Objective To investigate the role of cytochrome P450 2E1 (CYP2E1) in trichloroethylene (TCE)-induced skin sensitization and liver damage in guinea pigs, using diallyl sulfide (DAS), a CYP2E1 inhibitor, as an intervention. Methods Specific pathogen-free female guinea pigs were randomly divided into blank control group, solvent control group, positive control (2,4-dinitrochlorobenzene) group, TCE-exposure group, and DAS-intervention group. Skin sensitization experiments were conducted using the guinea pig TCE maximal dose-skin sensitization test. Urinary trichloroacetic acid levels were determined following TCE induction and challenge. At 48 hours after the final challenge, serum liver function markers and inflammatory cytokines levels were detected. Histopathological examination on skin and liver tissues was performed, and hepatic CYP2E1 protein expression and oxidative stress indicators were assessed. Results The sensitization rates of guinea pigs were 100.0%, 75.0%, and 33.3% in the positive control, TCE-exposure, and DAS-intervention groups, respectively, while the blank control and solvent control groups were both 0.0%. Compared with the guinea pigs in TCE-exposure group, those in the DAS-intervention group had lower urinary trichloroacetic acid levels at intradermal induction, local induction, first challenge, and 24 hours after the final challenge time point (all P<0.05). Histopathology of guinea pigs showed dermal inflammatory infiltration and basal keratinocyte necrosis in the TCE-exposure group, whereas only mild dermal inflammation was observed in the DAS-intervention group. The guinea pigs in TCE-exposure group exhibited diffuse hepatocellular necrosis, while hepatic damage in the DAS-intervention group was alleviated, characterized by only mild hepatocellular steatosis and hepatocyte swelling around the central vein. The skin sensitization rate of guinea pigs in the TCE-exposure group increased (all P<0.01), the serum alanine aminotransferase (ALT )activity, the levels of interleukin (IL)-2, IL-17, and tumor necrosis factor-α (TNF- α) increased (all P<0.05), the relative expression of CYP2E1 protein, the activity of superoxide dismutase (SOD), and the level of malondialdehyde in liver tissue increased (all P<0.05), while the activity of catalase decreased (P<0.05), compared with the blank control and solvent control groups. The serum ALT activity and the levels of IL-2, IL-17, and TNF-α of guinea pigs in DAS-intervention group reduced (all P<0.05), as well as CYP2E1 protein expression, SOD activity, and malondialdehyde level in liver tissue reduced (all P<0.05), compared with the TCE-exposure group. Conclusion TCE can induce hepatic CYP2E1 expression, thereby promoting oxidative stress and inflammatory responses, which contributes to skin sensitization and liver damage. DAS alleviates TCE-induced toxic effects on skin and liver by inhibiting CYP2E1 expression.

RNA-based gene therapy has been widely used for various diseases, and extensive studies have proved that suitable delivery routes greatly help the development of RNA therapeutics. Identifying a safe and effective delivery system is key to realizing RNA therapeutics' clinical translation. Inhalation is a non-invasive pulmonary delivery modality that can enhance the retention of therapeutic agents in the lungs with negligible toxicity, thereby improving patient compliance. Inhaled RNA therapeutics are increasingly becoming an area of focus for researchers; however, only several clinical trials have explored inhaled delivery of RNA for pulmonary diseases. This review presents an overview of recent advances in inhaled delivery systems for RNA therapeutics, including viral and nonviral systems, highlighting state of the art regarding inhalation in the messenger RNA (mRNA) field. We also summarize the applications of mRNA inhalants in infectious and other lung diseases. Simultaneously, the research progresses on small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and different types of RNA are also discussed to provide new strategies for developing RNA inhalation therapy. Finally, we clarify the challenges inhaled RNA-based therapeutics face before their widespread adoption and provide insights to help advance this exciting field to the bedside.

Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.

Triple-negative breast cancer (TNBC) represents an aggressive breast cancer subtype with poor prognosis and limited targeted treatment options. This investigation examined the anti-cancer potential of Caerulomycin A (Cae A), a natural compound derived from marine actinomycetes, against TNBC. Cae A demonstrated selective inhibition of viability and proliferation in TNBC cell lines, including 4T1, MDA-MB-231, and MDA-MB-468, through apoptosis induction. Mechanistic analyses revealed that the compound induced sustained endoplasmic reticulum (ER) stress and subsequent upregulation of C/EBP homologous protein (CHOP) expression, resulting in mitochondrial damage-mediated apoptosis. Inhibition of ER stress or CHOP expression knockdown reversed mitochondrial damage and apoptosis, highlighting the essential role of ER stress and CHOP in Cae A's anti-tumor mechanism. Both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) decreased in TNBC cells following Cae A treatment, indicating reduced mitochondrial respiratory and glycolytic capacities. This diminished energy metabolism potentially triggers ER stress and subsequent apoptosis. Furthermore, Cae A exhibited significant anti-tumor effects in the 4T1 tumor model in vivo without apparent toxicity. The compound also effectively inhibited human TNBC organoid growth. These results indicate that Cae A may serve as a potential therapeutic agent for TNBC, with its efficacy likely mediated through the disruption of glucose metabolism and the induction of ER stress-associated apoptosis.
Humans ; Endoplasmic Reticulum Stress/drug effects* ; Triple Negative Breast Neoplasms/genetics* ; Apoptosis/drug effects* ; Cell Line, Tumor ; Female ; Animals ; Glucose/metabolism* ; Mice ; Cell Proliferation/drug effects* ; Transcription Factor CHOP/genetics* ; Antineoplastic Agents/pharmacology* ; Mitochondria/metabolism* ; Mice, Inbred BALB C

More and more attention is being paid by all parties to the use of pricing and investment for achievement transforma-tion.It is of great significance to enhance the technological transformation ability and economic operation and management ability of public hospitals.Beijing,Shanghai,and Shenzhen have explored the introduction of local special policies to support local public hos-pitals in converting results through priced investment.However,compared with the mature support policies of relevant national regula-tory departments for universities,the improvement are still needed.It compared the pricing and investment policies of universities and relevant local public hospitals from key aspects and contents such as decision-making power of pricing and investment,share-holding platform requirements,completion reward standards,and tax preferential policies,and analyzed the shortcomings of pricing and investment policies in public hospitals.Then it proposed some suggestions,such as exploring innovative models of achievement transformation and shareholding platforms which suitable for public hospitals,further clarifying the content of decision-making exemp-tion policies and asset loss handling procedures.It puts forward countermeasures and suggestions to better promote the transformation of scientific and technological achievements in public hospitals.

More and more attention is being paid by all parties to the use of pricing and investment for achievement transforma-tion.It is of great significance to enhance the technological transformation ability and economic operation and management ability of public hospitals.Beijing,Shanghai,and Shenzhen have explored the introduction of local special policies to support local public hos-pitals in converting results through priced investment.However,compared with the mature support policies of relevant national regula-tory departments for universities,the improvement are still needed.It compared the pricing and investment policies of universities and relevant local public hospitals from key aspects and contents such as decision-making power of pricing and investment,share-holding platform requirements,completion reward standards,and tax preferential policies,and analyzed the shortcomings of pricing and investment policies in public hospitals.Then it proposed some suggestions,such as exploring innovative models of achievement transformation and shareholding platforms which suitable for public hospitals,further clarifying the content of decision-making exemp-tion policies and asset loss handling procedures.It puts forward countermeasures and suggestions to better promote the transformation of scientific and technological achievements in public hospitals.

OBJECTIVE To investigate the effect of bs-5-YHEDA iron chelating peptide combined with semaglutide on the cognitive ability and pathological characteristics of D-Gal-induced Alzheimer's disease(AD) model mice. METHODS Forty mice were randomly divided into 5 groups, namely the healthy control group, PBS group, bs-5-YHEDA iron chelating peptide group, combined treatment group and positive control group, with 8 mice in each group, half of each sex. Except for the healthy control group, D-galactose was injected to induce the AD mice model for 6 weeks. For 3 consecutive weeks starting from the 4th week, the bs-5-YHEDA iron chelating peptide group was injected with bs-5-YHEDA(1 mg·mL–1) once every other day at 200 µL in the tail vein; the bs-5-YHEDA iron chelating peptide(1 mg·mL–1) and semaglutide(25 nmol·kg–1·d–1) were given alternately once a day in the combination treatment group; the positive control group was given memantine(3.3 mg·kg–1·d–1) by gavage every other day. The healthy control group and PBS group were injected with the equal dose of PBS. At the end of treatment, the learning memory ability of mice was detected by the Morris water maze method, whole brain and whole blood were dissected, and pathological changes in hippocampal region were observed by HE staining, and Aβ expression and Tau protein phosphorylation levels were detected by immunohistochemistry, enzyme-linked immunosorbent assay and immunoblotting. RESULTS In the Morris water maze spatial exploration experiment, the differences in the number of times the mice traversed the platform, the ratio of swimming distance to the target quadrant, and the time ratio were statistically significant in each group(P<0.05); compared with the PBS group, the ratio of swimming distance to the target quadrant increased in the combined treatment group, and the differences were statistically significant(P<0.05). The results of HE staining showed that compared with the healthy control mice, the hippocampal area in the PBS group showed reduced levels of pyramidal cells, disorganized arrangement, cell edema, and deep staining of nuclei consolidation. Cellular disorganization, deep staining of nuclei and apoptosis in the hippocampus were significantly improved in each treatment group after drug treatment. Immunohistochemistry and Western blotting results showed that the Aβ expression levels and Tau protein phosphorylation levels were significantly higher in the PBS-administered mice compared with the healthy control mice, and the Aβ expression levels and Tau protein phosphorylation levels were reduced in each group after drug treatment, with statistically significant differences(P<0.01 or P<0.001 ). CONCLUSION The combination of bs-5-YHEDA iron chelating peptide and semaglutide can effectively improve the learning and memory ability and pathological characteristics of AD mice, but from the results of immunohistochemistry and immunoblotting experiments, the improvement of pathological characteristics of AD mice in the combination treatment group is not obvious compared with the single bs-5-YHEDA iron chelating peptide group, suggesting that there may be a threshold effect of our designed dual-target combination treatment on the cognitive improvement of AD mice, and the optimization and validation of the effect of multi-target combination treatment need further study.

More and more attention is being paid by all parties to the use of pricing and investment for achievement transforma-tion.It is of great significance to enhance the technological transformation ability and economic operation and management ability of public hospitals.Beijing,Shanghai,and Shenzhen have explored the introduction of local special policies to support local public hos-pitals in converting results through priced investment.However,compared with the mature support policies of relevant national regula-tory departments for universities,the improvement are still needed.It compared the pricing and investment policies of universities and relevant local public hospitals from key aspects and contents such as decision-making power of pricing and investment,share-holding platform requirements,completion reward standards,and tax preferential policies,and analyzed the shortcomings of pricing and investment policies in public hospitals.Then it proposed some suggestions,such as exploring innovative models of achievement transformation and shareholding platforms which suitable for public hospitals,further clarifying the content of decision-making exemp-tion policies and asset loss handling procedures.It puts forward countermeasures and suggestions to better promote the transformation of scientific and technological achievements in public hospitals.

More and more attention is being paid by all parties to the use of pricing and investment for achievement transforma-tion.It is of great significance to enhance the technological transformation ability and economic operation and management ability of public hospitals.Beijing,Shanghai,and Shenzhen have explored the introduction of local special policies to support local public hos-pitals in converting results through priced investment.However,compared with the mature support policies of relevant national regula-tory departments for universities,the improvement are still needed.It compared the pricing and investment policies of universities and relevant local public hospitals from key aspects and contents such as decision-making power of pricing and investment,share-holding platform requirements,completion reward standards,and tax preferential policies,and analyzed the shortcomings of pricing and investment policies in public hospitals.Then it proposed some suggestions,such as exploring innovative models of achievement transformation and shareholding platforms which suitable for public hospitals,further clarifying the content of decision-making exemp-tion policies and asset loss handling procedures.It puts forward countermeasures and suggestions to better promote the transformation of scientific and technological achievements in public hospitals.

More and more attention is being paid by all parties to the use of pricing and investment for achievement transforma-tion.It is of great significance to enhance the technological transformation ability and economic operation and management ability of public hospitals.Beijing,Shanghai,and Shenzhen have explored the introduction of local special policies to support local public hos-pitals in converting results through priced investment.However,compared with the mature support policies of relevant national regula-tory departments for universities,the improvement are still needed.It compared the pricing and investment policies of universities and relevant local public hospitals from key aspects and contents such as decision-making power of pricing and investment,share-holding platform requirements,completion reward standards,and tax preferential policies,and analyzed the shortcomings of pricing and investment policies in public hospitals.Then it proposed some suggestions,such as exploring innovative models of achievement transformation and shareholding platforms which suitable for public hospitals,further clarifying the content of decision-making exemp-tion policies and asset loss handling procedures.It puts forward countermeasures and suggestions to better promote the transformation of scientific and technological achievements in public hospitals.