Combination Therapy with a TLR7 Agonist and a BRD4 Inhibitor Suppresses Tumor Growth via Enhanced Immunomodulation.

JQ-1 is a typical BRD4 inhibitor with the ability to directly fight tumor cells and evoke antitumor immunity via reducing the expression of PD-L1. However, problems arise with the development of JQ-1 in clinical trials, such as marked lymphoid and hematopoietic toxicity, leading to the investigation of combination therapy. SZU-101 is a TLR7 agonist designed and synthesized by our group with potent immunostimulatory activity. Therefore, we hypothesized that combination therapy of SZU-101 and JQ-1 would target innate immunity and adaptive immunity simultaneously, to achieve a better antitumor efficacy than monotherapy. In this study, the repressive effects of the combination administration on tumor growth and metastasis were demonstrated in both murine breast cancer and melanoma models. In 4T1 tumor-bearing mice, i.t. treatment with SZU-101 in combination with i.p. treatment with JQ-1 suppressed the growth of tumors at both injected and uninjected sites. Combination therapy increased M1/M2 ratio in TAMs, decreased PD-L1 expression and promoted the recruitment of activated CD8+ T cells in the TME. In summary, the improved therapeutic efficacy of the novel combination therapy appears to be feasible for the treatment of a diversity of cancers.

Safety and efficacy of melatonin supplementation as an add-on treatment for infantile epileptic spasms syndrome: A randomized, placebo-controlled, double-blind trial.

This was a prospective, randomized, double-blind, single-center placebo-controlled trial to assess the efficacy and safety of melatonin as an add-on treatment for infantile epileptic spasms syndrome (IESS). Participants aged 3 months to 2 years with a primary diagnosis of IESS were recruited and assigned to two groups in a 1:1 ratio. Both treatment groups received a combination of adrenocorticotrophic hormone (ACTH) and magnesium sulfate (MgSO4 ) for 2 weeks, and the treatment group also received melatonin (3 mg) between 20:00 and 21:00 daily, 0.5-1 h before bedtime. The study's primary endpoint was the average reduction rate in spasm frequency assessed by seizure diaries. Secondary endpoints included assessment of the response rate, EEG hypsarrhythmia (Kramer score), and psychomotor development (Denver Developmental Screening Test, DDST). Sleep quality was assessed by using the Brief Infant Sleep Questionnaire (BISQ), the Infant Sleep Assessment Scale (ISAS), and actigraphy. Safety parameters were also evaluated. Statistical analyses were conducted on intention-to-treat and per-protocol populations. The trial is registered at Clinicaltrials.gov (ChiCTR2000036208). Out of 119 screened patients, 70 were randomized and 66 completed treatments. In the intention-to-treat population, there were no significant differences in the average percentage reduction of spasm frequency (median [interquartile range, IQR: Q3-Q1], 100% [46.7%] vs. 66.7% [55.3%], p = .288), the 3-day response rate (51.4% vs. 37.1%, p = .229), the 28-day response rate (42.9% vs. 28.6%, p = .212), EEG Kramer scores (2 [3.5] vs. 2 [3], p = .853), or DDST comprehensive months (5 [2.5] vs. 6 [6], p = .239) between the melatonin (n = 35) and placebo (n = 35) groups. However, caregivers reported improved sleep quality after melatonin treatment, with 85.7% reporting regular sleep compared to 42.9% with placebo (42.9%, p < .001). The melatonin group had lower ISAS scores in 4-11-month-old patients compared to the placebo (mean ± SD, 29.3 ± 4.4 vs. 35.2 ± 5.9, p < .001). Moreover, the median (IQR) value of sleep-onset latency was shortened by 6.0 (24.5) min after melatonin treatment, while that in the placebo group was extended by 3.0 (22.0) min (p = .030). The serum melatonin (6:00 h) level (pg/mL) of the children in the melatonin group after treatment was significantly higher than in the placebo group (median [IQR], 84.8 [142] vs. 17.5 [37.6], p < .001). No adverse effects related to melatonin were observed in the study, and there were no significant differences in adverse effects between the melatonin and placebo groups. Although not statistically significant, the results of this randomized clinical trial proved that melatonin supplementation, as an add-on treatment, can improve spasm control rate in the treatment of IESS. For IESS children treated with ACTH, the addition of melatonin was found to improve sleep quality, shorten sleep onset latency, and increase blood melatonin levels. Moreover, it was observed to be a safe treatment option.

Managing mineral phosphorus application with soil residual phosphorus reuse in Canada.

With limited phosphorus (P) supplies, increasing P demand, and issues with P runoff and pollution, developing an ability to reuse the large amounts of residual P stored in agricultural soils is increasingly important. In this study, we investigated the potential for residual soil P to maintain crop yields while reducing P applications and losses in Canada. Using a P cycling model coupled with a soil P dynamics model, we analyzed soil P dynamics over 110 years across Canada's provinces. We found that using soil residual P may reduce mineral P demand as large as 132 Gg P year-1 (29%) in Canada, with the highest potential for reducing P applications in the Atlantic provinces, Quebec, Ontario, and British Columbia. Using residual soil P would result in a 21% increase in Canada's cropland P use efficiency. We expected that the Atlantic provinces and Quebec would have the greatest runoff P loss reduction with use of residual soil P, with the average P loss rate decreasing from 4.24 and 1.69 kg ha-1 to 3.45 and 1.38 kg ha-1 , respectively. Ontario, Manitoba, and British Columbia would experience relatively lower reductions in P loss through use of residual soil P, with the average runoff P loss rate decreasing from 0.44, 0.36, and 4.33 kg ha-1 to 0.19, 0.26, and 4.14 kg ha-1 , respectively. Our study highlights the importance of considering residual soil P as a valuable resource and its potential for reducing P pollution.

Hepatoprotective Effect of Medicine Food Homology Flower Saffron against CCl4-Induced Liver Fibrosis in Mice via the Akt/HIF-1α/VEGF Signaling Pathway.

Liver fibrosis refers to a complex inflammatory response caused by multiple factors, which is a known cause of liver cirrhosis and even liver cancer. As a valuable medicine food homology herb, saffron has been widely used in the world. Saffron is commonly used in liver-related diseases and has rich therapeutic and health benefits. The therapeutic effect is satisfactory, but its mechanism is still unclear. In order to clarify these problems, we planned to determine the pharmacological effects and mechanisms of saffron extract in preventing and treating liver fibrosis through network pharmacology analysis combined with in vivo validation experiments. Through UPLC-Q-Exactive-MS analysis, a total of fifty-six nutrients and active ingredients were identified, and nine of them were screened to predict their therapeutic targets for liver fibrosis. Then, network pharmacology analysis was applied to identify 321 targets for saffron extract to alleviate liver fibrosis. Functional and pathway enrichment analysis showed that the putative targets of saffron for the treatment of hepatic fibrosis are mainly involved in the calcium signaling pathway, the HIF-1 signaling pathway, endocrine resistance, the PI3K/Akt signaling pathway, lipid and atherosclerosis, and the cAMP signaling pathway. Based on the CCl4-induced liver fibrosis mice model, we experimentally confirmed that saffron extract can alleviate the severity and pathological changes during the progression of liver fibrosis. RT-PCR and Western blotting analysis confirmed that saffron treatment can prevent the CCl4-induced upregulation of HIF-1α, VEGFA, AKT, and PI3K, suggesting that saffron may regulate AKT/HIF-1α/VEGF and alleviate liver fibrosis.

Evaluating the effect of body mass index and 25-hydroxy-vitamin D level on basal cell carcinoma using Mendelian randomization.

Basal cell carcinoma (BCC) is the most common cancer with a rising incidence among white-skinned individuals. A number of epidemiological studies have suggested that obesity and serum 25-hydroxy-vitamin D (25(OH)D) levels may affect the arising of BCC. To address this, we selected 443 and 96 single nucleotide polymorphisms (SNPs) associated with body mass index (BMI) and serum level of 25(OH)D from large-scale genome-wide association studies (GWAS), respectively. The univariable and multivariable two-sample Mendelian randomization (MR) analyses were conducted with a series of sensitivity analyses to ensure the results were reliable and reproducible. The results of univariable two-sample MR analysis showed that higher BMI was related to lower risk for BCC (Odds ratio(OR) = 0.90; 95% confidence interval (CI),[0.81,0.99]; p = 0.02). In addition, this causal effect of BMI on BCC still remained (OR = 0.88; 95%CI,[- 0.22, - 0.03], p-value = 0.008) after adjusting for 25(OH)D level in the multivariable MR analysis. However, the results suggested that 25(OH)D level was not associated with BCC(OR = 1.02; 95%CI, [0.94,1.09], p-value = 0.67). In conclusion, similar to the conclusions of retrospective observational studies, the MR results indicate that high BMI is an independent protective factor for BCC. Meanwhile, vitamin D levels may not be causally associated with the risk of basal cell carcinoma and increasing vitamin D supplementation is unlikely to reduce the risk.

Reconstituting Low-Density Lipoprotein with NIR-Absorbing Organic Photothermal Agents for Targeted Killing of Cancer Cells.

Photothermal therapy (PTT) systems typically do not possess intrinsic tumor-targeting capability, resulting in indiscriminate thermal damage to both cancer and normal cells. Herein, a low-density lipoprotein (LDL)-based nanosystem (denoted as MTTQ@LDL) is reported for targeted photothermal killing of cancer cells. Such a nanosystem is fabricated by reconstituting the lipophilic core of LDL with an organic photothermal agent MTTQ. The reconstitution process improves the supramolecular photothermal effects of MTTQ assemblies, which contributes to the significantly enhanced photothermal conversion efficiency (41.3% vs. 16.2%). MTTQ@LDL can actively target LDL receptor-overexpressed cancer cells via receptor-mediated endocytosis, enabling the selective killing of cancer cells over normal cells (98% vs. 7%) post-NIR irradiation. Reconstituted LDL can serve as a promising platform for targeted delivery of functional materials, holding great promise in tumor eradication in vivo.

Analysis of LncRNA43234-Associated ceRNA Network Reveals Oil Metabolism in Soybean.

Soybean [Glycine max (Linn.) Merr.] is an important oil crop. Long noncoding RNAs (lncRNAs) play a variety of functions in plants. However, their function in the soybean oil synthesis pathway is yet to be uncovered. Here, the lncRNA43234 gene related to soybean oil synthesis was screened, and the full-length cDNA sequence of the lncRNA was obtained using rapid amplification of cDNA ends. Overexpression of lncRNA43234 increased the content of crude protein in seeds, decreased the content of oleic acid, and affected the content of alanine and arginine in free amino acids. RNA interference of the lncRNA43234 gene decreased the crude protein content in seeds. Quantitative real-time polymerase chain reaction analysis revealed that lncRNA43234 influenced the expression of XM_014775786.1 associated with phosphatidylinositol metabolism by acting as a decoy for miRNA10420, thereby affecting the content of soybean oil. Our results provide insights into how lncRNA-mediated competing endogenous RNA regulatory networks are involved in soybean oil synthesis.

A Portable Nucleic Acid Sensor Based on PCR for Simple, Rapid, and Sensitive Testing of Botrytis cinerea in Ginseng.

Botrytis cinerea is a ubiquitous pathogen that can infect at least 200 dicotyledonous plant species including many agriculturally and economically important crops. In Ginseng, the fungus may cause ginseng gray mold disease, causing great economic losses in the ginseng industry. Therefore, the early detection of B. cinerea in the process of ginseng production is necessary for the disease prevention and control of the pathogen's spread. In this study, a polymerase chain reaction-nucleic acid sensor (PCR-NAS) rapid detection technique was established, and it can be used for field detection of B. cinerea through antipollution design and portable integration. The present study showed that the sensitivity of PCR-NAS technology is 10 times higher than that of traditional PCR-electrophoresis, and there is no need for expensive detection equipment or professional technicians. The detection results of nucleic acid sensors can be read by the naked eye in under 3 min. Meanwhile, the technique has high specificity for the detection of B. cinerea. The testing of 50 field samples showed that the detection results of PCR-NAS were consistent with those of the real-time quantitative PCR (qPCR) method. The PCR-NAS technique established in this study can be used as a novel nucleic acid field detection technique, and it has a potential application in the field detection of B. cinerea to achieve early warning of the pathogen infection.

Bioaugmentation with Tetrasphaera to improve biological phosphorus removal from anaerobic digestate of swine wastewater.

Tetrasphaera-enhanced biological phosphorus removal (T-EBPR) was developed by augmenting conventional EBPR (C-EBPR) with Tetrasphaera to improve phosphorus removal from anaerobic digestate of swine wastewater. At influent total phosphorus (TP) concentrations of 45-55 mg/L, T-EBPR achieved effluent TP concentration of 4.17 ± 1.02 mg/L, 54 % lower than that in C-EBPR (8.98 ± 0.76 mg/L). The enhanced phosphorous removal was presumably due to the synergistic effect of Candidatus Accumulibacter and Tetrasphaera occupying different ecological niches. Bioaugmentation with Tetrasphaera promoted the polyphosphate accumulation metabolism depending more on the glycolysis pathway, as evidenced by an increase in intracellular storage compounds of glycogen and polyhydroxyalkanoates by 0.87 and 0.34 mmol C/L, respectively. The enhanced intracellular storage capacity was coincidentally linked to the increase in phosphorus release and uptake rates by 1.23 and 1.01 times, respectively. These results suggest bioaugmentation with Tetrasphaera could be an efficient way for improved phosphorus removal from high-strength wastewater.

Compound K is a potential clinical anticancer agent in prostate cancer by arresting cell cycle.

BACKGROUND: Ginsenosides, phenolic compounds, and polysaccharides are the bioactive constituents of Panax ginseng Meyer. Compound K (CK) is a secondary ginsenoside with better bioavailability. It is also a promising anticancer agent. PURPOSE: We aimed to evaluate the effect of CK on prostate cancer (PCa) and its potential mechanisms. STUDY DESIGN: The proliferation, migration and cell cycle of PCa cells after CK treatment were assessed in various PCa cell lines. Docetaxel was used as a positive control drug. Unlike other published studies, the potential mechanisms of CK (50 µM) were investigated by an unbiased global transcriptome sequencing in the current study. METHODS: Key CK related genes (CRGs) with prognostic significance were identified and verified by bioinformatic methods using data from the TCGA dataset and GSE21034 dataset. The role of CDK1 in the effect of CK treatment on PCa cells was investigated by overexpression of CDK1. RESULTS: CK inhibited the proliferation and migration of PCa cells at concentrations (less than 25 µM) without obvious cytotoxicity. Five key CRGs with prognostic significance were identified, including CCNA2, CCNB2, CCNE2, CDK1, and PKMYT1, which are involved in cell cycle pathways. CK inhibited the expression of these 5 genes and the cell cycle of PCa cells. According to the results of bioinformatic analysis, the expression of the five key CRGs was strongly associated with poor prognosis and advanced pathological stage and grade of PCa. In addition, CK could restore androgen sensitivity in castration-resistant PCa cells, probably by inhibiting the expression of CDK1. After CDK1 overexpression, the inhibition of proliferation and migration of PCa cells by CK was decreased. The inhibition on the phosphorylation of AKT by CK was also reduced. CONCLUSION: CK can inhibit PCa cells, and the mechanisms may be associated with the inhibition of cell cycle pathways through CDK1. CK is also a potential clinical anticancer agent for treating PCa.

Paeonol ameliorates diabetic erectile dysfunction by inhibiting HMGB1/RAGE/NF-kB pathway.

BACKGROUND: The management of diabetes mellitus-induced erectile dysfunction (DMED) is progressively becoming tricky due to the surge in the number of patients and the poor efficiency of phosphodiesterase type 5 inhibitors in DMED. Paeonol (Pae), as a traditional Chinese medicine, has been more and more widely used in the treatment of diabetic complications. However, whether Pae could be a potential therapeutic drug of DMED needs to be further evaluated. OBJECTIVES: To investigate the pharmacological effect and possible mechanism of Pae in the treatment of DMED. METHODS: Intraperitoneal streptozotocin injection and an apomorphine test were used to construct the model of DMED. Seventeen DMED rats were divided into two groups: DMED group (n = 8) and DMED+Pae group (Pae; 100 mg/kg/d; oral administration; n = 9). In addition, there were still 10 normal age-matched male rats as control group. Four weeks later, the cavernous nerve electric stimulation was carried out to measure the erectile response. Moreover, the corpus cavernosum smooth muscle cells (CCSMCs) were primarily isolated and exposed to high glucose (HG) stimulation, Pae treatment and glycyrrhizin (GL; the selective inhibitor of HMGB1). After an incubation for 1 week, the CCSMCs were harvested for detection. RESULTS: The impairment of erectile function was observed in DMED rats compared with control samples, accompanied by the upregulation of HMGB1/RAGE/NF-κB Pathway. The lower nitric oxide and cGMP level and the higher level of inflammation, fibrosis, and apoptosis were also observed in DMED rats. It showed contrast that Pae treatment could improve the erectile function, as well as histologic alteration and related molecular changes. In addition, Pae could downregulate the HMGB1/RAGE/NF-κB pathway to regulate the apoptosis and inflammation levels of CCSMCs in high-glucose conditions, which is similar to the results of GL treatment. CONCLUSION: Pae alleviated ED in DMED rats, likely by inhibiting HMGB1/RAGE/NF-κB Pathway, inflammatory, apoptosis, and fibrotic activity, and moderating endothelial dysfunction. Our study provide evidence for a potential new therapy for DMED.

Lonicera caerulea (Haskap berries): a review of development traceability, functional value, product development status, future opportunities, and challenges.

Lonicera caerulea is a honeysuckle plant with a long development history. It is defined as a "homology of medicine and food" fruit because it is rich in bioactive substances. By-products (such as pomace, leaves, stems, and flowers), which also have beneficial values, will be produced during processing. Nevertheless, the reuse of derivatives and the further development of new products of Lonicera caerulea are still a challenge. Firstly, this paper traced the development history of Lonicera caerulea and summarized its primary nutrients and bioactive substances, subsequently discussed the research progress and underlying molecular mechanisms of its functional properties, and introduced the application and potential of Lonicera caerulea in the fields of food, health products, cosmetics, medicine, and materials. Finally, this paper put forward the future research direction to promote the development of the Lonicera caerulea industry. To sum up, Lonicera caerulea, as a potential raw material, can be used to produce more functional products. Besides, more in-depth clinical trials are needed to clarify the specific molecular mechanism of the practical components of Lonicera caerulea and improve the rate of development and utilization.HighlightsThe original species of Lonicera caerulea subgroup had appeared on the earth as early as the end of the third century.Lonicera caerulea has been introduced into North America since the 18th century, but the introduction process has not ended until now.Lonicera caerulea widely exists in Eurasia and North America and it has excellent cold tolerance, early maturity and ornamental.The fruits, stems, leaves and flowers of Lonicera caerulea all have bioactive value, but the specific molecular mechanism and utilization need to be improved.Lonicera caerulea has been widely used in food, medicine, health products, cosmetics and materials, but there are still great challenges.

Lysine promotes proliferation and ß-casein synthesis through the SLC6A14-ERK1/2-CDK1-mTOR signaling pathway in bovine primary mammary epithelial cells.

Lysine, as the first limiting amino acid in dairy cows, has been shown to play an important role in milk synthesis and cell proliferation. However, the underlying mechanism remains unclear. In this study, we isolated bovine primary mammary epithelial cells (BMECs) and studied the mechanism in which lysine promotes cell proliferation and ß-casein synthesis through overexpression and knockdown of CDK1 and supplements BCH, U0126, and rapamycin in BMECs. Results show that 0.7 mM lysine can significantly promote cell proliferation and the synthesis of ß-casein in BMECs. In addition, lysine activates the ERK signaling pathway to promote the expression of CDK1. Further studies have shown that CDK1 can promote cell proliferation and the synthesis of ß-casein through the mTOR signaling pathway in BMECs. Lastly, lysine can promote cell proliferation and the synthesis of ß-casein through SLC6A14 in BMECs. The above results indicate that lysine promotes cell proliferation and the synthesis of ß-casein through the SLC6A14-ERK-CDK1-mTOR signaling pathway in BMECs.

External treatment of traditional Chinese medicine for functional dyspepsia in children: Protocol for a systematic review and network meta-analysis.

BACKGROUND: Functional dyspepsia (FD) is a common digestive system disease in pediatrics, usually affects normal growth and increases health care expenditure. Many investigations have demonstrated that external treatment of traditional Chinese medicine (TCM) has certain advantages in the treatment of FD children, but the effectiveness, safety, and advantages of various methods have not been confirmed by high-quality meta-analyses. This study will conduct a systematic review and network meta-analysis to evaluate the differences and effectiveness in external treatments of TCM, in order to provide a reference for further clinical treatment for FD in children. METHODS: Nine electronic databases, including PubMed, Medline, Embase, Web of Science, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Chinese Scientific Journal Database, Wan-Fang Database and one clinical trial register platforms: ClinicalTrials.gov (www.ClinicalTrials.gov/) will be searched using English and Chinese search strategies. All eligible studies are randomized controlled trials of TCM external treatment for FD in children, published on or before July 20, 2022. The screening process will be developed by 2 independent authors, and network meta-analysis will be performed with RevMan (V5.3) software. RESULTS: This study will provide a high-quality synthesis to assess the effectiveness and safety on the external treatment of TCM for children with FD. CONCLUSION: The results of this study will provide evidence to judge whether the external treatment of TCM are effective interventions for children with FD. ETHICS AND DISSEMINATION: The results of this meta-analysis and meta-regression will be disseminated through publication in a peer-reviewed journal and presented at a relevant conference. The information used in the network meta-analysis does not contain individual patient data. Therefore, ethical approval was not required. PROSPERO REGISTRATION NUMBER: CRD42022360429.

GPX4 Alleviates Diabetes Mellitus-Induced Erectile Dysfunction by Inhibiting Ferroptosis.

Pharmacological therapy of diabetes mellitus-induced erectile dysfunction (DMED) is intractable owig to the poor response to phosphodiesterase type 5 inhibitors (PDE5i). The surge in the number of diabetic patients makes it extremely urgent to find a novel therapy for DMED. Ferroptosis is a recently discovered form of cell death evoked by lipid peroxidation and is related to several diabetic complications. GPX4, an important phospholipid hydroperoxidase, can alleviate ferroptosis and maintain redox balance via reducing lipid peroxides. However, whether GPX4 can be a prospective target of DMED needs to be determined. Fifty rats were randomly divided into control group, DMED group, DMED + negative control group (DMED + NC group), DMED + low-dose group (1 × 106 infectious units), and DMED + high-dose group (2 × 106 infectious units). Erectile function was assessed 4 weeks after intracavernous injection of GPX4 or negative control lentivirus. The penile shafts were collected for subsequent molecular biological and histological analysis. The results demonstrated that erectile function of the rats in DMED and DMED + NC groups was extremely impaired and was improved in a dose-dependent manner with GPX4 lentivirus (GPX4-LV) injection. Additionally, upregulation of the ACSL4-LPCAT3-LOX pathway, iron overload, oxidative stress, fibrosis, and decreased endothelial and smooth muscle cell numbers were observed in the corpus cavernosum of DMED group. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway was inhibited, and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was promoted in DMED rats. The above histologic alterations and related molecular changes were alleviated after GPX4-LV injection. The results revealed that GPX4 improved erectile function by modulating ferroptosis during DMED progression. This finding is of paramount significance in deciphering the molecular mechanism of hyperglycemia-induced ferroptosis, thereby providing a prospective target for preventing the development of DMED.

A Smart Photothermal Nanosystem with an Intrinsic Temperature-Control Mechanism for Thermostatic Treatment of Bacterial Infections.

Photothermal therapy (PTT) has attracted extensive attention in disease treatments. However, conventional photothermal systems do not possess a temperature-control mechanism, which poses a serious risk to healthy tissues and/or organs due to inevitable thermal damage. Herein, a smart photothermal nanosystem with an intrinsic temperature-control mechanism for thermostatic treatment of bacterial infections is reported. The smart photothermal nanosystem is constructed by loading a thermochromic material into a hollow-structured silica nanocarrier, in which the thermochromic material is composed of naturally occurring phase-change materials (PCMs), a proton-responsive spirolactone, and a proton source. The resulting nanosystem shows strong near-infrared (NIR) absorption and efficient photothermal conversion in solid PCMs but becomes NIR-transparent when PCMs are melted upon NIR irradiation. Such an attractive feature can precisely regulate the photothermal equilibrium temperature to the melting point of PCMs, regardless of the variation in external experimental parameters. In contrast to conventional PTT with severe thermal damage, the reported smart photothermal nanosystem provides an internal protection mechanism on healthy tissues and/or organs, which remarkably accelerates the recovery of bacteria-infected wounds. The smart photothermal nanosystem is a versatile PTT platform, holding great promise in the safe and efficient treatment of bacterial infections and multimodality synergistic therapy.

Ciclopirox targets cellular bioenergetics and activates ER stress to induce apoptosis in non-small cell lung cancer cells.

BACKGROUND: Lung cancer remains a major cause of cancer-related mortality throughout the world at present. Repositioning of existing drugs for other diseases is a promising strategy for cancer therapies, which may rapidly advance potentially promising agents into clinical trials and cut down the cost of drug development. Ciclopirox (CPX), an iron chelator commonly used to treat fungal infections, which has recently been shown to have antitumor activity against a variety of cancers including both solid tumors and hematological malignancies in vitro and in vivo. However, the effect of CPX on non-small cell lung cancer (NSCLC) and the underlying mechanism is still unclear. METHODS: CCK-8, clonal formation test and cell cycle detection were used to observe the effect of inhibitor on the proliferation ability of NSCLC cells. The effects of CPX on the metastasis ability of NSCLC cells were analyzed by Transwell assays. Apoptosis assay was used to observe the level of cells apoptosis. The role of CPX in energy metabolism of NSCLC cells was investigated by reactive oxygen species (ROS) detection, glucose uptake, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) experiments. Western blot was used to examine the protein changes. RESULTS: We report that CPX inhibits NSCLC cell migration and invasion abilities through inhibiting the epithelial-mesenchymal transition, impairing cellular bioenergetics, and promoting reactive oxygen species to activate endoplasmic reticulum (ER) stress-induced apoptotic cell death. Moreover, CPX intraperitoneal injection can significantly inhibit NSCLC growth in vivo in a xenograft model. CONCLUSIONS: Our study revealed that CPX targets cellular bioenergetics and activates unfolded protein response in ER to drive apoptosis in NSCLC cells, indicating that CPX may be a potential therapeutic drug for the treatment of NSCLC. Video Abstract.

Serum Metabolomics Analysis for Biomarkers of Lactobacillus plantarum FRT4 in High-Fat Diet-Induced Obese Mice.

Lactobacillus plantarum is considered a potential probiotic supplementation for treating obesity. However, the underlying molecular mechanism is poorly understood. Our previous study displayed that L. plantarum FRT4 alleviated obesity in mice fed a high-fat diet (HFD) through ameliorating the HFD-induced gut microbiota dysbiosis. To explore the roles of FRT4 in obesity prevention, in this study, we investigated changes in serum metabolomic phenotype by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) and analyzed the pathway of HFD-fed Kunming female mice orally administered with FRT4 for eight weeks. Using orthogonal partial least squares discriminant analysis (OPLS-DA), metabolite patterns with significant changes were observed. 55 metabolites including phosphatidylcholine, lysophophatidylcholine, sphingomyelin, serotonin, indole-3-methyl aceta, indole-3-carbinol, indole-5,6-quino, 11,12-DHET, prostaglandin B2, leukotriene B4, and 3-hydroxybenzoic acid were identified as potential biomarkers associated with obesity, which were mainly involving in glycerophospholipid metabolism, tryptophan metabolism, and arachidonic acid metabolism. Perturbations of 14 biomarkers could be regulated by FRT4 intervention. These metabolites may serve as valuable biomarkers to understand the mechanisms by which intake of diets containing FRT4 contributes to the treatment or prevention of obesity. Thus, FRT4 can be a promising dietary supplement for the prevention of HFD-induced obesity.

Two new ent-kaurane glucosides from the fruits of Xanthium strumarium subsp. sibiricum.

The chemical investigation of the fruits of Xanthium strumarium (Asteraceae) led to the isolation of two new ent-kauranoid glucosides named 2-O-(6-O-isocaleryl-ß-D-glucopyranosyl) atractyligenin (1) and 2-O-(2-O-isovaleryl-ß-D-glucopyranosyl) atractyligenin (2), together with one known compound. Their structures were established by comprehensive spectroscopic analysis coupled with single-crystal X-ray diffraction and electronic circular dichroism data. All compounds and their aglycone were evaluated for their anti-proliferative activities in vitro against three human cancer cell lines.

A Sensitive and Reliable Organic Fluorescent Nanothermometer for Noninvasive Temperature Sensing.

Sensing temperature at the subcellular level is of great importance for the understanding of miscellaneous biological processes. However, the development of sensitive and reliable organic fluorescent nanothermometers remains challenging. In this study, we report the fabrication of a novel organic fluorescent nanothermometer and study its application in temperature sensing. First of all, we synthesize a dual-responsive organic luminogen that can respond to the molecular state of aggregation and environmental polarity. Next, natural saturated fatty acids with sharp melting points as well as reversible and rapid phase transition are employed as the encapsulation matrix to correlate external heat information with the fluorescence properties of the luminogen. To apply the composite materials for biological application, we formulate them into colloidally dispersed nanoparticles by a technique that combines in situ surface polymerization and nanoprecipitation. As anticipated, the resultant zwitterionic nanothermometer exhibits sensitive, reversible, reliable, and multiparametric responses to temperature variation within a narrow range around the physiological temperature (i.e., 37 °C). Taking spectral position, fluorescence intensity, and fluorescence lifetime as the correlation parameters, the maximum relative thermal sensitivities are determined to be 2.15% °C-1, 17.06% °C-1, and 17.72% °C-1, respectively, which are much higher than most fluorescent nanothermometers. Furthermore, we achieve the multimodal temperature sensing of bacterial biofilms using these three complementary fluorescence parameters. Besides, we also fabricate a cationic form of the nanothermometer to facilitate efficient cellular uptake, holding great promise for studying thermal behaviors in biological systems.