ObjectiveThis study aims to investigate the effect of Liuwei Dihuangwan on the autophagy function in the hippocampus of senescence-accelerated mouse prone 8 （SAMP8） by regulating the expression of glycoprotein non-metastatic melanoma protein B （GPNMB）. Furthermore， it is designed to explore the mechanism of the method of tonifying the kidneys and replenishing essence in the treatment of Alzheimer's disease （AD）. MethodsIn experiment 1， 24 5-month-old SAMP8 mice were randomly and equally divided into the model group， and the low-， middle- and high-dose（0.59，1.18，2.36 g·kg^-1） Liuwei Dihuangwan groups. At the same time， six 5-month-old senescence accelerated mouse resistant 1 （SAMR1） mice were used as the control group. The learning and memory ability was evaluated through novel object recognition experiment. Serum cortisol （Cort）， adrenocorticotropic hormone （ACTH） and urine 17-hydroxycorticosteroid （17-OHCS） levels were detected by enzyme-linked immunosorbent assay （ELISA）. The ultrastructure of hippocampal neurons was observed by transmission electron microscope （TEM）， and the expression levels of hippocampal GPNMB， a disintegrin and metalloproteinase 10 （ADAM10） and autophagy-related proteins were detected by Western blot. In experiment 2， 18 SAMP8 mice were randomly and equally divided into the model group， vector control group （Vector）， and GPNMB overexpression group （GPNMB^OE）. Lentiviral vectors were stereotactically injected into the brain （2 μL per side in the GPNMB^OE group）. Western blot was used to detect the expression of the above target proteins in the hippocampus； In Experiment 3， 24 SAMP8 mice were randomly and equally divided into the model group， Liuwei Dihuangwan group， Liuwei Dihuangwan+negative control （NC） group， and Liuwei Dihuangwan+GPNMB silencing group （shGPNMB）. Before drug treatment， the Liuwei Dihuangwan+NC group and the Liuwei Dihuangwan+shGPNMB group were injected with negative control and GPNMB silencing lentivirus， respectively. Western blot was used to detect the expression of the above target proteins in the hippocampus. ResultsThe novel object discrimination index of mice in the model group was significantly lower than that of mice in the control group （P<0.01）. The novel object discrimination index of mice in the medium- and high-dose Liuwei Dihuangwan groups was significantly higher than that of mice in the model group （P<0.01）. Aggregated autolysosomes were observed in the normal hippocampus tissue by TEM. In the model group， mitochondria were dominant， and no typical characteristic autophagosomes were observed. In the low- and medium-dose Liuwei Dihuangwan groups， a small number of autolysosomes and autophagosomes with double-membrane structures were observed. In the high-dose Liuwei Dihuangwan group， the number of autophagosomes and autolysosomes was greater than that in the low- and medium-dose groups. The results of ELISA and Western blot showed that compared with the control group， the levels of serum Cort， ACTH， and urine 17-OHCS in the model group were substantially increased， while the expression of hippocampal ADAM10， Beclin1， and microtubule associated-protein light chain 3-Ⅱ/Ⅰ （LC3 Ⅱ/Ⅰ） was significantly decreased. The expression of GPNMB and ubiquitin binding protein p62 was significantly increased （P<0.05， P<0.01）. Compared with the model group， the serum Cort and ACTH levels in the low-， medium-， and high-dose Liuwei Dihuangwan groups were significantly reduced， while only the urine 17-OHCS level in the high-dose group was significantly reduced. The hippocampal GPNMB， ADAM10， Beclin1， and LC3 Ⅱ/Ⅰ expression levels in the medium-， and high-dose groups of Liuwei Dihuangwan were significantly increased compared to the model group， whereas the expression of p62 was significantly reduced （P<0.01）. The above indicators showed a progressive trend among the three groups. Compared with the model group， the GPNMB^OE group showed a significant increase in GPNMB， ADAM10， Beclin1， LC3 Ⅱ/Ⅰ expression， and a significant decrease in p62 expression （P<0.01）. Compared with the model group， the expression of GPNMB， ADAM10， Beclin1， and LC3 Ⅱ/Ⅰ in the hippocampus of the Liuwei Dihuangwan group significantly increased， while the expression of p62 significantly decreased （P<0.01）. Compared with the Liuwei Dihuangwan group， the Liuwei Dihuangwan+shGPNMB group showed a significant decrease in GPNMB， ADAM10， Beclin1， LC3 Ⅱ/Ⅰ， and a significant increase in p62 expression （P<0.01）. ConclusionLiuwei Dihuangwan can enhance hippocampal autophagy function and improve AD by upregulating GPNMB expression.

Oroxylin A (OA), a natural compound extracted from Scutellaria baicalensis, demonstrates preventive potential against ultraviolet B (UVB)-induced non-melanoma skin cancer (NMSC), the most prevalent cancer worldwide with increasing incidence. Utilizing SKH-1 hairless mice exposed to UVB, this study showed that OA delayed NMSC onset and alleviated acute skin damage. Mechanistic investigations revealed its dual action: inhibiting inflammation and enhancing nucleotide excision repair (NER) by stabilizing XPA, a crucial deoxyribonucleic acid (DNA) repair protein. This stabilization occurred through OA's interaction with glucose-regulated protein 94 (GRP94), which disrupted murine double minute 2 (MDM2)-mediated XPA ubiquitination and proteasomal degradation. By maintaining XPA levels, OA expedited photoproduct clearance and diminished genomic instability, ultimately impeding NMSC development. These findings suggest OA as a promising chemopreventive agent targeting the GRP94/MDM2-XPA axis to counteract UVB-induced carcinogenesis.
Animals ; Ultraviolet Rays/adverse effects* ; Skin Neoplasms/prevention & control* ; Flavonoids/pharmacology* ; Mice ; Xeroderma Pigmentosum Group A Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-mdm2/genetics* ; DNA Repair/drug effects* ; Scutellaria baicalensis/chemistry* ; Mice, Hairless ; Skin/radiation effects*

Gastric cancer is a malignant tumor with high prevalence worldwide and limited therapeutic options.Chimeric antigen receptor T-cell(CAR-T)therapy has emerged as a promising approach for gastric cancer treatment;however,its application faces substantial challenges.This review provides comprehensive summary of the recent advances in CAR-T cell therapy for gastric cancer,systematic analysis of critical break throughs and core challenges from target discovery to clinical translation,and outlining of future perspectives.We describe the criter-ia for ideal target selection and highlight the current research landscape of major targets,including CLDN18.2 that demonstrated efficacy,and targets facing distinct challenges,including HER-2,CEA,EpCAM,and MUC1.This review also finely dissects three central barriers restrict-ing CAR-T cell efficacy,and discusses corresponding countermeasures:overcoming the immunosuppressive tumor microenvironment through strategies such as local delivery,armored CAR-T cells,and combination therapies;engineering approaches including affinity modula-tion and logic-gate designs to mitigate on-target/off-tumor toxicity;and optimization of manufacturing processes and reduction of costs via early leukapheresis,rapid production platforms,and universal CAR-T cell strategies.Future multidimensional,integrative,and innovative strategies are pivotal for achieving comprehensive break throughs in CAR-T cell therapy for solid tumors.

Objective To explore the potential mechanism of Xinnao Maikang in improving ApoE-/-atherosclerosis mice based on PPARγ/LXRα/ABCA1 pathway.Methods Totally 50 ApoE-/-mice were randomly divided into model group,atorvastatin group,Xinnao Maikang high-,medium-and low-dosage groups,and fed with high-fat diet for 12 weeks to establish atherosclerosis model.Another 10 C57BL/6J mice were selected as normal group,and atorvastatin group was given atorvastatin calcium suspension by intragastric administration,Xinnao Maikang high-,medium-and low-dosage groups were given Xinnao Maikang Decoction 56,28,14 g/kg by intragastric administration,the normal group and model group were given equal volume of normal saline by intragastric administration for 8 weeks.Liver index of mice was detected,serum lipid level of mice was detected by automatic biochemical analyzer,TC and TG contents in liver tissue were detected by biochemical kit,morphology of aortic intima and liver tissue were observed by HE staining,lipid deposition in liver tissue was observed by oil red O staining,the expressions of PPARγ,LXRα,ABCA1,ABCG1 and SR-BⅠ in liver tissue were detected by Western blot.Results Compared with the normal group,the liver index in the model group significantly increased(P<0.05),the contents of serum TC,TG and LDL-C significantly increased(P<0.05),and the contents of HDL-C significantly decreased(P<0.05),the contents of TC and TG in liver tissue increased(P<0.05),the aortic wall was thickened,the number of subcutaneous foam cells increased,the arrangement of liver cells were disaffected,and a large number of fat vacuoles could be seen,the protein expressions of PPARγ,LXRα,ABCA1,ABCG1 and SR-BⅠ in liver tissue significantly decreased(P<0.01).Compared with the model group,the liver index of Xinnao Maikang high-,medium-and low-dosage groups and atorvastatin group significantly decreased(P<0.05),the serum contents of TC,TG and LDL-C significantly decreased(P<0.05),and the HDL-C contents significantly increased(P<0.05),the contents of TC and TG in liver tissue significantly decreased(P<0.05),the aortic wall thickened and the subcutaneous foam cells decreased,the liver cells were arranged neatly,and fat degeneration was reduced to varying degrees,the protein expressions of PPARγ,LXRα,ABCA1,ABCG1 and SR-BⅠ in liver tissue of Xinnao Maikang high-dosage group and atorvastatin group significantly increased(P<0.05,P<0.01).Conclusion Xinnao Maikang can decrease blood lipid level,reduce atherosclerotic plaque and reduce lipid deposition in liver of atherosclerotic mice,and its mechanism may be related to regulating PPARγ/LXRα/ABCA1 pathway,regulating lipid metabolism,promoting reverse cholesterol transport.

Background: The immune system plays a critical role in the development and progression of osteoporosis and fractures. However, the causal relationships between antibody immune responses, immune cells, and these bone conditions remain unclear. This study aimed to explore these relationships using Mendelian randomization (MR) analysis. Methods: We collected complete blood count data from patients with fractures and healthy individuals and analyzed their differences. Then, we conducted a 2-sample, 2-step MR analysis to investigate the causal effects of antibody immune responses on osteoporosis and fractures, using inverse-variance weighted (IVW) as the primary method. We also explored whether immune cells mediate the pathway between antibodies and osteoporosis or fractures. Finally, we analyzed the functions and expression levels of key genes involved. Results: Overall, the fracture group exhibited increased white blood cell count, absolute neutrophil count, absolute monocyte count, platelet count, and their respective proportions, while absolute lymphocyte count, absolute eosinophil count, absolute basophil count, red blood cell count, and their proportions were decreased. We identified 44 causal relationships between antibodies and osteoporosis or fractures, with 7 supported by multiple MR methods, and 5 showing odds ratios significantly deviating from 1 in the IVW analysis. Epstein-Barr virus-related antibodies had a notable impact on osteoporosis and fractures. The human leukocyte antigen (HLA) gene family, particularly HLA-DPB1, emerged as a significant risk factor. However, immune cells were not found to mediate these effects. Conclusions This study elucidated the causal relationships between antibody immune responses, immune cells, and osteoporosis or fractures. The HLA gene family plays a crucial role in the interaction between antibodies and these bone conditions, with HLA-DPB1 identified as a key risk gene. Immune cells do not serve as mediators in this process. These findings provide valuable insights for future research.

Background: The immune system plays a critical role in the development and progression of osteoporosis and fractures. However, the causal relationships between antibody immune responses, immune cells, and these bone conditions remain unclear. This study aimed to explore these relationships using Mendelian randomization (MR) analysis. Methods: We collected complete blood count data from patients with fractures and healthy individuals and analyzed their differences. Then, we conducted a 2-sample, 2-step MR analysis to investigate the causal effects of antibody immune responses on osteoporosis and fractures, using inverse-variance weighted (IVW) as the primary method. We also explored whether immune cells mediate the pathway between antibodies and osteoporosis or fractures. Finally, we analyzed the functions and expression levels of key genes involved. Results: Overall, the fracture group exhibited increased white blood cell count, absolute neutrophil count, absolute monocyte count, platelet count, and their respective proportions, while absolute lymphocyte count, absolute eosinophil count, absolute basophil count, red blood cell count, and their proportions were decreased. We identified 44 causal relationships between antibodies and osteoporosis or fractures, with 7 supported by multiple MR methods, and 5 showing odds ratios significantly deviating from 1 in the IVW analysis. Epstein-Barr virus-related antibodies had a notable impact on osteoporosis and fractures. The human leukocyte antigen (HLA) gene family, particularly HLA-DPB1, emerged as a significant risk factor. However, immune cells were not found to mediate these effects. Conclusions This study elucidated the causal relationships between antibody immune responses, immune cells, and osteoporosis or fractures. The HLA gene family plays a crucial role in the interaction between antibodies and these bone conditions, with HLA-DPB1 identified as a key risk gene. Immune cells do not serve as mediators in this process. These findings provide valuable insights for future research.

Background: The immune system plays a critical role in the development and progression of osteoporosis and fractures. However, the causal relationships between antibody immune responses, immune cells, and these bone conditions remain unclear. This study aimed to explore these relationships using Mendelian randomization (MR) analysis. Methods: We collected complete blood count data from patients with fractures and healthy individuals and analyzed their differences. Then, we conducted a 2-sample, 2-step MR analysis to investigate the causal effects of antibody immune responses on osteoporosis and fractures, using inverse-variance weighted (IVW) as the primary method. We also explored whether immune cells mediate the pathway between antibodies and osteoporosis or fractures. Finally, we analyzed the functions and expression levels of key genes involved. Results: Overall, the fracture group exhibited increased white blood cell count, absolute neutrophil count, absolute monocyte count, platelet count, and their respective proportions, while absolute lymphocyte count, absolute eosinophil count, absolute basophil count, red blood cell count, and their proportions were decreased. We identified 44 causal relationships between antibodies and osteoporosis or fractures, with 7 supported by multiple MR methods, and 5 showing odds ratios significantly deviating from 1 in the IVW analysis. Epstein-Barr virus-related antibodies had a notable impact on osteoporosis and fractures. The human leukocyte antigen (HLA) gene family, particularly HLA-DPB1, emerged as a significant risk factor. However, immune cells were not found to mediate these effects. Conclusions This study elucidated the causal relationships between antibody immune responses, immune cells, and osteoporosis or fractures. The HLA gene family plays a crucial role in the interaction between antibodies and these bone conditions, with HLA-DPB1 identified as a key risk gene. Immune cells do not serve as mediators in this process. These findings provide valuable insights for future research.

Background Kurtosis reflecting noise's temporal structure is an effective metric for evaluating noise-induced hearing loss (NIHL), and its threshold is still unclear. Objective To explore the energy range of kurtosis and the threshold of NIHL induced by kurtosis in this energy rangeMethods Using cross-sectional design, 4631 noise-exposed workers in manufacturing industry were selected. The hearing loss and noise exposure data of each worker were collected. Logistic regression model was used to establish the dose-response relationship between noise exposure and hearing loss and estimate the range of energy effects. Restricted cubic spline model was utilized to analyze the dose-response relationship curves of kurtosis to noise-induced hearing loss (NIHI) and high-frequency noise-induced hearing loss (HFNIHL) under different 8 h equivalent sound levels (L_{EX,8 h}), as well as to estimate the kurtosis effect threshold. Results The logistic regression model analysis showed that the prevalence of NIHI and HFNIHL increased significantly with increase of L_{EX,8 h} for steady noise; when L_{EX,8 h} of non-steady noise was 80-100 dB(A), the risk of hearing loss increased with an increase in kurtosis (P<0.05). The restricted cubic spline model showed that when L_{EX,8 h} of non-steady noise was 0-80 dB(A) or >100 dB(A), there was no significant relationship between kurtosis and NIHI or HFNIHL. When L_{EX,8 h} was 80-100 dB(A), there was a significant nonlinear dose-response relationship between kurtosis and NIHL or HFNIHL (P <0.001), and kurtosis > 28.08 exerted effect in elevating NIHI or HFNIHL. Conclusion The effect threshold of kurtosis on NIHL is 28.08 when non-steady noise levels are in the range of 80-100 dB(A). The effect threshold of kurtosis needs further verification.

Background Noise-induced hearing loss (NIHL) is a prevalent occupational health problem in workplace settings, with non-steady noise exposure being particularly widespread. Although kurtosis-adjusted equivalent sound level (\begin{document}$ {{L'}}_{\text{EX,}\text{8}\text{ h}} $\end{document}) methods based on linear regression are available to assess hearing damage, the complexity of kurtosis effects necessitates introducing new metrics through nonlinear regression to improve predictive accuracy for hearing loss from non-steady noise exposure. Objective To examine the adjustment terms [\begin{document}$ \mathrm{lg}(\beta _{N}/{\beta }_{G}) $\end{document}] and coefficients (λ) of \begin{document}$ {{L'}}_{\text{EX,}\text{8}\text{ h}} $\end{document} using nonlinear regression and evaluate the method’s effectiveness in assessing occupational hearing loss associated with non-steady noise exposure. Methods A cross-sectional study design was employed, enrolling 1034 manufacturing workers and evaluating noise exposure to estimate hearing loss metrics. Quantile regression analysis quantified the proportional contributions of influencing factors for noise-induced permanent threshold shift at 3, 4, and 6 kHz frequencies (NIPTS₃₄₆). \begin{document}$ {{L'}}_{\text{EX,}\text{8}\text{ h}} $\end{document} was computed using multiple linear regression and nonlinear least squares optimization. Paired t-tests analyzed predictive efficacy before and after kurtosis adjustment to evaluate its impact on ISO 1999 NIPTS₃₄₆ predictions. Chow tests compared the similarity of logistic regression curves for high-frequency noise-induced hearing loss (HFNIHL) incidence between non-steady noise (\begin{document}$ {{L'}}_{\text{EX,}\text{8}\text{ h}} $\end{document}) and steady noise (\begin{document}$ {{L}}_{\text{EX,}\text{8}\text{ h}} $\end{document}), thereby validating the effectiveness of \begin{document}$ {{L'}}_{\text{EX,}\text{8}\text{ h}} $\end{document}. Results The quantile regression analysis showed that kurtosis was a significant indicator of occupational hearing loss risk from non-steady noise (contribution rate was 27.5%, P<0.05). The linear regression and nonlinear least squares methods obtained six different combinations of coefficients (λ) and adjustment terms [\begin{document}$ \mathrm{lg}(\beta _{N}/{\beta }_{G}) $\end{document}]. Incorporating these \begin{document}$ {{L'}}_{\text{EX,}\text{8}\text{ h}} $\end{document} adjustments into the ISO 1999 predictive model significantly reduced NIPTS underestimation (from 14.2 dB HL with \begin{document}$ {{L}}_{\text{EX,}\text{8}\text{ h}} $\end{document} to 11.5–5.6 dB HL with \begin{document}$ {{L'}}_{\text{EX,}\text{8}\text{ h}} $\end{document}, P < 0.001). The model \begin{document}$ {{{L'}}_{\text{EX,}\text{8}\text{ h}\text{,6}}=L}_{\mathrm{E}\mathrm{X},8\;\mathrm{h}}+7.9\mathrm{lg}({{\beta }_{N}}/{10}) $\end{document} achieved the most significant improvement, reducing underestimation by 8.7 dB HL. The logistic curve analysis further demonstrated that all \begin{document}$ {{L'}}_{\text{EX,}\text{8}\text{ h}} $\end{document} dose-response relationships for non-steady noise aligned more closely with the steady noise group than \begin{document}$ {{L}}_{\text{EX,}\text{8}\text{ h}} $\end{document}, with \begin{document}$ {{L'}}_{\text{EX,}\text{8}\text{ h}\text{,6}} $\end{document} showing the smallest divergence (difference: 4.1%). Conclusions \begin{document}$ {{L'}}_{\text{EX,}\text{8}\text{ h}} $\end{document} demonstrates superior efficacy in assessing the risk of occupational hearing loss induced by non-steady noise exposure. The \begin{document}$ {{L'}}_{\text{EX,}\text{8}\text{ h}} $\end{document} metric, constructed by calculating adjustment terms and coefficients through nonlinear regression analysis, exhibits greater effectiveness than linear regression methods in evaluating occupational hearing loss associated with non-steady noise exposure.

Background Temporal kurtosis (without frequency weighting, i.e., Z-weighted kurtosis) can evaluate noise-induced hearing loss (NIHL). However, few studies have considered the function of frequency weighting (A- or C-weighted) kurtosis on NIHL. Objective To study the significance of A- and C-weighted kurtosis adjustment for equivalent sound level (L'_{EX,8 h}) in evaluating occupational hearing loss. Methods A cross-sectional survey was used to select 973 noise-exposed workers in seven industries as the subjects. The noise exposure of all workers was assessed by distributions of A-, C-, and Z-weighted kurtosis (e.g., K_A, K_C, and K_Z) and respective adjusted equivalent sound level (e.g., L'_{EX,8 h}-K_A, L'_{EX,8 h}-K_C, and L'_{EX,8 h}-K_Z). The significance of A- and C-weighted kurtosis in evaluating NIHL was evaluated by correlations between three types of L'_{EX,8 h} and NIHL, and improvement of noise-induced permanent threshold shift (NIPTS) underestimation predicted by the ISO prediction model (Acoustics—Estimation of noise-induced hearing loss, ISO 1999-2013). Results The median K_A, K_C, and K_Z were 68.33, 28.22, and 19.82, respectively. The binary logistic regression showed that L_{EX, 8 h}-K_A, L_{EX, 8 h}-K_C, and L'_{EX, 8 h}-K_Z were risk factors for NIHL (OR>1, P<0.001). The receiver operating characteristic (ROC) curve showed that when the outcome variable was noise-induced hearing impairment (NIHI), the areas under the curves corresponding to L'_{EX,8 h}-K_A, L'_{EX,8 h}-K_C, and L'_{EX,8 h}-K_Z were 0.625, 0.628, and 0.625, respectively. When the outcome variable was high-frequency noise-induced hearing loss (HFNIHL), the areas under the curves corresponding to L'_{EX,8 h}-K_A, L'_{EX, 8 h}-K_C, and L'_{EX,8 h}-K_Z were 0.624, 0.623, and 0.622, respectively (P<0.05). The order of underestimation improvement values predicted by L'_{EX,8 h} for NIPTS₁₂₃₄ was: L'_{EX,8 h}-K_A (4.68 dB HL)>L'_{EX,8 h}-K_C (4.38 dB HL)>L'_{EX,8 h}-K_Z (4.28 dB HL) (P<0.001). The order of underestimation improvement values predicted by L'_{EX,8 h}-K for NIPTS₃₄₆ was: L'_{EX,8 h}-K_A (7.20 dB HL)>L'_{EX,8 h}-K_C (6.83 dB HL)>L'_{EX,8 h}-K_Z (6.71 dB HL) (P<0.001). Conclusion The adjustment of A- and C-weighted kurtosis to equivalent sound level L_{EX,8 h} can effectively improve the accuracy of the ISO 1999 prediction model in NIPTS prediction, and compared with the C-weighted, the A-weighted kurtosis can improve the result of the ISO 1999 prediction model in terms of underestimating NIPTS.