Ribosomal Dysregulation in Metastatic Laryngeal Squamous Cell Carcinoma: Proteomic Insights and CX-5461's Therapeutic Promise.

One of the main barriers to the successful treatment of laryngeal squamous cell carcinoma (LSCC) is postoperative progression, primarily due to tumor cell metastasis. To systematically investigate the molecular characteristics and potential mechanisms underlying the metastasis in laryngeal cancer, we carried out a TMT-based proteomic analysis of both cancerous and adjacent non-cancerous tissues from 10 LSCC patients with lymph node metastasis (LNM) and 10 without. A total of 5545 proteins were quantified across all samples. We identified 57 proteins that were downregulated in LSCC with LNM, which were enriched in cell adhesion pathways, and 69 upregulated proteins predominantly enriched in protein production pathways. Importantly, our data revealed a strong correlation between increased ribosomal activity and the presence of LNM, as 18 ribosomal subunit proteins were found to be upregulated, with RPS10 and RPL24 being the most significantly overexpressed. The potential of ribosomal proteins, including RPS10 and RPL24, as biomarkers for LSCC with LNM was confirmed in external validation samples (six with LNM and six without LNM) using Western blotting and immunohistochemistry. Furthermore, we have confirmed that the RNA polymerase I inhibitor CX-5461, which impedes ribosome biogenesis in LSCC, also decreases the expression of RPS10, RPL24, and RPS26. In vitro experiments have revealed that CX-5461 moderately reduces cell viability, while it significantly inhibits the invasion and migration of LSCC cells. It can enhance the expression of the epithelial marker CDH1 and suppress the expression of the mesenchymal markers CDH2, VIM, and FN at a dose that does not affect cell viability. Our study broadens the scope of the proteomic data on laryngeal cancer and suggests that ribosome targeting could be a supplementary therapeutic strategy for metastatic LSCC.

The discovery of a novel single-function intermolecular Diels-Alder enzyme for the biosynthesis of hetero-dimer lithocarpins.

The deep-sea fungus Phomopsis lithocarpus FS508 produces tenellone-macrolide conjugated hetero-dimer lithocarpins A-G with anti-tumor activities. The deficiency of new intermolecular Diels-Alder (DA) enzymes hindered the development of new bioactive hetero-dimers. A novel single-function intermolecular DA enzyme, g7882, was initially discovered in this study. The deletion of g7882 led to the disappearance of lithocarpin A and an increase in precursor level . the overexpression of g7882 significantly improved lithocarpin A yield. The in vitro function of g7882DA was also confirmed by biochemical reaction using tenellone B as a substrate. Additionally, the knockout of KS modules of PKS in cluster 41 and cluster 81 (lit cluster) eliminated the production of lithocarpins, which firstly explains the biosynthetic process of hetero-dimer lithocarpins mediated by DA enzyme in FS508. Furthermore, the removal of a novel acetyltransferase GPAT in cluster 41 and the oxidoreductase, prenyltransferase in cluster81 resulted in the reduction of lithocarpin A in P. lithocarpus. The overexpression of gpat in P. lithocarpus FS508 improved the yield of lithocarpin A significantly and produced a new tenellone derivative lithocarol G. This study offers a new DA enzyme tool for the biosynthesis of novel hetero-dimer and biochemical clues for the biosynthetic logic elucidation of lithocarpins.

The efficacy and safety of FcRn inhibitors in patients with myasthenia gravis: a systematic review and meta-analysis.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease that causes local or generalized muscle weakness. Complement inhibitors and targeting of the neonatal Fc receptor (FcRn) to block IgG cycling are two novel and successful mechanisms. METHODS: PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov were systematically searched to identify relevant studies published before May 18, 2023. Review Manager 5.3 software was used to assess the data. RESULTS: We pooled 532 participants from six randomized controlled trials (RCTs). Compared to the placebo, the FcRn inhibitors were more efficacy in Myasthenia Gravis Activities of Daily Living (MG-ADL) (MD = - 1.69 [- 2.35, - 1.03], P < 0.00001), MG-ADL responder (RR = 2.01 [1.62, 2.48], P < 0.00001), Quantitative Myasthenia Gravis (QMG) (MD = - 2.45 [- 4.35, - 0.55], P = 0.01), Myasthenia Gravis Composite (MGC) (MD = - 2.97 [- 4.27, - 1.67], P < 0.00001), 15-item revised version of the Myasthenia Gravis Quality of Life (MGQoL15r) (MD = - 2.52 [- 3.54, - 1.50], P < 0.00001), without increasing the risk of safety. The subgroup analysis showed that efgartigimod was more effective than placebo in MG-ADL responders. Rozanolixizumab was more effective than the placebo except in QMG, and batoclimab was more effective than the placebo except in MG-ADL responder. Nipocalizumab did not show satisfactory efficacy in all outcomes. With the exception of rozanolixizumab, all drugs showed non-inferior safety profiles to placebo. CONCLUSION: FcRn inhibitors have good efficacy and safety in patients with MG. Among them, efgartigimod and nipocalimab were effective without causing an increased safety risk. Rozanolixizumab, despite its superior efficacy, caused an increased incidence of adverse events. Current evidence does not suggest that nipocalimab is effective in patients with MG.

Preparation and characterization of ι-carrageenan nanocomposite hydrogels with dual anti-HPV and anti-bacterial activities.

Sexually transmitted diseases (STDs) are usually caused by co-infections of bacteria and viruses. However, there is a lack of products that possess both antibacterial and antiviral activities without using chemical drugs. Here, we developed a carrageenan silver nanoparticle composite hydrogel (IC-AgNPs-Gel) based on the antiviral activity of iota carrageenan (IC) and the antibacterial effect of silver nanoparticles (AgNPs) to prevent STDs. IC-AgNPs-Gel showed excellent biocompatibility, hemostasis, antibacterial and antiviral effects. IC-AgNPs-Gel not only effectively prevented S. aureus, E. coli, P. aeruginosa, and C. albicans without using antibiotics, but also significantly inhibited human papilloma virus (HPV)-16 and HPV-6 without using chemotherapy drugs. Moreover, IC-AgNPs-Gel showed the effects of accelerating infected wound healing and reducing inflammation in a rat wound model infected with S. aureus. Therefore, the multifunctional hydrogel shows great potential application prospect in preventing STDs.

Curcumin Induces Apoptosis by Suppressing XRCC4 Expression in Hepatocellular Carcinoma.

Curcumin is a chemical with various pharmacological activities used for cancer treatment. It inhibits hepatocellular carcinoma (HCC) by inducing apoptosis. Here, the mechanism underlying the effect of curcumin on the apoptosis of HCC cells was studied. Cell counting kit-8 and plate cloning assays were used to assess the proliferation of HCC cells, and acridine orange/ethidium bromide and Annexin V/PI staining were used to analyze their apoptosis. HCC xenograft tumor models were established to validate anti-cancer effects of curcumin. Expression levels of XRCC4 protein in tumor tissues were assessed by immunohistochemistry. Correlation between XRCC4 expression and the prognosis of patients with HCC was analyzed by integrating publicly available gene expression data. Curcumin inhibited HCC cells proliferation in a dose-dependent manner. Compared with the control group, curcumin significantly promoted the apoptosis of HCC cells in vitro and in vivo. Immunohistochemical analysis revealed that curcumin downregulated XRCC4 expression levels in HCC tissues. Prognosis of HCC patients with high XRCC4 expression was poorer than that of patients with low XRCC4 expression. Therefore, curcumin exerts anti-cancer effects by inhibiting cell proliferation and promoting cell apoptosis in HCC. This may be due to curcumin interference in the repair process of the nonhomologous DNA terminal link of HCC cells by downregulating XRCC4 expression.

Armcx1 attenuates secondary brain injury in an experimental traumatic brain injury model in male mice by alleviating mitochondrial dysfunction and neuronal cell death.

Armcx1 is highly expressed in the brain and is located in the mitochondrial outer membrane of neurons, where it mediates mitochondrial transport. Mitochondrial transport promotes the removal of damaged mitochondria and the replenishment of healthy mitochondria, which is essential for neuronal survival after traumatic brain injury (TBI). This study investigated the role of Armcx1 and its potential regulator(s) in secondary brain injury (SBI) after TBI. An in vivo TBI model was established in male C57BL/6 mice via controlled cortical impact (CCI). Adeno-associated viruses (AAVs) with Armcx1 overexpression and knockdown were constructed and administered to mice via stereotactic cortical injection. Exogenous miR-223-3p mimic or inhibitor was transfected into cultured cortical neurons, which were then scratched to simulate TBI in vitro. It was found that Armcx1 expression decreased significantly, while miR-223-3p levels increased markedly in peri-lesion tissues after TBI. The overexpression of Armcx1 significantly reduced TBI-induced neurological dysfunction, neuronal cell death, mitochondrial dysfunction, and axonal injury, while the knockdown of Armcx1 had the opposite effect. Armcx1 was potentially a direct target of miR-223-3p. The miR-223-3p mimic obviously reduced the Armcx1 protein level, while the miR-223-3p inhibitor had the opposite effect. Finally, the miR-223-3p inhibitor dramatically improved mitochondrial membrane potential (MMP) and increased the total length of the neurites without affecting branching numbers. In summary, our results suggest that the decreased expression of Armcx1 protein in neurons after experimental TBI aggravates secondary brain injury, which may be regulated by miR-223-3p. Therefore, this study provides a potential therapeutic approach for treating TBI.

Marine Sulfated Polysaccharide PMGS Synergizes with Paclitaxel in Inhibiting Cervical Cancer In Vitro.

The incidence and mortality of cervical cancer in female malignancies are second only to breast cancer, which brings a heavy health and economic toll worldwide. Paclitaxel (PTX)-based regimens are the first-class choice; however, severe side effects, poor therapeutic effects, and difficulty in effectively preventing tumor recurrence or metastasis are unavoidable. Therefore, it is necessary to explore effective therapeutic interventions for cervical cancer. Our previous studies have shown that PMGS, a marine sulfated polysaccharide, exhibits promising anti-human papillomavirus (anti-HPV) effects through multiple molecular mechanisms. In this article, a continuous study identified that PMGS, as a novel sensitizer, combined with PTX exerted synergistic anti-tumor effects on cervical cancer associated with HPV in vitro. Both PMGS and PTX inhibited the proliferation of cervical cancer cells, and the combination of PMGS with PTX displayed significant synergistic effects on Hela cells. Mechanistically, PMGS synergizes with PTX by enhancing cytotoxicity, inducing cell apoptosis and inhibiting cell migration in Hela cells. Collectively, the combination of PTX and PMGS potentially provides a novel therapeutic strategy for cervical cancer.

Salicylic acid promotes terpenoid synthesis in the fungi Sanghuangporus baumii.

Sanghuangporus baumii is a medicinal fungi with anti-inflammatory, liver protection and antitumour effects. Terpenoids are one of the main medicinal ingredients of S. baumii. However, terpenoid production by wild-type S. baumii cannot meet the market demand, which affects its application in medical care. Therefore, exploring how to increase terpenoid content in S. baumii is a promising path in this research field. Salicylic acid (SA) is a secondary metabolite. In this study, a concentration of 350 µmol/L SA was added into fungal cultivations for 2 and 4 days, and then the transcriptome and metabolome of untreated mycelia and treated with SA were analysed. The expression of some genes in the terpenoids biosynthesis pathway increased in SA-induced cultivations, and the content of isopentenyl pyrophosphate (IPP) and geranylgeranyl-PP (GGPP) increased significantly as well as the contents of triterpenoids, diterpenoids, sesquiterpenoids and carotenoids. The gene FPS was considered to be a key gene regulating terpenoid biosynthesis. Therefore, FPS was overexpressed in S. baumii by Agrobacterium tumefaciens-mediated genetic transformation. The gene FPS and its downstream gene (LS) expression levels were confirmed to be increased in the FPS overexpressing transformant, and terpenoid content was 36.98% higher than that of the wild-type strain in the evaluated cultivation conditions.

Comprehensive analysis of novel cancer prediction genes and tumor microenvironment infiltration in colon cancer.

BACKGROUND: Colon cancer with high incidence and mortality is a severe public health problem. As an emerging therapy, immunotherapy has played an active clinical role in tumor treatment, but only a small number of patients respond. METHODS: By univariate Cox regression analysis of 165 novel cancer prediction genes (NCPGs), 29 NCPGs related to prognosis were screened. Based on these 29 NCPGs and 336 differentially expressed genes, we constructed two colon cancer subgroups and three gene clusters and analyzed prognosis, activation pathways, and immune infiltration characteristics under various modification patterns. Then each patient was scored and divided into high or low NCPG_score groups. A comprehensive evaluation between NCPG_score and clinical characteristics, tumor microenvironment (TME), tumor somatic mutations, and the potential for immunotherapy was conducted. RESULTS: Patients with high NCPG_score were characterized by high tumor mutation burden and high microsatellite instability and were more suitable for immunotherapy. CONCLUSIONS: This study screened 29 NCPGs as independent prognostic markers in colon cancer patients, demonstrating their TME, clinicopathological features, and potential roles in immunotherapy, helping to assess prognosis and guiding more personalized immunotherapy.

Tubular Polypyrrole with Chloride Ion Dopants as an Ultrafast Organic Anode for High-Power Lithium-Ion Batteries.

Polypyrrole (PPy), as a representative p-type conductive polymer, attracts wide attention for energy storage materials. However, the sluggish reaction kinetics and low specific capacity of PPy impede its application in high-power lithium-ion batteries (LIBs). Herein, tubular PPy with chloride and methyl orange (MO) anionic dopants is synthesized and investigated as an anode for LIBs. The Cl- and MO anionic dopants can increase the ordered aggregation and the conjugation length of pyrrolic chains, forming plentiful conductive domains and affecting the conduction channel inside the pyrrolic matrix, thereby achieving fast charge transfer and Li+ ion diffusion, low ion transfer energy barriers, and rapid reaction kinetics. On account of the above synergistic effect, PPy electrodes deliver a high specific capacity of 2067.8 mAh g-1 at 200 mA g-1 and a remarkable rate capacity of 1026 mAh g-1 at 10 A g-1 , realizing high energy density (724 Wh kg-1 ) and power density (7237 W kg-1 ) simultaneously.

Organic Cathode Materials for Rechargeable Aluminum-Ion Batteries.

Organic electrode materials (OEMs) have shown enormous potential in ion batteries because of their varied structural components and adaptable construction. As a brand-new energy-storage device, rechargeable aluminum-ion batteries (RAIBs) have also received a lot of attention due to their high safety and low cost. OEMs are expected to stand out among many traditional RAIB cathode materials. However, how to improve the electrochemical performance of OEMs in RAIBs on a laboratory scale is still challenging. This work reviews and discusses the uses of conductive polymers, carbonyl compounds, imine polymers, polycyclic aromatic hydrocarbons, organic frameworks, and other organic materials as the cathodes of RAIBs, as well as energy-storage mechanisms and research progress. It is hoped that this Review can provide the design guidelines for organic cathode materials with high capacity and great stability used in aluminum-organic batteries and develop more efficient organic energy storage cathodes.

The development of multifunctional sulfated polyguluronic acid-based polymeric micelles for anticancer drug delivery.

Numerous disseminated tumor cells specifically overexpress P-selectin. Therefore, it was thought to be a potential target for tumor therapy. Herein, we described a novel P-selectin-targeted glycosyl ligand-sulfated polyguluronic acid (PGS), as an oriented carrier of P-selectin-targeted drug delivery system. Specifically, the PGS-SS-DOX polymeric micelles were constructed to confirm the practicability of the PGS carrier as a new P-selectin-targeted ligand. PGS-SS-DOX micelles comprised P-selectin-targeted PGS, doxorubicin (DOX) as an anticarcinogen, and pH/redox dual-sensitive bio-linker facilitating drug release in tumor tissues. In vitro and in vivo data showed that PGS-SS-DOX micelles significantly increased tumor cell killing capacity and exhibited a favorable biocompatibility comparison with Free-DOX. This work proved that PGS was an ideal low immunogenic, biodegradable drug carrier for the delivery of anti-cancer drugs. The facile PGS-SS-drug micelle system provided enormous opportunities for treating disseminated tumors utilizing many irreplaceable anticarcinogens.

MLSP: A bioinformatics tool for predicting molecular subtypes and prognosis in patients with breast cancer.

The molecular landscape in breast cancer is characterized by large biological heterogeneity and variable clinical outcomes. Here, we performed an integrative multi-omics analysis of patients diagnosed with breast cancer. Using transcriptomic analysis, we identified three subtypes (cluster A, cluster B and cluster C) of breast cancer with distinct prognosis, clinical features, and genomic alterations: Cluster A was associated with higher genomic instability, immune suppression and worst prognosis outcome; cluster B was associated with high activation of immune-pathway, increased mutations and middle prognosis outcome; cluster C was linked to Luminal A subtype patients, moderate immune cell infiltration and best prognosis outcome. Combination of the three newly identified clusters with PAM50 subtypes, we proposed potential new precision strategies for 15 subtypes using L1000 database. Then, we developed a robust gene pair (RGP) score for prognosis outcome prediction of patients with breast cancer. The RGP score is based on a novel gene-pairing approach to eliminate batch effects caused by differences in heterogeneous patient cohorts and transcriptomic data distributions, and it was validated in ten cohorts of patients with breast cancer. Finally, we developed a user-friendly web-tool (https://sujiezhulab.shinyapps.io/BRCA/) to predict subtype, treatment strategies and prognosis states for patients with breast cancer.

Formation Mechanism of Monocyclic Aromatic Hydrocarbons during Pyrolysis of Styrene Butadiene Rubber in Waste Passenger Car Tires.

The production of aromatic hydrocarbons from the waste tire pyrolysis attracts more and more attention because of its tremendous potential. Based on styrene-butadiene rubber (SBR), which is the main rubber in the waste passenger car tires, this work studies the temperature influence on primary pyrolysis product distribution by experimental techniques (Py-GC/MS, TG-MS), and then, the formation mechanism of monocyclic aromatic hydrocarbons (MAHs) observed in the experiment was analyzed by first-principles calculations. The experimental results show that the MAHs during the pyrolysis mainly include styrene, toluene, and xylene, and subsequent calculations showed that these compounds were formed through a series of primary and secondary reactions. The formation pathways of these typical MAHs were studied via the reaction energy barrier analysis, respectively. It shows that the MAHs were not only derived from the benzene ring in the SBR chain but also generated from short-chain alkenes through the Diels-Alder reaction. The obtained pyrolysis reaction mechanism provides theoretical guidance for the regulation of the pyrolysis product distribution of MAHs.

Clinical significance of neutrophil gelatinase-associated lipocalin and sdLDL-C for coronary artery disease in patients with type 2 diabetes mellitus aged ≥ 65 years.

BACKGROUND AND AIMS: Although type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) share many common pathological and physiological characteristics, there are few studies assessing the predictive capacity of novel biomarkers in occurrence and development of CAD in T2DM patients aged ≥ 65 years. In addition, T2DM patients aged ≥ 65 years are prone to CAD. Therefore, it is of great significance to find novel biomarkers for the development CAD in T2DM. METHODS: In this retrospective cohort study, 579 T2DM patients aged ≥ 65 years were consecutively enrolled in this work, and 177 of whom had major adverse cardiovascular and cerebrovascular events (MACCE: cardiovascular or cerebrovascular death, acute coronary syndrome, coronary stent implantation, and stroke) during the follow up. Univariate and multivariate factors were employed to analyze the correlation between each variable and the occurrence of MACCE, and the Spearman's rank correlation analysis was performed to assess the relationships between Neutrophil gelatinase-associated lipocalin (NGAL) and small dense low-density lipoprotein-cholesterol (LDL-C) (sdLDL-C). The receiver operating characteristic (ROC) curve was adopted to determine the predictive value of NGAL and sdLDL-C elevation for MACCE in T2DM patients aged ≥ 65 years. RESULTS: After a median 48 months follow-up [19, (10 ~ 32) ], the levels of NGAL, sdLDL-C, hemoglobin A1c (HbA1c), LDL-C, and apolipoprotein B (ApoB) were significantly higher while those of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A I (ApoA-I) were lower in MACCE positive group. NGAL correlated to body mass index (BMI) (r = 0.391, P = 0.001) and triglyceride (TG) (r = 0.228, P = 0.032), and high-sensitivity CRP (hsCRP) (r = 0.251, P = 0.007), and neutrophils (r = 0.454, P = 0.001), sdlDL-C level was found to be positively correlated with LDL-C (r = 0.413, P = 0.001), TG (r = 0.432, P = 0.001), and ApoB (r = 0.232, P = 0.002); and it was negatively correlated with HDL-C (r = -0.362, P = 0.031) and ApoA-I (r = -0.402, P = 0.001). Age-adjusted Cox regression analysis showed that NGAL (HR = 1.006, 95% confidence interval (CI): 1.005-1.008, P < 0.001) and sdLDL-C (HR = 1.052, 95% CI: 1.037-1.066, P < 0.001) were independently associated with occurrence of MACCE. ROC curve analysis showed that NGAL (area under ROC (AUC) = 0.79, 95% CI: 0.75-0.84, P < 0.001) and sdlDL-C (AUC = 0.76, 95% CI: 0.72-0.80, P < 0.001) could predict the occurrence of MACCE (area under ROC. NGAL combined with sdlDL-C could predict the occurrence of MACCE well (AUC = 0.87, 95% CI: 0.84-0.90, P < 0.001). CONCLUSION: The higher NGAL and sdLDL-C in T2DM patients aged ≥ 65 years were significantly and independently associated with the risk of MACCE, and showed higher clinical values than other lipid biomarkers or other chronic inflammation, so they were expected to be the most effective predictors of MACCE assessment.

The genetic algorithm-aided three-stage ensemble learning method identified a robust survival risk score in patients with glioma.

Ensemble learning is a kind of machine learning method which can integrate multiple basic learners together and achieve higher accuracy. Recently, single machine learning methods have been established to predict survival for patients with cancer. However, it still lacked a robust ensemble learning model with high accuracy to pick out patients with high risks. To achieve this, we proposed a novel genetic algorithm-aided three-stage ensemble learning method (3S score) for survival prediction. During the process of constructing the 3S score, double training sets were used to avoid over-fitting; the gene-pairing method was applied to reduce batch effect; a genetic algorithm was employed to select the best basic learner combination. When used to predict the survival state of glioma patients, this model achieved the highest C-index (0.697) as well as area under the receiver operating characteristic curve (ROC-AUCs) (first year = 0.705, third year = 0.825 and fifth year = 0.839) in the combined test set (n = 1191), compared with 12 other baseline models. Furthermore, the 3S score can distinguish survival significantly in eight cohorts among the total of nine independent test cohorts (P < 0.05), achieving significant improvement of ROC-AUCs. Notably, ablation experiments demonstrated that the gene-pairing method, double training sets and genetic algorithm make sure the robustness and effectiveness of the 3S score. The performance exploration on pan-cancer showed that the 3S score has excellent ability on survival prediction in five kinds of cancers, which was verified by Cox regression, survival curves and ROC curves together. To enable its clinical adoption, we implemented the 3S score and other two clinical factors as an easy-to-use web tool for risk scoring and therapy stratification in glioma patients.

Mushrooms Do Produce Flavonoids: Metabolite Profiling and Transcriptome Analysis of Flavonoid Synthesis in the Medicinal Mushroom Sanghuangporus baumii.

Mushrooms produce a large number of medicinal bioactive metabolites with antioxidant, anticancer, antiaging, and other biological activities. However, whether they produce flavonoids and, if so, how they synthesize them remains a matter of some debate. In the present study, we combined flavonoid-targeted metabolomics and transcriptome analysis to explore the flavonoid synthesis in the medicinal mushroom Sanghuangporus baumii. The S. baumii synthesized 81 flavonoids on a chemically defined medium. The multiple classes of flavonoids present were consistent with the biosynthetic routes in plants. However, paradoxically, most of the genes that encode enzymes involved in the flavonoid biosynthetic pathway are missing from S. baumii. Only four genes related to flavonoid synthesis were found in S. baumii, among which phenylalanine ammonia lyase gene (PAL) is a key gene regulating flavonoid synthesis, and overexpression of SbPAL increases the accumulation of flavonoids. These results suggest that the flavonoid synthesis pathway in S. baumii is different from that in known plants, and the missing genes may be replaced by genes from the same superfamilies but are only distantly related. Thus, this study provides a novel method to produce flavonoids by metabolic engineering using mushrooms.

Expression Analysis of Lanosterol Synthase Gene in Dynamic Accumulation of Triterpenoids in Sanghuangporus baumii.

BACKGROUND: Sanghuangporus baumii is a traditional Chinese medicine with anti- cancer, anti-tumor, and anti-inflammatory effects. Triterpenoids are one of the main medicinal ingredients found in S. baumii. However, the dynamic changes of triterpenoids content and its molecular regulation mechanism are still unclear. OBJECTIVE: Some studies have shown that Lanosterol synthase ( LS) is a key enzyme involved in the mevalonate pathway (MVA pathway) to produce lanosterol, which is a precursor for synthesizing S. baumii triterpenoids. Therefore, the study of LS gene and expression characteristics can provide clues for the further study of triterpenoids synthesis. METHODS: The PCR, RACE PCR, RT-PCR, homologous recombination and prokaryotic expression technology were used to research the gene characteristic and dynamic changes of LS transcription level. RESULTS: The S. baumii LS sequence included a 5'-untranslated region (129 bp), a 3'-untranslated region (87 bp), and an open reading frame (2,229 bp) encoding 734 amino acids. The S. baumii LS protein was expressed in E. coli BL21 (DE3). The transcription start site of the S. baumii LS promoter sequence ranged from 1 740 bp to 1790 bp. The LS promoter contained 12 CAAT-boxes, 5 ABREs, 6 G-Boxes, 6 CGTCA-motifs, and so on. The LS transcription levels were the highest on day 11 in mycelia (1.6-fold), and the triterpenoids content also gradually increased. The transcription levels began to decrease on day 13, but the triterpenoids content still increased. CONCLUSION: The S. baumii LS was cloned and characterized to help to understand the mechanism of triterpenoids synthesis. In addition, we studied the relationship between LS transcription level and triterpenoid dynamic accumulation, and we found that they had a certain correlation.

A Novel PTP1B Inhibitor-Phosphate of Polymannuronic Acid Ameliorates Insulin Resistance by Regulating IRS-1/Akt Signaling.

Protein tyrosine phosphatase 1B (PTP1B) is a critical negative modulator of insulin signaling and has attracted considerable attention in treating type 2 diabetes mellitus (T2DM). Low-molecular-weight polymannuronic acid phosphate (LPMP) was found to be a selective PTP1B inhibitor with an IC50 of 1.02 ± 0.17 µM. Cellular glucose consumption was significantly elevated in insulin-resistant HepG2 cells after LPMP treatment. LPMP could alleviate oxidative stress and endoplasmic reticulum stress, which are associated with the development of insulin resistance. Western blot and polymerase chain reaction (PCR) analysis demonstrated that LPMP could enhance insulin sensitivity through the PTP1B/IRS/Akt transduction pathway. Furthermore, animal study confirmed that LPMP could decrease blood glucose, alleviate insulin resistance, and exert hepatoprotective effects in diabetic mice. Taken together, LPMP can effectively inhibit insulin resistance and has high potential as an anti-diabetic drug candidate to be further developed.

Targeting the Epithelial-to-Mesenchymal Transition in Cancer Stem Cells for a Better Clinical Outcome of Glioma.

Glioma is one of the most common malignant tumors of the central nervous system with a poor prognosis at present due to lack of effective treatment options. Its initiation, migration, and multipotency are affected by cancer stem cell's transition. Previous studies imply that changes in the cancer stem cells can affect the malignant differentiation of the tumor. We found that the epithelial-to-mesenchymal transition (EMT)-related regulatory pathway is an important target for tumor therapy. In this review, we discuss the transition factor of EMT and 3 specific pathways that affect the EMT of cancer stem cells during tumor development. We conclude that targeting the EMT process of cancer stem cells can be a feasible approach in the treatment of glioma.