Human naïve pluripotent stem cells (PSCs) hold great promise for embryonic development studies. Existing induction and culture strategies for these cells, heavily dependent on MEK inhibitors, lead to widespread DNA hypomethylation, aberrant imprinting loss, and genomic instability during extended culture. Here, employing high-content analysis alongside a bifluorescence reporter system indicative of human naïve pluripotency, we screened over 1,600 chemicals and identified seven promising candidates. From these, we developed four optimized media-LAY, LADY, LUDY, and LKPY-that effectively induce and sustain PSCs in the naïve state. Notably, cells reset or cultured in these media, especially in the LAY system, demonstrate improved genome-wide DNA methylation status closely resembling that of pre-implantation counterparts, with partially restored imprinting and significantly enhanced genomic stability. Overall, our study contributes advancements to naïve pluripotency induction and long-term maintenance, providing insights for further applications of naïve PSCs.
Humans ; DNA Methylation/drug effects* ; Genomic Instability ; Pluripotent Stem Cells/metabolism* ; Cell Culture Techniques/methods* ; Cells, Cultured

Lipids play an important role in the regulation of cell life processes. Although there are various lipid detection methods, Raman spectroscopy, a non-invasive technique, provides the detailed chemical composition of lipid profiles without a complex sample preparation procedure and possesses greater potential in basic biology, clinical diagnosis and disease therapy. In this review, we summarized the characteristics and advantages of Raman-based techniques and their primary contribution to illustrating cellular lipid metabolism.

Bispecific antibodies （BsAbs）， as an important recent innovation in the field of tumor immunotherapy in recent years， can simultaneously or sequentially target different antigens or two different epitopes of the same antigen. Compared with traditional monoclonal antibodies， they can produce superior therapeutic effects. This article reviews the progress in clinical applications and safety research of BsAbs in cancer therapy， revealing that they （such as blinatumomab， glofitamab， teclistamab， amivantamab， etc.） exhibit significant therapeutic efficacy against hematological malignancies， lung cancer， cervical cancer， melanoma， and other cancers. For cytokine release syndrome （CRS） induced by BsAbs， prophylactic or pre-emptive medication is commonly administered in clinical practice； for neurotoxicity and infections triggered by BsAbs， clinical practice necessitates rigorous monitoring of patients’ vital signs and the provision of essential treatments. In addition， different BsAbs exhibit variations in escalation dose， infusion rate， storage duration， and equipment requirements. Therefore， strict adherence to the instructions in the drug package inserts is essential during clinical operations to ensure safety and therapeutic efficacy. In the future， more multicenter trials need to be conducted to validate the efficacy and safety of BsAbs across different tumor types and patient populations， and long-term follow-up data should be accumulated to optimize treatment cycles and dosage regimens.

Lacking therapeutic targets highlights the crucial roles of chemotherapy and radiotherapy in the clinical management of triple-negative breast cancer (TNBC). To relieve the side effects of the chemoradiotherapy combination regimen, we design and develop a self-assembled micelle nanosystem consisting of perfluorocarbon chain-modified cisplatin prodrug. By incorporating perfluorodecalin, this nanosystem can effectively carry ozone and promote irradiation-derived reactive oxygen species (ROS) production. By leveraging the perfluorocarbon sidechain, the nanosystem exhibits efficient internalization by TNBC cells and effectively escapes from lysosomal entrapment. Under X-ray irradiation, ozone-generated ROS disrupts the intracellular redox balance, thereby facilitating the release of cisplatin in a reduction-responsive manner mediated by reduced glutathione. Moreover, oxygen derived from ozone decomposition enhances the efficacy of radiotherapy by alleviating tumor hypoxia. Notably, the combination of irradiation with ozone-loaded cisplatin prodrug nano system synergistically prompts antitumor efficacy and reduces cellular/systemic toxicity in vitro and in vivo. Furthermore, the combo regimen remodels the tumor microenvironment into an immune-favored state by triggering immunogenic cell death and relieving hypoxia, which provides a promising foundation for a combination regimen of immunotherapy. In conclusion, our nanosystem presents a novel strategy for integrating chemotherapy and radiotherapy to optimize the efficacy and safety of TNBC clinical treatment.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint damage, accompanied by the accumulation of plasma cells, which contributes to its pathogenesis. Understanding the genetic alterations occurring during plasma cell differentiation in RA can deepen our comprehension of its pathogenesis and guide the development of targeted therapeutic interventions. Here, our study elucidates the intricate molecular mechanisms underlying plasma cell differentiation by demonstrating that PRDX1 interacts with DOK3 and modulates its degradation by the autophagy-lysosome pathway. This interaction results in the inhibition of plasma cell differentiation, thereby alleviating the progression of collagen-induced arthritis. Additionally, our investigation identifies Salvianolic acid B (SAB) as a potent small molecular glue-like compound that enhances the interaction between PRDX1 and DOK3, consequently impeding the progression of collagen-induced arthritis by inhibiting plasma cell differentiation. Collectively, these findings underscore the therapeutic potential of developing chemical stabilizers for the PRDX1-DOK3 complex in suppressing plasma cell differentiation for RA treatment and establish a theoretical basis for targeting PRDX1-protein interactions as specific therapeutic targets in various diseases.

High mobility group box 1 (HMGB1), when released extracellularly, plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system. In experimental autoimmune encephalomyelitis (EAE), a condition that models multiple sclerosis, the levels of extracellular HMGB1 and interleukin-33 (IL-33) have been found to be inversely correlated. However, the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive. Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes, upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice. Conversely, the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes. These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.
Animals ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; Astrocytes/metabolism* ; Interleukin-33/metabolism* ; HMGB1 Protein/metabolism* ; Acetylation ; Mice, Knockout ; Mice, Inbred C57BL ; p300-CBP Transcription Factors/metabolism* ; Mice ; Spinal Cord/metabolism* ; Cells, Cultured ; Female ; Signal Transduction

Objective:To discuss the clinical efficacy of microwave ablation(MWA)and surgical treatment in the patients with Hashimoto thyroiditis(HT)complicated with T1aN0M0 stage papillary thyroid carcinoma(PTC),and to clarify the feasibility and advantages of MWA as a minimally invasive treatment modality.Methods:A retrospective cohort study was used.A total of 165 patients diagnosed with HT complicated with T1aN0M0 stage PTC from January 2018 to December 2020 were selected and divided into MWA group(82 cases)and surgery group(83 cases).The patients in MWA group underwent MWA treatment under ultrasound guidance,and the patients in surgery group underwent unilateral thyroid lobectomy+unilateral lymph node dissection.The median follow-up time was(65.98±7.32)months.The indicators such as age,preoperative tumor volume,operation time,intraoperative blood loss,hospital stay,hospitalization cost,tumor progression,incidence of postoperative complications,changes in thyroid function,tumor recurrence rate,and life quality score of the patients in two groups were recorded and analyzed.Results:There were no significant differences in the baseline sample data including age,gender,preoperative tumor volume,margin,shape,aspect ratio,calcification,and preoperative thyroid function between two groups(P>0.05).Compared with surgery group,the operation time,intraoperative blood loss,hospital stay,and hospitalization cost of the patients in MWA group were significantly decreased(P<0.01),and there was no significant difference in the incidence of postoperative complications(P>0.05).All nodules in the patients in MWA group achieved complete ablation within 18 months.The functional thyroid parenchyma in the patients in MWA group was well preserved after operation,and the thyroid function was maintained within the normal physiological range during the follow-up period.The Thyroid Cancer-specific Quality of Life Questionnaire(THYCA-QoL)results showed that compared with MWA group,the scores of voice,sympathetic nerve symptoms,throat/mouth problems,psychological,sensory problems,scar,and chills of the patients in surgery group were significantly inecreased(P<0.05).There was no significant difference in the tumor progression rate between two groups(P>0.05).Conclusion:During the median follow-up period,both MWA and surgical treatment achieve satisfactory clinical efficacy in the patients with HT complicated with T1aN0M0 stage PTC.MWA treatment has significant advantages in operation time,intraoperative blood loss,hospital stay,hospitalization cost,quality of life,and preservation of thyroid function,and it can be used as a minimally invasive treatment option for such patients,but its long-term oncological safety needs to be further evaluated by extending the follow-up.

Objective To analyze TCM master Yan Zhenghua's medication rules of ascending,descending,floating and sinking properties for the treatment of respiratory diseases,inherit his valuable academic experience.Methods Using four books edited by Professor Yan Zhenghua's disciples as the main source,Professor Yan Zhenghua's prescriptions for clinical treatment of respiratory diseases were systematically collected and analyzed.Statistical analysis was conducted on the patients'gender and age,differentiation of diseases and syndrome types of the prescriptions,as well as the properties of ascending,descending,floating and sinking,dosage,and commonly used pairs of Chinese materia medica.Results Totally 208 prescriptions were included in this study,involving 178 kinds of Chinese materia medica and 64 kinds of monarch drug,most of them were descending and sinking drug,and the whole prescription was mainly descending and sinking.On average,each prescription used 13.2 kinds of Chinese materia medica,and most dosage points were within the range of conventional dosage.Among later adding medicines,Houttuyniae Herba had the highest frequency of use.The medicinal pairs of Asteris Radix et Rhizoma-Cynanchi Stauntonii Rhizoma et Radix,Cynanchi Stauntonii Rhizoma et Radix-Stemonae Radix and Asteris Radix et Rhizoma-Stemonae Radix were often used.Armeniacae Semen Amarum,Fritillariae Thunbergii Bulbus,and Asteris Radix et Rhizoma were commonly used in those descending and sinking prescriptions.Conclusion In the treatment of respiratory diseases,Professor Yan Zhenghua prefers to use descending and sinking drugs with ascending and floating drugs and dual trend drugs to regulate qi activity,and has the characteristics of Menghe medical school,which is"mild and flexible medication".

ObjectiveTo investigate the protective mechanism of Qianyang Yuyin granules （QYYY） on aldosterone-induced podocyte injury. MethodA total of 30 C57BL/6J mice were randomly divided into five groups： control group， model group， QYYY low dose （QYYY-L） group， QYYY high dose （QYYY-H） group， and spironolactone （SPL） group， with six mice in each group. Except for the control group， mice were implanted with osmotic minipumps and injected continuously with aldosterone （300 μg·kg^-1·d^-1） to induce renal injury. The drug administration group was given low and high doses （2.6， 5.2 g·kg^-1·d^-1） of QYYY and SPL （18 mg·kg^-1·d^-1） for 28 days. The renal pathological changes of mice were observed by hematoxylin-eosin （HE） staining and Masson staining. The expression levels of Nephrin， Desmin， B-cell lymphoma-2 （Bcl-2）， Bcl-2-associated X （Bax）， cleaved Caspase-3， nuclear receptor subfamily 3 group C member 2 （NR3C2）， extracellular regulated protein kinases （ERK）， and phospho-ERK （p-ERK） in kidney tissue were detected by Western blot. The apoptosis levels of kidney tissue were detected by TdT-mediated dUTP nick and labeling （TUNEL） staining， and the superoxide dismutase （SOD） levels were detected. In vitro， the mice were divided into five groups： Control group， model group （aldosterone concentration of 200 nmol·L^-1）， QYYY-L group， QYYY medium dose （QYYY-M） group， and QYYY-H group （25， 50， and 100 mg·L^-1）. The effect of different concentrations of QYYY on the relative viability of aldosterone-induced podocytes was detected by cell proliferation and viability assay （CCK-8）. The expressions of Nephrin， Desmin， Bax， Bcl-2， cleaved Caspase-3， NR3C2， and p-ERK/ERK were detected by Western blot. AnnexinV-FITC/PI flow cytometry was used to detect the apoptosis levels of podocytes. Reactive oxygen species （ROS） in podocytes were observed by DCFH-DA. ResultCompared with the control group， the model group showed structural pathological changes and fibrotic conditions in the kidney， increased apoptosis levels （P<0.01）， and decreased SOD levels （P<0.01）. Aldosterone concentration at 200 nmol·L^-1 showed a significant decrease in podocyte activity （P<0.05）. Podocytes in the model group showed structural pathological changes， disordered arrangement of intercellular microfilaments， increased apoptosis levels （P<0.01）， and increased intracellular ROS levels （P<0.01）. The protein expressions of Nephrin， Bcl-2， and p-ERK/ERK in kidney tissue and podocytes were decreased （P<0.05， P<0.01）. The protein expressions of Desmin， Bax， cleaved Caspase-3， and NR3C2 were increased （P<0.05， P<0.01）. Compared with the model group， QYYY alleviated the structural damage and fibrosis of the kidney， decreased the apoptosis levels （P<0.05， P<0.01）， and enhanced the SOD content of the kidney （P<0.05， P<0.01）. QYYY improved the activity of podocytes （P<0.05， P<0.01）， restored the foot process structure of podocytes， and decreased apoptosis levels （P<0.01） and ROS levels of podocytes （P<0.01）. The protein expressions of Nephrin， Bcl-2， and p-ERK/ERK in kidney tissue and podocytes were increased （P<0.05， P<0.01）， and the protein expressions of Desmin， Bax， cleaved Caspase-3， and NR3C2 were down-regulated （P<0.05， P<0.01）. ConclusionQYYY improves aldosterone-induced podocyte injury by regulating the NR3C2/ROS/ERK pathway.