Dermal extracellular matrix molecules in skin development, homeostasis, wound regeneration and diseases.

The extracellular matrix (ECM) is a dynamic structure that surrounds and anchors cellular components in tissues. In addition to functioning as a structural scaffold for cellular components, ECMs also regulate diverse biological functions, including cell adhesion, proliferation, differentiation, migration, cell-cell interactions, and intracellular signaling events. Dermal fibroblasts (dFBs), the major cellular source of skin ECM, develop from a common embryonic precursor to the highly heterogeneous subpopulations during development and adulthood. Upon injury, dFBs migrate into wound granulation tissue and transdifferentiate into myofibroblasts, which play a critical role in wound contraction and dermal ECM regeneration and deposition. In this review, we describe the plasticity of dFBs during development and wound healing and how various dFB-derived ECM molecules, including collagen, proteoglycans, glycosaminoglycans, fibrillins and matricellular proteins are expressed and regulated, and in turn how these ECM molecules play a role in regulating the function of dFBs and immune cells. Finally, we describe how dysregulation of ECM matrix is associated the pathogenesis of wound healing related skin diseases, including chronic wounds and keloid.

Efficacy, safety, and survival findings after long-term follow-up of ZGJAK002: A phase 2 study comparing jaktinib at 100 mg twice daily (BID) and 200 mg once daily (QD) in patients with myelofibrosis.

Jaktinib, a novel JAK and ACVR1 inhibitor, has exhibited promising results in treating patients with myelofibrosis (MF). ZGJAK002 is a Phase 2 trial aimed to assess the efficacy and safety of jaktinib 100 mg BID (N = 66) and 200 mg QD (N = 52) in JAK inhibitor-naive patients with intermediate- or high-risk MF. We herein present the long-term data with a median follow-up of 30.7 months. At data cutoff, 30.3% of patients in 100 mg BID and 28.8% in 200 mg QD were still continuing their treatment. The 100 mg BID group displayed a numerically higher best spleen response compared with the 200 mg QD group (69.7% vs. 46.2%), with 50.4% from the BID and 51.2% from the QD group maintaining spleen responses over 120 weeks. The 36-month survival rates were 78.2% in BID and 73.6% in QD group. The tolerability of jaktinib remained well, and common grade ≥3 adverse drug reactions included anemia (15.2% vs. 21.2%), thrombocytopenia (15.2% vs. 11.5%), and infectious pneumonia (10.6% vs. 1.9%) in BID and QD groups, respectively. By comparing the two groups, the incidence of adverse events (AEs) were similar, except for drug-related serious AEs (24.2% vs. 9.6%) and AEs leading to treatment discontinuation (15.2% vs. 7.7%), which were higher in BID group. The percentages of AEs resulting in death were comparable, with 6.1% in BID and 5.8% in QD group. These analyses further support the long-term durable efficacy and acceptable safety of jaktinib at 100 mg BID and 200 mg QD doses for treating MF.

Effect of Epidermoid Cysts on the Efficacy of Intralesional Corticosteroid Therapy for Hypertrophic Scars and Keloids: A Prospective Pilot Study.

BACKGROUND: Patients with hypertrophic scars (HSs) or keloids occasionally have epidermoid cysts (ECs), and the effect of ECs on the effectiveness of intralesional corticosteroids (ILCs) treatment in these patients has not been reported. OBJECTIVE: This study aims to evaluate the influence of ECs on the outcomes of ILCs treatment in patients with HSs or keloids. MATERIALS AND METHODS: This prospective study included 572 patients with keloids ( n = 461) or HSs ( n = 111). Patients received intralesional triamcinolone acetonide injection (0.05 mL/injection) at a concentration of 40 mg/mL and every 28 days for 4 sessions, with a 1-year follow-up. RESULTS: A higher incidence of ECs was observed in keloid patients (16.92%) compared with HSs patients (7.21%). Keloid patients with ECs were older ( p = .008) and had a longer disease duration ( p = .0148), higher Vancouver scar scale (VSS) scores ( p = .04), and greater thickness ( p = .006). Keloid patients with ECs showed less improvement in VSS scores ( p < .0001) and thickness ( p < .0001) after ILCs treatment, with a higher recurrence rate ( p < .0001). The overall complication rate in keloid patients with ECs after ILCs treatment was 49.51%. CONCLUSION: Epidermoid cysts under keloids were associated with a poor response to ILCs therapy. Therefore, it is recommended to incorporate ultrasonography as a routine examination for keloid patients to aid in better decision making in clinical practice.

Chondroitin Sulfate/Dermatan Sulfate Hybrid Chains from Swim Bladder: Isolation, Structural Analysis, and Anticoagulant Activity.

Glycosaminoglycans (GAGs) with unique structures from marine animals show intriguing pharmacological activities and negligible biological risks, providing more options for us to explore safer agents. The swim bladder is a tonic food and folk medicine, and its GAGs show good anticoagulant activity. In this study, two GAGs, CMG-1.0 and GMG-1.0, were extracted and isolated from the swim bladder of Cynoscion microlepidotus and Gadus morhua. The physicochemical properties, precise structural characteristics, and anticoagulant activities of these GAGs were determined for the first time. The analysis results of the CMG-1.0 and GMG-1.0 showed that they were chondroitin sulfate (CS)/dermatan sulfate (DS) hybrid chains with molecular weights of 109.3 kDa and 123.1 kDa, respectively. They were mainly composed of the repeating disaccharide unit of -{IdoA-α1,3-GalNAc4S-ß1,4-}- (DS-A). The DS-B disaccharide unit of -{IdoA2S-α1,3-GalNAc4S-ß1,4-}- also existed in both CMG-1.0 and GMG-1.0. CMG-1.0 had a higher proportion of CS-O disaccharide unit -{-GlcA-ß1,3-GalNAc-ß1,4-}- but a lower proportion of CS-E disaccharide unit -{-GlcA-ß1,3-GalNAc4S6S-ß1,4-}- than GMG-1.0. The disaccharide compositions of the GAGs varied in a species-specific manner. Anticoagulant activity assay revealed that both CMG-1.0 and GMG-1.0 had potent anticoagulant activity, which can significantly prolong activated partial thromboplastin time. GMG-1.0 also can prolong the thrombin time. CMG-1.0 showed no intrinsic tenase inhibition activity, while GMG-1.0 can obviously inhibit intrinsic tenase with EC50 of 58 nM. Their significantly different anticoagulant activities may be due to their different disaccharide structural units and proportions. These findings suggested that swim bladder by-products of fish processing of these two marine organisms may be used as a source of anticoagulants.

Structural Elucidation of a Glucan from Trichaster palmiferus by Its Degraded Products and Preparation of Its Sulfated Derivative as an Anticoagulant.

Echinoderms have been attracting increasing attention for their polysaccharides, with unique chemical structure and enormous potential for preparing drugs to treat diseases. In this study, a glucan (TPG) was obtained from the brittle star Trichaster palmiferus. Its structure was elucidated by physicochemical analysis and by analyzing its low-molecular-weight products as degraded by mild acid hydrolysis. The TPG sulfate (TPGS) was prepared, and its anticoagulant activity was investigated for potential development of anticoagulants. Results showed that TPG consisted of a consecutive α1,4-linked D-glucopyranose (D-Glcp) backbone together with a α1,4-linked D-Glcp disaccharide side chain linked through C-1 to C-6 of the main chain. The TPGS was successfully prepared with a degree of sulfation of 1.57. Anticoagulant activity results showed that TPGS significantly prolonged activated partial thromboplastin time, thrombin time, and prothrombin time. Furthermore, TPGS obviously inhibited intrinsic tenase, with an EC50 value of 77.15 ng/mL, which was comparable with that of low-molecular-weight heparin (LMWH) (69.82 ng/mL). TPGS showed no AT-dependent anti-FIIa and anti-FXa activities. These results suggest that the sulfate group and sulfated disaccharide side chains play a crucial role in the anticoagulant activity of TPGS. These findings may provide some information for the development and utilization of brittle star resources.

Physiological and transcriptomic analysis reveal the regulatory mechanism underlying grain quality improvement induced by rice ratooning.

BACKGROUND: Ratoon rice cropping has been introduced for increased rice production in southern China and, as a result, has been becoming increasingly popular. However, only a few studies have addressed the regulatory mechanism underlying grain quality improvement induced by rice ratooning. RESULTS: In this study, parameters of rice quality, including head rice yield, chalky grain percentage, grain chalkiness degree, hardness and taste value, were shown to be much improved in the ratooning season rice as compared to its counterparts main and late cropping season rice, indicating that such an improvement was irrespective of seasonal effects. In addition, the nutritional components of grains varied greatly between main-cropping season rice, ratooning season rice and late-cropping season rice and displayed a significant correlation with rice quality. Finally, the regulatory mechanism underlying rice quality improvement revealed that gibberellin-dominated regulation and plant hormone signal transduction jointly contributed to a decrease in formation of chalky grains. CONCLUSION: This work improves our knowledge on rice quality improvement under rice ratooning, particularly on the regulatory mechanism of plant hormones. © 2022 Society of Chemical Industry.

Safety and efficacy of jaktinib in the treatment of Janus kinase inhibitor-naïve patients with myelofibrosis: Results of a phase II trial.

Myelofibrosis (MF) is associated with several constitutional symptoms. Currently, there are few therapeutic options for MF. Jaktinib, a novel, small-molecule inhibitor of JAK, is currently being studied for its potential to treat MF. This phase 2 trial investigated efficacy and safety of jaktinib in the treatment of MF patients. The primary end point was the proportion of patients with ≥35% reduction in spleen volume (SVR35, proportion of patients with ≥35% reduction in spleen volume) at week 24. The secondary end points included improvement of anemia, rates of symptom response, and safety profile. Between January 8, 2019 and August 29, 2020, 118 patients were recruited and treated with either jaktinib 100 mg BID or 200 mg QD. At week 24, 54.8% (34/62) of patients in the 100 mg BID group and 31.3% (15/48) in the 200 mg QD group achieved SVR35 (p = .0199). Jaktinib treatment increased hemoglobin level to ≥20 g/L in 35.6% (21/59) of patients with hemoglobin ≤100 g/L at baseline. The proportion of patients who achieved a ≥50% improvement in total symptom score at week 24 was 69.6% (39/56) in the BID group and 57.5% (23/40) in the QD group. The most common ≥ grade 3 hematological treatment-emergent adverse events (TEAEs; ≥ 10%) were anemia (100 mg BID: 24.2%, 200 mg QD: 28.8%), thrombocytopenia (16.7%, 11.5%), and neutropenia (3.0%, 11.5%). All non-hematological TEAEs were mild. These results indicate that jaktinib can shrink the spleen, improve anemia, and other clinical symptoms with good tolerability.

Genome-wide identification and molecular evolution analysis of the heat shock transcription factor (HSF) gene family in four diploid and two allopolyploid Gossypium species.

Heat shock transcription factors (HSFs) can regulate plant development and stress response. The comprehensive evolutionary history of the HSF family remains elusive in cotton. In this study, each cotton species had 78 members in Gossypium barbadense and Gossypium hirsutum. The diploid species had 39 GaHSFs in Gossypium arboreum, 31 GrHSFs in Gossypium raimondii, 34 GtHSFs in Gossypium turneri, and 34 GlHSFs in Gossypium longicalyx. The HSF family in cotton can be classified into three subfamilies, with seven groups in subfamily A and five groups in subfamily B. Different groups exhibited distinct gene proportions, conserved motifs, gene structures, expansion rates, gene loss rates, and cis-regulatory elements. The paleohexaploidization event led to the expansion of the HSF family in cotton, and the gene duplication events in six Gossypium species were inherited from their common ancestor. The HSF family in diploid species had a divergent evolutionary history, whereas two cultivated tetraploids presented a highly conserved evolution of the HSF family. The HSF members in At and Dt subgenomes of the cultivated tetraploids showed a different evolution from their corresponding diploid donors. Some HSF members were regarded as key candidates for regulating cotton development and stress response. This study provided the comprehensive information on the evolutionary history of the HSF family in cotton.

Physicochemical Properties and Anticoagulant Activity of Purified Heteropolysaccharides from Laminaria japonica.

Laminaria japonica is widely consumed as a key food and medicine. Polysaccharides are one of the most plentiful constituents of this marine plant. In this study, several polysaccharide fractions with different charge numbers were obtained. Their physicochemical properties and anticoagulant activities were determined by chemical and instrumental methods. The chemical analysis showed that Laminaria japonica polysaccharides (LJPs) and the purified fractions LJP0, LJP04, LJP06, and LJP08 mainly consisted of mannose, glucuronic acid, galactose, and fucose in different mole ratios. LJP04 and LJP06 also contained minor amounts of xylose. The polysaccharide fractions eluted by higher concentration of NaCl solutions showed higher contents of uronic acid and sulfate group. Biological activity assays showed that LJPs LJP06 and LJP08 could obviously prolong the activated partial thromboplastin time (APTT), indicating that they had strong anticoagulant activity. Furthermore, we found that LJP06 exerted this activity by inhibiting intrinsic factor Xase with higher selectivity than other fractions, which may have negligible bleeding risk. The sulfate group may play an important role in the anticoagulant activity. In addition, the carboxyl group and surface morphology of these fractions may affect their anticoagulant activities. The results provide information for applications of L. japonica polysaccharides, especially LJP06 as anticoagulants in functional foods and therapeutic agents.

Pharmacodynamics-based approach for efficacious human dose projection of BMS-986260, a small molecule transforming growth factor beta receptor 1 inhibitor.

Transforming growth factor beta (TGF-ß) is a pleiotropic cytokine that has a wide array of biological effects. For decades, tumor biology implicated TGF-ß as an attractive therapeutic target due to its immunosuppressive effects. Toward this end, multiple pharmaceutical companies developed a number of drug modalities that specifically target the TGF-ß pathway. BMS-986260 is a small molecule, selective TGF-ßR1 kinase inhibitor that was under preclinical development for oncology. In vivo studies across mouse, rat, dog, and monkey and cryopreserved hepatocytes predicted human pharmacokinetics (PK) and distribution of BMS-986260. Efficacy studies of BMS-986260 were undertaken in the MC38 murine colon cancer model, and target engagement, as measured by phosphorylation of SMAD2/3, was assessed in whole blood to predict the clinical efficacious dose. The human clearance is predicted to be low, 4.25 ml/min/kg. BMS-986260 provided a durable and robust antitumor response at 3.75 mg/kg daily and 1.88 mg/kg twice-daily dosing regimens. Phosphorylation of SMAD2/3 was 3.5-fold less potent in human monocytes than other preclinical species. Taken together, the projected clinical efficacious dose was 600 mg QD or 210 mg BID for 3 days followed by a 4-day drug holiday. Mechanism-based cardiovascular findings in the rat ultimately led to the termination of BMS-986260. This study describes the preclinical PK characterization and pharmacodynamics-based efficacious dose projection of a novel small molecule TGF-ßR1 inhibitor.

Isotschimgine alleviates nonalcoholic steatohepatitis and fibrosis via FXR agonism in mice.

Farnesoid X receptor (FXR) agonist obeticholic acid (OCA) has emerged as a potential therapy for nonalcoholic fatty liver disease (NAFLD). However, the side effects of OCA may limit its application in clinics. We identified previously that isotschimgine (ITG) is a non-steroidal FXR selective agonist and has potent therapeutic effects on NAFLD in mice. Here, we aimed to evaluate the therapeutic effects of ITG on nonalcoholic steatohepatitis (NASH) and fibrosis in mice. We used methionine and choline deficient (MCD) diet-induced NASH mice, bile duct ligation (BDL), and carbon tetrachloride (CCl4 )-treated hepatic fibrosis mice to investigate the effects of ITG on NASH, fibrosis, and cholestatic liver injury. Our results showed that ITG improved steatosis and inflammation in the liver of MCD diet-fed mice, as well as alleviated fibrosis and inflammation in the liver of CCl4 -treated mice. Furthermore, ITG attenuated serum bile acid levels, and reduced vacuolization, inflammatory infiltration, hepatic parenchymal necrosis, and collagen accumulation in the liver of BDL mice. Mechanistically, ITG increased the expression of FXR target genes. These data suggest that ITG is an FXR agonist and may be developed as a novel therapy for NASH, hepatic fibrosis, or primary biliary cholangitis.

Seismic Damage Identification Method for Curved Beam Bridges Based on Wavelet Packet Norm Entropy.

Curved beam bridges, whose line type is flexible and beautiful, are an indispensable bridge type in modern traffic engineering. Nevertheless, compared with linear bridges, curved beam bridges have more complex internal forces and deformation due to the curvature; therefore, this type of bridge is more likely to suffer damage in strong earthquakes. The occurrence of damage reduces the safety of bridges, and can even cause casualties and property loss. For this reason, it is of great significance to study the identification of seismic damage in curved beam bridges. However, there is currently little research on curved beam bridges. For this reason, this paper proposes a damage identification method based on wavelet packet norm entropy (WPNE) under seismic excitation. In this method, wavelet packet transform is adopted to highlight the damage singularity information, the Lp norm entropy of wavelet coefficient is taken as a damage characteristic factor, and then the occurrence of damage is characterized by changes in the damage index. To verify the feasibility and effectiveness of this method, a finite element model of Curved Continuous Rigid-Frame Bridges (CCRFB) is established for the purposes of numerical simulation. The results show that the damage index based on WPNE can accurately identify the damage location and characterize the severity of damage; moreover, WPNE is more capable of performing damage location and providing early warning than the method based on wavelet packet energy. In addition, noise resistance analysis shows that WPNE is immune to noise interference to a certain extent. As long as a series of frequency bands with larger correlation coefficients are selected for WPNE calculation, independent noise reduction can be achieved.

Pervasive duplication, biased molecular evolution and comprehensive functional analysis of the PP2C family in Glycine max.

BACKGROUND: Soybean (Glycine max) is an important oil provider and ecosystem participant. The protein phosphatase 2C (PP2C) plays important roles in key biological processes. Molecular evolution and functional analysis of the PP2C family in soybean are yet to be reported. RESULTS: The present study identified 134 GmPP2Cs with 10 subfamilies in soybean. Duplication events were prominent in the GmPP2C family, and all duplicated gene pairs were involved in the segmental duplication events. The legume-common duplication event and soybean-specific tetraploid have primarily led to expanding GmPP2C members in soybean. Sub-functionalization was the main evolutionary fate of duplicated GmPP2C members. Meanwhile, massive genes were lost in the GmPP2C family, especially from the F subfamily. Compared with other genes, the evolutionary rates were slower in the GmPP2C family. The PP2C members from the H subfamily resembled their ancestral genes. In addition, some GmPP2Cs were identified as the putative key regulator that could control plant growth and development. CONCLUSIONS: A total of 134 GmPP2Cs were identified in soybean, and their expansion, molecular evolution and putative functions were comprehensively analyzed. Our findings provided the detailed information on the evolutionary history of the GmPP2C family, and the candidate genes can be used in soybean breeding.

Identification of isotschimgine as a novel farnesoid X receptor agonist with potency for the treatment of obesity in mice.

Obesity and its associated non-alcoholic fatty liver disease (NAFLD) have become epidemic medical problems worldwide; however, the current available therapeutic options are limited. Farnesoid X receptor (FXR) has recently emerged as an attractive target for obesity treatment. Here we demonstrate that isotschimgine (ITG), a constituent in genus Ferula, as a novel FXR agonist with anti-obesity and anti-hepatic steatosis effects. The results showed that ITG activated the FXR transactivity and bound with the ligand binding dormain (LBD) of FXR with gene reporter assays and AlphaScreen assays. In high-fat diet-induced obese (DIO) mice, ITG lowered body weight and fat mass, improved insulin resistance and hepatic steatosis. Mechanistic studies showed that ITG altered the expression levels of FXR downstream genes, lipid synthesis and energy metabolism genes in the liver of mice. Our findings suggest that ITG is a novel FXR agonist and may be a potential therapeutic choice for obesity associated with NAFLD.

The relation between Helicobacter pylori immunoglobulin G seropositivity and leukocyte telomere length in US adults from NHANES 1999-2000.

BACKGROUND: Helicobacter pylori (H pylori) immunoglobulin G (IgG) seropositivity is prevalent but its relation with leukocyte telomere length (LTL), a cellular aging biomarker, is unclear. METHODS: Among 3,472 participants from the National Health and Nutrition Examination Survey (NHANES) cycle 1999-2000, LTL was measured with the quantitative polymerase chain reaction. H pylori IgG was measured by enzyme-linked immunosorbent assays and defined as seropositivity with an immune status ratio score > 0.9. We used linear regression models to examine the relation of H pylori IgG seropositivity with continuous LTL and logistic regression for the relation with short LTL (<10th percentile of the population distribution) adjusting for potential confounders. We stratified the analyses by a priori selected variables. RESULTS: Population prevalence of H pylori IgG seropositivity was 31.5% in the overall population with higher prevalence found in those with older age, other races than non-Hispanic whites, lower education, and being born out of the United States. Continuous LTL was non-significantly shorter in those with H Pylori IgG seropositivity versus seronegativity (mean difference = -40.3 bp, 95% CI: -112.4, 31.9). This difference was not significant after adjusting for potential confounders nor stratifying by potential effect modifiers. H Pylori IgG seropositivity was significantly associated with short LTL among the elderly (55-75 years, adjusted OR: 3.06, 95% CI: 1.17, 7.99), but not in the overall population (OR: 1.28, 95% CI: 0.81-2.02). CONCLUSION: H Pylori IgG seropositivity was not associated with continuous LTL in the general population but may be associated with an excessively short LTL in the elderly.

Incorporation of amino moiety to alepterolic acid improve activity against cancer cell lines: Synthesis and biological evaluation.

Aleuritopteris argentea (S. G. Gmél.) Fée is a medicinal fern consisting of an ent-labdane diterpene, i.e. alepterolic aicd, as the major metabolite. We recently isolated grams of alepterolic acid from A. argentea enabling subsequent structural modification. By incorporation of amino moiety to alepterolic acid, fifteen amide derivatives were synthesized, characterized, and further biological evaluated regarding their activity against four cancer cells and normal human liver cells. The potency of synthesized amides dramatically improved as compared to alepterolic aicd itself. The best hit (compound 11) inhibits HeLa cells with an IC50 of 7.39 ± 0.80 µM, and is nearly nontoxic to normal cells. Compound 11 exhibits an inhibitory effect on the colony forming ability of the four cancer cells, especially of HeLa cells. Moreover, it induces apoptosis of HeLa cells by decreasing mitochondrial membrane potential and altering expression of apoptosis-associated proteins. Release of cytochrome c, activation of caspases-3, caspases-9 and alteration of Bax/Bcl-2 balance was detected in the biological assays. These results imply that compound 11 can inhibit the proliferation of cervical cancer cell line HeLa and induce apoptosis through the mitochondrial pathway. These findings encourage further rational structural modification of 15- carboxyl group of alepterolic acid.

Ectopic Expression of Gs5PTase8, a Soybean Inositol Polyphosphate 5-Phosphatase, Enhances Salt Tolerance in Plants.

Inositol polyphosphate 5-phosphatases (5PTases) function in inositol signaling by regulating the catabolism of phosphoinositol derivatives. Previous reports showed that 5PTases play a critical role in plant development and stress responses. In this study, we identified a novel 5PTase gene, Gs5PTase8, from the salt-tolerance locus of chromosome 3 in wild soybean (Glycine soja). Gs5PTase8 is highly up-regulated under salt treatment. It is localized in the nucleus and plasma membrane with a strong signal in the apoplast. Ectopic expression of Gs5PTase8 significantly increased salt tolerance in transgenic BY-2 cells, soybean hairy roots and Arabidopsis, suggesting Gs5PTase8 could increase salt tolerance in plants. The overexpression of Gs5PTase8 significantly enhanced the activities of catalase and ascorbate peroxidase under salt stress. The seeds of Gs5PTase8-transgenic Arabidopsis germinated earlier than the wild type under abscisic acid treatment, indicating Gs5PTase8 would alter ABA sensitivity. Besides, transcriptional analyses showed that the stress-responsive genes, AtRD22, AtRD29A and AtRD29B, were induced with a higher level in the Gs5PTase8-transgenic Arabidopsis plants than in the wild type under salt stress. These results reveal that Gs5PTase8 play a positive role in salt tolerance and might be a candidate gene for improving soybean adaptation to salt stress.

AMPKα1 overexpression improves postoperative cognitive dysfunction in aged rats through AMPK-Sirt1 and autophagy signaling.

Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients who undergo surgery involving anesthesia. Its underlying mechanisms remain unclear. Autophagy plays an important role in the damage and repair of the nervous system and is associated with the development of POCD. Using a rat model, adenosine monophosphate-activated protein kinase α1 (AMPKα1), an important autophagy regulator, was found to be significantly downregulated in rats with POCD that was induced by sevoflurane anesthesia or by appendectomy. Overexpression of AMPKα1-ameliorated POCD, as indicated by decreased escape latencies and increased target quadrant swimming times, swimming distances, and platform crossing times during Morris water maze tests. AMPKα1 overexpression activated autophagy signals by increasing the expression of light chain 3 II (LC3-II) and Beclin1 and decreasing the expression of p62 in the hippocampus of rats with POCD. Moreover, blocking autophagy by 3-methyladenine partly attenuated AMPKα1-mediated POCD improvement. Furthermore, overexpression of AMPKα1 could upregulate the expression of p-AMPK and Sirt1 in the hippocampus of rats with POCD. Intriguingly, inhibiting AMPK signals via Compound C effectively attenuated AMPKα1-mediated POCD improvement, concomitant with the downregulation of p-AMPK, Sirt1, LC3-II, and Beclin1 and the upregulation of p62. We thus concluded that overexpression of AMPKα1 can improve POCD via the AMPK-Sirt1 and autophagy signaling pathway.

Definite chemoradiotherapy is a competent treatment option in FIGO stage IB2 cervical cancer compared with radical surgery +/- neoadjuvant chemotherapy.

BACKGROUND: To compare the treatment outcomes of different treatment modalities for International Federation of Gynecology and Obstetrics (FIGO) stage IB2 cervical cancer. METHODS: From January 2002 to July 2016, 91 patients with FIGO stage IB2 squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma of the cervix were enrolled. All of them received one of the following treatment modalities, including intensity-modulated radiotherapy (IMRT) with concurrent platinum-based chemotherapy (CCRT group, n = 27), radical surgery with or without adjuvant treatment (RH group, n = 25), or neoadjuvant chemotherapy followed by radical surgery with or without adjuvant treatment (NACT group, n = 39). Overall survival (OS), disease free survival (DFS), loco-regional failure-free survival (LRFFS) and distant metastasis-free survival (DMFS) were compared among the three different groups. RESULTS: The median follow up durations were 63.3 months for the CCRT group, 83.5 months for the NACT group, and 89.8 months for the RH group, respectively. The 5-year OS, DFS, LRFFS and DMFS for CCRT group vs. NACT group vs. RH group were 80.1% vs. 94.1% vs. 93.8% (p = 0.197), 79.5% vs. 79.3% vs. 91.0% (p = 0.401), 88.1% vs. 81.8% vs. 95.8% (p = 0.253), and 83.3% vs. 88.8% vs. 95.2% (p = 0.422). No significant prognostic factor was found in OS. Age > 48 was significant in predicting poor DFS and DMFS. The non-squamous cell carcinoma was a significant predictor of poor DFS, LRFFS and DMFS. CONCLUSION: CCRT is a feasible therapeutic option with acceptable acute and chronic treatment-related toxicities for patients who cannot tolerate radical surgery or neoadjuvant chemotherapy.

The Function of Inositol Phosphatases in Plant Tolerance to Abiotic Stress.

Inositol signaling is believed to play a crucial role in various aspects of plant growth and adaptation. As an important component in biosynthesis and degradation of myo-inositol and its derivatives, inositol phosphatases could hydrolyze the phosphate of the inositol ring, thus affecting inositol signaling. Until now, more than 30 members of inositol phosphatases have been identified in plants, which are classified intofive families, including inositol polyphosphate 5-phosphatases (5PTases), suppressor of actin (SAC) phosphatases, SAL1 phosphatases, inositol monophosphatase (IMP), and phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-related phosphatases. The current knowledge was revised here in relation to their substrates and function in response to abiotic stress. The potential mechanisms were also concluded with the focus on their activities of inositol phosphatases. The general working model might be that inositol phosphatases would degrade the Ins(1,4,5)P3 or phosphoinositides, subsequently resulting in altering Ca2+ release, abscisic acid (ABA) signaling, vesicle trafficking or other cellular processes.