Inhibition of Ferroptosis by Mesenchymal Stem Cell-Derived Exosomes in Acute Spinal Cord Injury: Role of Nrf2/GCH1/BH4 Axis.

OBJECTIVE: The therapeutic benefits of exosomes obtained from mesenchymal stem cells (MSCs) in acute spinal cord injury (SCI) have been demonstrated in recent years, but the precise mechanisms remain unknown. In this study, the efficacy and mechanisms of MSC-derived exosomes (MSC-Exo) in acute SCI were investigated. METHODS: By utilizing a BV2 ferroptosis cellular model and an SCI rat model, we investigated the effects of MSC-Exo on iron death related indicators and NF-E2 related factor 2 (Nrf2)/GTP cyclolase I (GCH1)/5,6,7,8-tetrahydrobiopterin (BH4) signaling axis, as well as their therapeutic effects on SCI rats. RESULTS: The results revealed that MSC-Exo effectively inhibited the production of ferrous iron, lipid peroxidation products malonaldehyde and reactive oxygen species, and ferroptosis-promoting factor prostaglandin-endoperoxide synthase 2. Concurrently, they upregulated ferroptosis suppressors FTH-1 (ferritin heavy chain 1), SLC7A11 (solute carrier family 7 member 11), FSP1 (ferroptosis suppressor protein 1), and GPX4 (glutathione peroxidase 4), contributing to enhanced neurological recovery in SCI rats. Further analysis showed the Nrf2/GTP/BH4 signaling pathway's critical role in suppressing ferroptosis. Additionally, MSC-Exo was found to inhibit lipopolysaccharide-induced ferroptosis in BV2 cells and SCI rats by activating the Nrf2/GCH1/BH4 axis. CONCLUSION: In summary, the study demonstrates that MSC-Exo mitigates microglial cell ferroptosis via the Nrf2/GCH1/BH4 axis, showing potential for preserving and restoring neurological function post-SCI.

[Corrigendum] MicroRNA­222­3p promotes tumor cell migration and invasion and inhibits apoptosis, and is correlated with an unfavorable prognosis of patients with renal cell carcinoma.

Following the publication of the above article, an interested reader drew to the attention of the Editorial Office that, in Fig. 3A on p. 530, two pairs of data panels were overlapping, such that certain of the panels appeared to have been derived from the same original sources where the results from differently performed experiments were intended to have been portrayed. The authors have examined their original data, and realize that errors associated with data handling/labelling during the preparation of the representative images in Fig. 3A had occurred. The revised version of Fig. 3, showing the correct data for the 'NC/ACHN/Invasion and Migration' data panels, the 'Inhibitor NC/786­O' panel and the 'Inhibitor NC/ACHN/Invasion' panel, is shown on the next page. The authors can confirm that the errors associated with this figure did not have any significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for giving them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 43: 525­534, 2019; DOI: 10.3892/ijmm.2018.3931].

Protective Effect of Silibinin on Lipopolysaccharide-Induced Endotoxemia by Inhibiting Caspase-11-Dependent Cell Pyroptosis.

OBJECTIVE: To explore the protective effect and the underlying mechanism of silibinin (SIB), one of the active compounds from Silybum marianum (L.) Gaertn in endotoxemia. METHODS: Mouse peritoneal macrophage were isolated via intraperitoneally injection of BALB/c mice with thioglycolate medium. Cell viability was assessed using the cell counting kit-8, while cytotoxicity was determined through lactate dehydrogenase cytotoxicity assay. The protein expressions of interleukin (IL)-1 α, IL-1 ß, and IL-18 were determined by enzyme-linked immunosorbent assay. Intracellular lipopolysaccharide (LPS) levels were measured by employing both the limulus amoebocyte lysate assay and flow cytometry. Additionally, proximity ligation assay was employed for the LPS and caspase-11 interaction. Mice were divided into 4 groups: the control, LPS, high-dose-SIB (100 mg/kg), and low-dose-SIB (100 mg/kg) groups (n=8). Zebrafish were divided into 4 groups: the control, LPS, high-dose-SIB (200 εmol/L), and low-dose-SIB (100 εmol/L) groups (n=30 for survival experiment and n=10 for gene expression analysis). The expression of caspase-11, gasdermin D (GSDMD), and N-GSDMD was determined by Western blot and the expressions of caspy2, gsdmeb, and IL-1 ß were detected using quantitative real-time PCR. Histopathological observation was performed through hematoxylineosin staining, and protein levels in bronchoalveolar lavage fluid were quantified using the bicinchoninicacid protein assay. RESULTS: SIB noticeably decreased caspase-11 and GSDMD-mediated pyroptosis and suppressed the secretion of IL-1 α, IL-1 ß, and IL-18 induced by LPS (P<0.05). Moreover, SIB inhibited the translocation of LPS into the cytoplasm and the binding of caspase-11 and intracellular LPS (P<0.05). SIB also attenuated the expression of caspase-11 and N-terminal fragments of GSDMD, inhibited the relative cytokines, prolonged the survival time, and up-regulated the survival rate in the endotoxemia models (P<0.05). CONCLUSIONS: SIB can inhibit pyroptosis in the LPS-mediated endotoxemia model, at least in part, by inhibiting the caspase-11-mediated cleavage of GSDMD. Additionally, SIB inhibits the interaction of LPS and caspase-11 and inhibits the LPS-mediated up-regulation of caspase-11 expression, which relieves caspase-11-dependent cell pyroptosis and consequently attenuates LPS-mediated lethality.

Erratum: [Corrigendum] miR­216a­5p acts as an oncogene in renal cell carcinoma.

[This corrects the article DOI: 10.3892/etm.2018.5881.].

Scenario analysis of energy consumption and related emissions in the transportation industry-a case study of Shaanxi Province.

In the context of pursuing carbon neutrality and balancing the use of fossil fuels with renewable energy, the transportation industry faces the challenge of accurately predicting energy demand, related emissions, and assessing the effectiveness of energy technologies and policies. This is crucial for formulating energy management plans and reducing carbon dioxide (CO2) and atmospheric pollutant emissions. Currently, research on energy consumption and emission forecasting primarily relies on energy consumption quantities and emission factors, which lack precision. This study employs the low emissions analysis platform (LEAP) model, utilizing a "bottom-up" modeling approach combined with scenario analysis to predict and analyze the energy demand and related emissions in the transportation industry. Compared to previous studies, the methodological framework proposed in this research offers higher precision and can explore energy-saving and emission-reduction pathways for different modes of transport, providing a valuable energy forecasting tool for transport policy formulation in other regions. The forecast results indicate that under the business-as-usual (BAU) scenario, by 2049, the energy consumption and related emissions in Shaanxi Province's transportation industry are expected to increase by 1.15 to 1.85 times compared to the baseline year. In the comprehensive (CP) scenario, the industry is projected to reach a carbon peak around 2033. The study also finds that energy consumption and emissions predominantly originate from private passenger vehicles, highway freight, and civil aviation passenger, which have the greatest potential for emission reduction under the transport structure optimized (TSO) scenario. Therefore, policymakers should consider regional development characteristics, combine different transportation modes, and specifically analyze the emission reduction potential of the transportation industry in various regions, formulating corresponding reduction policies accordingly.

[Retracted] Oncogenic miR-23a-5p is associated with cellular function in RCC.

Following the publication of this article, a concerned reader drew to the Editor's attention that, for the invasion and migration assay data shown in Fig. 4 on p. 2314, three pairs of data panels were overlapping, such that data which were intended to show the results from differently performed experiments were obtained from a smaller number of original sources. Moreover, after having conducted an internal investigation, the Editorial Office also observed that some of the flow cytometric data shown in Fig. 6 were duplicated in Fig. 7. Considering the number of overlapping data panels that have been identified in this published paper, the Editor of Molecular Medicine Reports has concluded that the article should be retracted from the publication on account of a lack of confidence in the integrity of the data. Upon contacting the authors about this matter, they accepted the decision to retract this paper. The Editor apologizes to the readership for any inconvenience caused, and thanks the interested reader for drawing this matter to our attention. [Molecular Medicine Reports 16: 2309-2317, 2017; DOI: 10.3892/mmr.2017.6829].

[Corrigendum] Identification of lncRNA EGOT as a tumor suppressor in renal cell carcinoma.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that, concerrning the Transwell cell migration and invasion assay data shown in Fig. 6A and B for the 786­O cell line on p. 7206, the pcDNA3.1­EGOT 'Migration' and 'Invasion' (a­1 and b­1) data panels appeared to contain overlapping sections of data, such that they were potentially derived from the same original source, where these panels were intended to show the results from differently performed experiments. The authors have re­examined their original data, and realize that the 'Invasion' (b­1) panel in Fig. 6B was inadvertently chosen incorrectly. The revised version of Fig. 6, now featuring the correct data for the 'Invasion' experiment (B1 in the replacement figure) in Fig. 6B, is shown on the next page. Note that this error did not adversely affect either the results or the overall conclusions reported in this study. All the authors agree with the publication of this corrigendum, and are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this. They also wish to apologize to the readership of the Journal for any inconvenience caused.[Molecular Medicine Reports 16: 7072­7079, 2017; DOI: 10.3892/mmr.2017.7470].

Heparanase interacting BCLAF1 to promote the development and drug resistance of ICC through the PERK/eIF2α pathway.

Intrahepatic cholangiocarcinoma (ICC) is a primary epithelial carcinoma known for its aggressive nature, high metastatic potential, frequent recurrence, and poor prognosis. Heparanase (HPSE) is the only known endogenous ß-glucuronidase in mammals. In addition to its well-established enzymatic roles, HPSE critically exerts non-catalytic function in tumor biology. This study herein aimed to investigate the non-enzymatic roles of HPSE as well as relevant regulatory mechanisms in ICC. Our results demonstrated that HPSE was highly expressed in ICC and promoted the proliferation of ICC cells, with elevated HPSE levels implicating a poor overall survival of ICC patients. Notably, HPSE interacted with Bcl-2-associated factor 1 (BCLAF1) to upregulate the expression of Bcl-2, which subsequently activated the PERK/eIF2α-mediated endoplasmic reticulum (ER) stress pathway to promote anti-apoptotic effect of ICC. Moreover, our in vivo experiments revealed that concomitant administration of gemcitabine and the Bcl-2 inhibitor navitoclax enhanced the sensitivity of ICC cells with highly expressed HPSE to chemotherapy. In summary, our findings revealed that HPSE promoted the development and drug resistance of ICC via its non-enzymatic function. Bcl-2 may be considered as an effective target with therapeutic potential to overcome ICC chemotherapy resistance induced by HPSE, presenting valuable insights into the development of novel therapeutic strategies against ICC.

[Corrigendum] microRNA­181a­5p functions as an oncogene in renal cell carcinoma.

Following the publication of the above article and a corrigendum in 2018 that corrected details of the correspondence information for authors, errors made in Fig. 5 and the funding details (doi: 10.3892/mmr.2018.9117), an interested reader drew to the authors' attention that, in Fig. 6 on p. 8515 showing the results of cell migration and invasion assay experiments, a pair of data panels were overlapping, such that data which were intended to show the results from differently performed experiments appeared to have been derived from the same original source. After having consulted their original data, the authors have realized that Fig. 6 was assembled incorrectly, The revised version of Fig. 6, now showing the correct data for the 'ACHN/migratory/NC' experiment, is shown on the next page. Note that all the authors approve of the publication of this corrigendum, and the authors are grateful to the Editor of Molecular Medicine Reports for granting them the opportunity to publish this. The authors regret their oversight in allowing this error to be included in the paper, and also apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 17: 8510­8517, 2018; DOI: 10.3892/mmr.2018.8899].

Erratum: [Corrigendum] miR­199b­5p serves as a tumor suppressor in renal cell carcinoma.

[This corrects the article DOI: 10.3892/etm.2018.6151.].

Anoikis resistance and immune escape mediated by Epstein-Barr virus-encoded latent membrane protein 1-induced stabilization of PGC-1α promotes invasion and metastasis of nasopharyngeal carcinoma.

BACKGROUND: Epstein-Barr virus (EBV) is the first discovered human tumor virus that is associated with a variety of malignancies of both lymphoid and epithelial origin including nasopharyngeal carcinoma (NPC). The EBV-encoded latent membrane protein 1 (LMP1) has been well-defined as a potent oncogenic protein, which is intimately correlated with NPC pathogenesis. Anoikis is considered to be a physiological barrier to metastasis, and avoiding anoikis is a major hallmark of metastasis. However, the role of LMP1 in anoikis-resistance and metastasis of NPC has not been fully identified. METHODS: Trypan blue staining, colony formation assay, flow cytometry, and TUNEL staining, as well as the detection of apoptosis and anoikis resistance-related markers was applied to evaluate the anoikis-resistant capability of NPC cells cultured in ultra-low adhesion condition. Co-immunoprecipitation (Co-IP) experiment was performed to determine the interaction among LMP1, PRMT1 and PGC-1α. Ex vivo ubiquitination assay was used to detect the ubiquitination level of PGC-1α. Anoikis- resistant LMP1-positive NPC cell lines were established and applied for the xenograft and metastatic animal experiments. RESULTS: Our current findings reveal the role of LMP1-stabilized peroxisome proliferator activated receptor coactivator-1a (PGC-1α) in anoikis resistance and immune escape to support the invasion and metastasis of NPC. Mechanistically, LMP1 enhances PGC-1α protein stability by promoting the interaction between arginine methyltransferase 1 (PRMT1) and PGC-1α to elevate the methylation modification of PGC-1α, thus endowing NPC cells with anoikis-resistance. Meanwhile, PGC-1α mediates the immune escape induced by LMP1 by coactivating with STAT3 to transcriptionally up-regulate PD-L1 expression. CONCLUSION: Our work provides insights into how virus-encoded proteins recruit and interact with host regulatory elements to facilitate the malignant progression of NPC. Therefore, targeting PGC-1α or PRMT1-PGC-1α interaction might be exploited for therapeutic gain for EBV-associated malignancies.

Galactose-functionalized injectable thermosensitive microgels for target specific uptake in hepatoma cells.

Microgels acts as a potential candidate for responsive composite materials, which has been favored by scientists because of its excellent colloid stability, easy integration, and most of their surface area can be used as support after modification. Specififically, microgels are fascinating capable of maintaining good biocompatibility and controlled-release in vivo and making the possible for applications in biomaterials and biomedicines. Besides, in the process of microgel synthesis, some targeting factors can be combined to achieve the purpose of cell targeting and uptake. Therefore, how to fundamentally design microgels is an urgent problem to be solved. In this study, we design and synthesize an injectable microgel P(DEGMA-co-OVNGal) that is made of 2-methyl-2-acrylate-2-(2-methoxy ethoxy) ethyl ester (DEGMA) and glycopolymer (OVNGal) that is thermoresponsive and contains galactose. When the content of crosslinking agent is regulated, the microgel will realize the transformation from sol to gel at the temperature around human body, causing the controlled release of the loaded drugs. With the increase of crosslinker content from 1% to 7%, the appearance of microgel changed from loose and ordered to compact and hard morphology, the swelling ratio of microgel decreased from 187% to 142%, and the phase volume transition temperature decreased from 29.2°C to 28°C. The results indicated that when the monomer ratio (DEGMA: OVNGal) increased from 2:1 to 40:1 with the amount of crosslinking agent at 1%, the particle size of microgel increased from 460 nm to 660 nm. In vitro released studies confirmed that the cumulative released DOX (doxorubicin, as a selected model drug) from the microgel can reach 50% after 7 days. Furthermore, in vitro experiments demonstrated that the injectable microgel P(DEGMA-co-OVNGal) can target HepG2 cells effectively and meantime dispalys excellent biocompatibility. Therefore, the injected microgels based on P(DEGMA-co-OVNGal) have the potential to serve as a robust and promising drug delivery carrier for targeted cancer therapy.

Green tea intake and the risk of hypertension in premenopausal women: the TCLSIH cohort study.

Background and aims: Tea polyphenols, such as green tea polyphenols, have been extensively studied as agents that ameliorate cardiovascular disease and blood pressure in vitro and in animal studies. However, epidemiological evidence for the association of green tea consumption with hypertension (HTN) is inconsistent. In addition, such an association has not been prospectively examined in the general adult population, particularly among young women. Therefore, we designed a cohort study to examine whether green tea consumption increases the risk of HTN in premenopausal women. Methods and results: This prospective cohort study investigated 6633 premenopausal female participants without hypertension, cardiovascular disease, and cancer at the baseline. Green tea consumption was measured at the baseline using a validated food frequency questionnaire. Hypertension was confirmed with the SBP ≥140 mm Hg-1 or with the DBP ≥90 mm Hg-1. Cox proportional hazards regression models were used to examine the association of green tea consumption with incident hypertension. A total of 488 first incident cases of hypertension occurred during 24 957 person-years of follow-up (median follow-up of 4.0 years). After adjustment for potential confounding variables, the multivariable hazard ratios (95% confidence intervals) for incident hypertension in premenopausal female participants with different green tea consumption frequencies were 1.00 (reference) for almost never, 0.84 (0.67, 1.07) for 1 cup per week, 1.02 (0.77, 1.35) for 2-6 cups per week, and 0.65 (0.44, 0.96) for ≥1 cup per day. Conclusions: The results from our prospective study indicate that the consumption of green tea is associated with a reduced risk of HTN in premenopausal women.

Aggregated coordination polymers of Ag+ with a cysteine derivative ligand containing an AIEgen.

We investigated coordination polymers of Ag+ with a cysteine-based thiol ligand designed to contain a tetraphenylethylene AIEgen (L- and D-1). The coordination polymers, forming in a variety of protic and aprotic organic solvents, such as THF, CH3CN and CH3OH, were shown to undergo aggregation in H2O/THF binary solvents at water volume fractions above 50%, where emission was substantially enhanced while the CD profile was reversed, yet the dependence of the CD signal on ee remained S-shaped for the polymers in the aprotic organic solvents THF and CH3CN, in contrast to that in protic solvents CH3OH and C2H5OH.

Potential roles of heparanase in cancer therapy: Current trends and future direction.

Heparanase (HPSE; heparanase-1) is an endo-ß-glucuronidase capable of degrading the carbohydrate moiety of heparan sulfate proteoglycans, thus modulating and facilitating the remodeling of the extracellular matrix and basement membrane. HPSE activity is strongly associated with major human pathological complications, including but not limited to tumor progress and angiogenesis. Several lines of literature have shown that overexpression of HPSE leads to enhanced tumor growth and metastatic transmission, as well as poor prognosis. Gene silencing of HPSE or treatment of tumor with compounds that block HPSE activity are shown to remarkably attenuate tumor progression. Therefore, targeting HPSE is considered as a potential therapeutical strategy for the treatment of cancer. Intriguingly, recent findings disclose that heparanase-2 (HPSE-2), a close homolog of HPSE but lacking enzymatic activity, can also regulate antitumor mechanisms. Given the pleiotropic roles of HPSE, further investigation is in demand to determine the precise mechanism of regulating action of HPSE in different cancer settings. In this review, we first summarize the current understanding of HPSE, such as its structure, subcellular localization, and tissue distribution. Furthermore, we systematically review the pro- and antitumorigenic roles and mechanisms of HPSE in cancer progress. In addition, we delineate HPSE inhibitors that have entered clinical trials and their therapeutic potential.

Soy Food Consumption Is Inversely Associated with Handgrip Strength: Results from the TCLSIH Cohort Study.

Background: Soy foods contain high levels of soy protein or isoflavones, which can stimulate muscle protein synthesis and increase antioxidant capacity, and thus ameliorate muscle strength decline. However, data from epidemiological studies investigating the association of habitual soy food consumption with muscle strength decline among general Chinese adults are limited. Methods: This study included 29,525 participants (mean age: 41.6 years; 16,933 (53.8%) males). Soy food consumption was evaluated using a validated 100-item food frequency questionnaire. Handgrip strength (HGS) was assessed with a hand dynamometer. Analysis of covariance were performed to assess the multivariable-adjusted least square means (LSM) and 95% confidence interval (CI) for HGS. Results: The multiple adjusted LSM (95% CI) of HGS across soy food consumption were 35.5 (34.2, 37.1) kg for <1 time per week, 36.1 (34.6, 37.6) kg for 1 time per week, 36.3 (34.8, 37.8) kg for 2−3 times per week, and 36.6 (35.1, 38.0) kg for ≥4 times per week (p for trend < 0.001). Compared to participants with soy food consumption less than one time per week, the multiple adjusted odds ratio (95% CI) of low HGS was 0.638 (0.485, 0.836) when the weekly consumption was ≥ 4 times (p for trend < 0.01). Conclusions: Higher habitual soy food consumption was positively associated with HGS in general Chinese adults. Consumption of soy foods may have beneficial effects on muscle health.

Utilizing network pharmacological analysis to investigate the key targets and mechanisms of kaempferol against oxaliplatin-induced neurotoxicity.

This study investigated the pharmacological mechanism of kaempferol in the treatment of oxaliplatin-induced neuropathic pain by network pharmacological method and cells experiment. The kaempferol and disease target genes were obtained from several databases, including TCMSP, SwissTargetPrediction, GeneCards, and CTD. Then, the common target genes of drugs and diseases were obtained using Venny online tools. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses were carried out to obtain the enriched molecular pathways associated with the kaempferol and disease. Finally, we constructed a neuropathic pain cell experiment to confirm the findings. 138 intersection targets were identified between targets of kaempferol and oxaliplatin-induced neurotoxicity. Enrichment analyses revealed that the IL-17 signaling pathway was associated with the therapeutic effects of kaempferol. Kaempferol down-regulated the mRNA expression levels of TNF-α, IL-6, and CCL2 in oxaliplatin-treated astrocytes. Our findings showed that kaempferol alleviated oxaliplatin-induced neurotoxicity via regulation of inflammation-related genes.

Formation of professor Mao Xiejun's thoughts on stomatological education / 中华口腔医学杂志

Professor Mao Xiejun wrote a report about dental education of China in 1935. From 1948 to 1950, he published three articles containing the educational idea of "developing dentistry into stomatology". When he served as the director of the Faculty of Dentistry of Peking University Medical School in July 1950, he proposed to rename the Faculty of Dentistry into the Faculty of Stomatology,which were approved by the Ministry of Health and the Ministry of Education of the People's Republic of China in one month. The Chinese Medical Association established the Society of Stomatology the next year. Later, dentistry was successively changed into stomatology, and medical content was integrated into dental education, which was of great significance and far-reaching influence. During the developments of the thought of stomatological education in China, Professor Mao Xiejun evidently played a pivotal role. In this paper, the formation process of the thoughts of stomatological education related to professor Mao Xiejun's contribution is elucidated through studying the archives, personal letters, and historical documents, so as to enrich the researches on the history of stomatology in China and to facilitate better understanding and promoting the development of stomatology.