respectivamente. El diámetro medio de los nervios era de aproximadamente 2 mm. El laparoscopio se colocó a través de la pared abdominal debajo de la 12 costilla en la línea axilar posterior, los mejores ángulos y distancias para la cirugía fueron de 50° y 80-110 mm, respectivamente. Los parámetros anatómicos de los nervios esplácnicos en la cavidad abdominal, así como el ángulo y la distancia para la esplacnicectomía laparoscópica retroperitoneal y los puntos de referencia anatómicos fueron presentados por el estudio. Además de las ventajas de la incisión pequeña, menos dolor y recuperación rápida, los parámetros anatómicos proporcionaron un enfoque práctico para la esplacnicectomía laparoscópica retroperitoneal.

Inhibition on Apoptosis Induced by Elevated Hydrostatic Pressure in Retinal Ganglion Cell-5 via Laminin Upregulating ß1-integrin/Focal Adhesion Kinase/Protein Kinase B Signaling Pathway.

BACKGROUND: Glaucoma is a progressive optic neuropathy characterized by degeneration of neurons due to loss of retinal ganglion cells (RGCs). High intraocular pressure (HIOP), the main risk factor, causes the optic nerve damage. However, the precise mechanism of HIOP-induced RGC death is not yet completely understood. This study was conducted to determine apoptosis of RGC-5 cells induced by elevated hydrostatic pressures, explore whether laminin is associated with apoptosis under pressure, whether laminin can protect RGCs from apoptosis and affirm the mechanism that regulates the process of RGCs survival. METHODS: RGC-5 cells were exposed to 0, 20, 40, and 60 mmHg in a pressurized incubator for 6, 12, and 24 h, respectively. The effect of elevated hydrostatic pressure on RGC-5 cells was measured by Annexin V-fluorescein isothiocyanate/propidium iodide staining, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and Western blotting of cleaved caspase-3 protein. Location and expression of laminin were detected by immunofluorescence. The expression of ß1-integrin, phosphorylation of focal adhesion kinase (FAK) and protein kinase B (PKB, or AKT) were investigated with real-time polymerase chain reaction and Western blotting analysis. RESULTS: Elevated hydrostatic pressure induced apoptosis in cultured RGC-5 cells. Pressure with 40 mmHg for 24 h induced a maximum apoptosis. Laminin was declined in RGC-5 cells after exposing to 40 mmHg for 24 h. After pretreating with laminin, RGC-5 cells survived from elevated pressure. Furthermore, ß1-integrin and phosphorylation of FAK and AKT were increased compared to 40 mmHg group. CONCLUSIONS: The data show apoptosis tendency of RGC-5 cells with elevated hydrostatic pressure. Laminin can protect RGC-5 cells against high pressure via ß1-integrin/FAK/AKT signaling pathway. These results suggest that the decreased laminin of RGC-5 cells might be responsible for apoptosis induced by elevated hydrostatic pressure, and laminin or activating ß1-integrin/FAK/AKT pathway might be potential treatments to prevent RGC loss in glaucomatous optic neuropathy.