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Bone cancer pain is a common symptom in cancer patients with bone metastases and the underlying mechanisms are largely unknown. The aim of this study is to explore the endogenous analgesic mechanisms to develop new therapeutic strategies for bone‐cancer induced pain (BCIP) as a result of metastases. MRMT‐1 tumor cells were injected into bilateral tibia of rats and X‐rays showed that the area suffered from bone destruction, accompanied by an increase in osteoclast numbers. In addition, rats with bone cancer showed apparent mechanical and thermal hyperalgesia at day 28 after intratibial MRMT‐1 inoculation. However, intrathecal injection of morphine or lentivirus‐mediated glial cell line‐derived neurotrophic factor RNAi (Lvs‐siGDNF) significantly attenuated mechanical and thermal hyperalgesia, as shown by increases in paw withdrawal thresholds and tail‐flick latencies, respectively. Furthermore, Lvs‐siGDNF interference not only substantially downregulated GDNF protein levels, but also reduced substance P immunoreactivity and downregulated the ratio of pERK/ERK, where its activation is crucial for pain signaling, in the spinal dorsal horn of this model of bone‐cancer induced pain. In this study, Lvs‐siGDNF gene therapy appeared to be a beneficial method for the treatment of bone cancer pain. As the effect of Lvs‐siGDNF to relieve pain was similar to morphine, but it is not a narcotic, the use of GDNF RNA interference may be considered as a new therapeutic strategy for the treatment of bone cancer pain in the future. The aim of this study is to explore the endogenous analgesic mechanisms to develop new therapeutic strategy for bone cancer pain induced by metastases. The effect of Lvs‐siGDNF to relief pain was similar the effect from morphine administration. GDNF RNAi therefor might be considered as a new therapeutic strategy for bone cancer pain treatment in the future.

Skeletal muscle and thermogenic adipose tissue are both critical for the maintenance of body temperature in mammals. However, whether these two tissues are interconnected to modulate thermogenesis and metabolic homeostasis in response to thermal stress remains inconclusive. Here, we report that human and mouse obesity is associated with elevated Musclin levels in both muscle and circulation. Intriguingly, muscle expression of Musclin is markedly increased or decreased when the male mice are housed in thermoneutral or chronic cool conditions, respectively. Beige fat is then identified as the primary site of Musclin action. Muscle-transgenic or AAV-mediated overexpression of Musclin attenuates beige fat thermogenesis, thereby exacerbating diet-induced obesity and metabolic disorders in male mice. Conversely, Musclin inactivation by muscle-specific ablation or neutralizing antibody treatment promotes beige fat thermogenesis and improves metabolic homeostasis in male mice. Mechanistically, Musclin binds to transferrin receptor 1 (Tfr1) and antagonizes Tfr1-mediated cAMP/PKA-dependent thermogenic induction in beige adipocytes. This work defines the temperature-sensitive myokine Musclin as a negative regulator of adipose thermogenesis that exacerbates the deterioration of metabolic health in obese male mice and thus provides a framework for the therapeutic targeting of this endocrine pathway. Interorgan communications play key roles in the regulation of whole-body energy metabolism. Here, the authors report the myokine Musclin as a negative regulator of beige adipose thermogenesis and systemic energy homeostasis through Tfr1/PKA signalling mediated muscle fat crosstalk.

Background During tumor formation and expansion, increasing glucose metabolism is necessary for unrestricted growth of tumor cells. Expression of key glycolytic enzyme alpha-enolase (ENO1) is controversial and its modulatory mechanisms are still unclear in non-small cell lung cancer (NSCLC). Methods The expression of ENO1 was examined in NSCLC and non-cancerous lung tissues, NSCLC cell lines, and immortalized human bronchial epithelial cell (HBE) by quantitative real-time reverse transcription PCR (qRT-PCR), immunohistochemistry, and Western blot, respectively. The effects and modulatory mechanisms of ENO1 on cell glycolysis, growth, migration, invasion, and in vivo tumorigenesis and metastasis in nude mice were also analyzed. Results ENO1 expression was increased in NSCLC tissues in comparison to non-cancerous lung tissues. Similarly, NSCLC cell lines A549 and SPCA-1 also express higher ENO1 than HBE cell line in both mRNA and protein levels. Overexpressed ENO1 significantly elevated NSCLC cell glycolysis, proliferation, clone formation, migration, and invasion in vitro , as well as tumorigenesis and metastasis in vivo by regulating the expression of glycolysis, cell cycle, and epithelial-mesenchymal transition (EMT)-associated genes. Conversely, ENO1 knockdown reversed these effects. More importantly, our further study revealed that stably upregulated ENO1 activated FAK/PI3K/AKT and its downstream signals to regulate the glycolysis, cell cycle, and EMT-associated genes. Conclusion This study showed that ENO1 is responsible for NSCLC proliferation and metastasis; thus, ENO1 might serve as a potential molecular therapeutic target for NSCLC treatment.

Four new germacrane sesquiterpene dilactones, 2β-hydroxyl-11β,13-dihydrodeoxymikanolide (1), 3β-hydroxyl-11β,13-dihydrodeoxymikanolide (2), 1α,3β-dihydroxy-4,9-germacradiene-12,8:15,6-diolide (3), and (11β,13-dihydrodeoxymikanolide-13-yl)-adenine (4), together with five known ones (5–9) were isolated from the aerial parts of Mikania micrantha. Their structures were elucidated on the basis of extensive spectroscopic analysis. Compound 4 is featured with an adenine moiety in the molecule, which is the first nitrogen-containing sesquiterpenoid so far isolated from this plant species. These compounds were evaluated for their in vitro antibacterial activity against four Gram-(+) bacteria of Staphyloccocus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), Bacillus cereus (BC) and Curtobacterium. flaccumfaciens (CF), and three Gram-(–) bacteria of Escherichia coli (EC), Salmonella. typhimurium (SA), and Pseudomonas Solanacearum (PS). Compounds 4 and 7–9 were found to show strong in vitro antibacterial activity toward all the tested bacteria with the MIC values ranging from 1.56 to 12.5 µg/mL. Notably, compounds 4 and 9 showed significant antibacterial activity against the drug-resistant bacterium of MRSA with MIC value 6.25 µg/mL, which was close to reference compound vancomycin (MIC 3.125 µg/mL). Compounds 4 and 7–9 were further revealed to show in vitro cytotoxic activity toward human tumor A549, HepG2, MCF-7, and HeLa cell lines, with IC50 values ranging from 8.97 to 27.39 μM. No antibacterial and cytotoxic activity were displayed for the other compounds. The present research provided new data to support that M. micrantha is rich in structurally diverse bioactive compounds worthy of further development for pharmaceutical applications and for crop protection in agricultural fields.

Background: Hemodialysis is often recommended to treat severe lithium poisoning. Nevertheless, the application rate of hemodialysis in patients with lithium poisoning is varied across different groups and the effect of hemodialysis is still undetermined. Therefore, this study aimed to analyze the hemodialysis rate of patients with lithium poisoning and to explore the clinical features of lithium-poisoned-patients treated or untreated with hemodialysis. Methods: Between 2001 and 2019, 36 patients treated at the Chang Gung Memorial Hospital for the management of lithium poisoning were stratified according to whether they were treated with hemodialysis (n = 7) or not (n = 29). Results: The patients were aged 50.7 ± 18.1 years. The poisoning patterns were acute on chronic (61.1%), chronic (25.0%) and acute (13.9%). The precipitating factors of dehydration and infection were noted in 36.1% and 25.0% of patients, respectively. Bipolar disorder (72.2%), depressive disorder (27.8%) and psychotic disorder (11.1%) were the top three psychiatric comorbidities. The hemodialysis group not only had a lower Glasgow Coma Scale (GCS) score (p = 0.001) but also had a higher respiratory failure rate (p = 0.033), aspiration pneumonia rate (p = 0.033) and acute kidney injury network (AKIN) score (p = 0.002) than the non-hemodialysis group. Although none of the patients died of lithium poisoning, the hemodialysis group required more endotracheal intubation (p = 0.033), more intensive care unit admission (p = 0.033) and longer hospitalization (p = 0.007) than the non-hemodialysis group. Conclusion: The analytical results revealed zero mortality rate and low hemodialysis rate (1.9%). Compared with patients without hemodialysis, patients receiving hemodialysis suffered severer lithium-associated complications and needed a more intensive care unit admission and longer hospital stay.

Background Familial hypercholesterolemia (FH) is an inherited disorder mainly marked by increased low-density lipoprotein cholesterol (LDL-C) concentrations and a heightened risk of early-onset arteriosclerotic cardiovascular disease (ASCVD). This study seeks to characterize the genetic spectrum and genotype‒phenotype correlations of FH in Chinese pediatric individuals. Methods Data were gathered from individuals diagnosed with FH either clinically or genetically at multiple hospitals across mainland China from January 2016 to June 2024. Results In total, 140 children and adolescents (mean age of 6.00 years) with clinically and genetically diagnosed FH were enrolled in the study, with 87 distinct variants identified in the LDLR , APOB and PCSK9 genes. Among the variants, 11 variants were newly identified worldwide, with 9 classified as “pathogenic” or “likely pathogenic”, and 2 classified as “variants of uncertain significance”. Additionally, the 5 most common variants in the study were c.1448G > A (p.W483*), c.1879G > A (p.A627T), c.1216C > A (p.R406R), and c.1747C > T (p.H583Y) in the LDLR gene, as well as c.10579C > T (p.R3527W) in the APOB gene, accounting for 49.29% (69/140) of all patients. These variants are primarily observed in the Asian or Chinese population and are distinct from those present in Caucasian groups. In this cohort, 105 patients were diagnosed with heterozygous FH (HeFH), while 35 were diagnosed with homozygous FH (HoFH). Finally, only 28.57% of the patients (40/140) were using lipid-lowering medications with 33.33% of HoFH patients initiating treatment after the age of 8. Additionally, only 3 compound heterozygous patients (2.14%) underwent liver transplantation because of significantly high lipid levels. Conclusion This study reveals the variable genotypes and phenotypes of children with FH in China and illustrates that the genotypes in the Chinese population differ from those in Caucasians, providing a valuable dataset for the clinical genetic screening of FH in China. Furthermore, the older age at diagnosis and treatment highlights the underdiagnosis and undertreatment of Chinese FH pediatric patients, suggesting that early identification should be improved through lipid or genetic screening, and that more timely and regular pharmacological treatments should be implemented.

Skeletal muscle plays a key role in metabolic homeostasis. Brg1/Brm-associated factor (Baf) 60c, a subunit of the mating type switching/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes, was previously identified to be robustly involved in glycolytic muscle function and systemic metabolic balance. However, whether Baf60c regulates the secreted factors and couples the skeletal muscle function to systemic metabolism remains unclear. Here, we uncover that Baf60c regulates the expression of a series of secreted factors, among which Musclin, a recently identified negative regulator of beige adipocyte thermogenesis, was top-ranked in the upregulated factors in Baf60c-deficient muscle. Mechanistically, Baf60c physically interacts with the transcription factor myocyte enhancer factor 2c (Mef2c) and modulates the chromatin accessibility at the proximal promoter regions upstream of the Musclin gene transcription start site (TSS), therefore negatively regulating Musclin gene expression in the skeletal muscle. Further in vivo metabolic assays demonstrate that muscle-specific Baf60c ablation inhibits thermogenesis and elevates blood glucose. Conversely, muscle-specific overexpression of Baf60c increases thermogenesis and energy expenditure and improves systemic glucose metabolism. Together, this work uncovers Baf60c/Mef2c-mediated chromatin remodeling signaling in myocytes that control adipose tissue thermogenesis and systemic metabolism through Musclin-mediated muscle-fat crosstalk.

Four new germacrane sesquiterpene dilactones, 2β-hydroxyl-11β,13-dihydrodeoxymikanolide (1), 3β-hydroxyl-11β,13-dihydrodeoxymikanolide (2), 1α,3β-dihydroxy-4,9-germacradiene-12,8:15,6-diolide (3), and (11β,13-dihydrodeoxymikanolide-13-yl)-adenine (4), together with five known ones (5–9) were isolated from the aerial parts of Mikania micrantha. Their structures were elucidated on the basis of extensive spectroscopic analysis. Compound 4 is featured with an adenine moiety in the molecule, which is the first nitrogen-containing sesquiterpenoid so far isolated from this plant species. These compounds were evaluated for their in vitro antibacterial activity against four Gram-(+) bacteria of Staphyloccocus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), Bacillus cereus (BC) and Curtobacterium. flaccumfaciens (CF), and three Gram-(–) bacteria of Escherichia coli (EC), Salmonella. typhimurium (SA), and Pseudomonas Solanacearum (PS). Compounds 4 and 7–9 were found to show strong in vitro antibacterial activity toward all the tested bacteria with the MIC values ranging from 1.56 to 12.5 µg/mL. Notably, compounds 4 and 9 showed significant antibacterial activity against the drug-resistant bacterium of MRSA with MIC value 6.25 µg/mL, which was close to reference compound vancomycin (MIC 3.125 µg/mL). Compounds 4 and 7–9 were further revealed to show in vitro cytotoxic activity toward human tumor A549, HepG2, MCF-7, and HeLa cell lines, with IC[sub.50] values ranging from 8.97 to 27.39 μM. No antibacterial and cytotoxic activity were displayed for the other compounds. The present research provided new data to support that M. micrantha is rich in structurally diverse bioactive compounds worthy of further development for pharmaceutical applications and for crop protection in agricultural fields.

Familial hypercholesterolemia (FH) is an inherited disorder mainly marked by increased low-density lipoprotein cholesterol (LDL-C) concentrations and a heightened risk of early-onset arteriosclerotic cardiovascular disease (ASCVD). This study seeks to characterize the genetic spectrum and genotype-phenotype correlations of FH in Chinese pediatric individuals. Data were gathered from individuals diagnosed with FH either clinically or genetically at multiple hospitals across mainland China from January 2016 to June 2024. In total, 140 children and adolescents (mean age of 6.00 years) with clinically and genetically diagnosed FH were enrolled in the study, with 87 distinct variants identified in the LDLR, APOB and PCSK9 genes. Among the variants, 11 variants were newly identified worldwide, with 9 classified as \"pathogenic\" or \"likely pathogenic\", and 2 classified as \"variants of uncertain significance\". Additionally, the 5 most common variants in the study were c.1448G > A (p.W483*), c.1879G > A (p.A627T), c.1216C > A (p.R406R), and c.1747C > T (p.H583Y) in the LDLR gene, as well as c.10579C > T (p.R3527W) in the APOB gene, accounting for 49.29% (69/140) of all patients. These variants are primarily observed in the Asian or Chinese population and are distinct from those present in Caucasian groups. In this cohort, 105 patients were diagnosed with heterozygous FH (HeFH), while 35 were diagnosed with homozygous FH (HoFH). Finally, only 28.57% of the patients (40/140) were using lipid-lowering medications with 33.33% of HoFH patients initiating treatment after the age of 8. Additionally, only 3 compound heterozygous patients (2.14%) underwent liver transplantation because of significantly high lipid levels. This study reveals the variable genotypes and phenotypes of children with FH in China and illustrates that the genotypes in the Chinese population differ from those in Caucasians, providing a valuable dataset for the clinical genetic screening of FH in China. Furthermore, the older age at diagnosis and treatment highlights the underdiagnosis and undertreatment of Chinese FH pediatric patients, suggesting that early identification should be improved through lipid or genetic screening, and that more timely and regular pharmacological treatments should be implemented.