ObjectiveTo investigate the therapeutic effect of sitravatinib on carbon tetrachloride （CCl₄）-induced liver fibrosis in mice. MethodsA total of 30 male C57BL/6J mice， aged 8 weeks， were randomly divided into control group， CCl₄ model group， and low- （5 mg/kg）， middle- （10 mg/kg）， and high-dose （20 mg/kg） sitravatinib groups. All mice except those in the control group were given intraperitoneal injection of CCl₄ for 4 consecutive weeks to induce liver fibrosis， and since the first day of modeling， the mice in the low-， middle-， and high-dose sitravatinib groups were given sitravatinib at the corresponding dose by gavage every day. The serum levels of total cholesterol （TC）， triglyceride （TG）， and alanine aminotransferase （ALT） were measured for the mice in each group； hepatic hydroxyproline content was measured； HE staining， Masson staining， and Sirius Red staining were used to observe liver histopathological changes； quantitative real-time PCR and Western blot were used to measure the mRNA and protein expression levels of α-smooth muscle actin （α-SMA） and collagen type I alpha 1 （Col1a1） in liver tissue. The therapeutic effect of sitravatinib was assessed based on the above results. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the control group， the model group had significant increases in the levels of TC， TG， and ALT （all P<0.05）， and there were no significant differences in the levels of TC， TG， and ALT between the model group and the low-， middle-， and high-dose sitravatinib groups （all P>0.05）. Hepatic hydroxyproline content decreased after sitravatinib intervention， with a significant difference between the middle-/high-dose sitravatinib groups and the CCl₄ model group （both P<0.05）. Histopathological staining showed that the sitravatinib treatment groups had a reduction in collagen deposition， along with thinning and fragmentation of fibrous septa， and in the high-dose sitravatinib group， 4 mice had a fibrosis stage of S0—S1 and 2 mice had a fibrosis stage of S2—S3， suggesting a certain degree of alleviation of liver fibrosis degree compared with the CCl₄ model group （mainly S3—S4）. The measurement of related molecules showed that sitravatinib downregulated the mRNA and protein expression levels of α-SMA and Col1a1 （all P<0.05）. ConclusionSitravatinib can effectively alleviate CCl₄-induced liver fibrosis in mice， possibly by inhibiting hepatic stellate cell activation and collagen synthesis.

To investigate the association between sleep-related phenotypes and the risk of malignancy in pulmonary nodules, and to provide complementary evidence from a general population cohort and genetic analyses.

ObjectiveTo investigate the potential mechanism of Huatan Sanjie Formula （化痰散结方， HSF） in the treatment of triple negative breast cancer （TNBC） based on the integrinβ1/focal adhesion kinase/yes-associated protein （integrinβ1/FAK/YAP） mechanotransduction signaling pathway. MethodsFifty BALB/c mice were randomly assigned to a model group， doxorubicin group， low-， medium-， and high-dose HSF groups， with 10 mice per group. An orthotopic TNBC transplantation model was established in all mice using syngeneic implantation of 4T1 cells. After successful modeling， mice in the model group received intragastric administration of normal saline 0.2 ml each day. Mice in the low-， medium-， and high-dose HSF groups received HSF by gavage at doses of 5.99， 11.97， and 23.94 g/（kg·d）， respectively. The doxorubicin group received intraperitoneal injections of doxorubicin （1.5 mg/kg） once every two days. All treatments lasted for 30 days. After the final administration， mice were sacrificed， and tumor weight and volume were measured. Hematoxylin-eosin （HE）， Masson's trichrome， and Sirius Red staining were performed to evaluate histopathological changes and collagen fiber deposition in tumor tissues. TUNEL staining was used to assess apoptosis. The Young's modulus of tumor tissues was measured using atomic force microscopy （AFM）. The nuclear-cytoplasmic localization of YAP was determined by immunofluorescence staining. Protein expression levels of integrinβ1， focal adhesion kinase （FAK）， YAP， and phosphorylated focal adhesion kinase （p-FAK） were detected by Western Blotting. The mRNA expression levels of integrinβ1， FAK， and YAP were assessed by quantitative real-time polymerase chain reaction （qRT-PCR）. Pearson correlation analysis was performed to evaluate the relationships among tumor tissue Young's modulus， apoptosis rate， and the expression levels of proteins related to the integrinβ1/FAK/YAP signaling pathway. ResultsCompared to the model group， tumor weight was significantly reduced in the doxorubicin group and the medium- and high-dose HSF groups， while tumor volume significantly decreased in the doxorubicin group and the high-dose HSF group （P＜0.01）. Tumor weight in the high-dose HSF group was significantly lower than that in the low-dose group， and tumor volume was significantly smaller than that in both the low- and medium-dose groups （P＜0.05）. Marked improvements in histopathological morphology were observed in the medium- and high-dose HSF groups and the doxorubicin group， while the proportion of collagen fiber deposition and the nuclear-to-cytoplasmic ratio of YAP were significantly reduced （P＜0.01）. Compared to the model group， all three HSF groups and the doxorubicin group exhibited significantly increased apoptosis rates， decreased Young's modulus， and reduced mRNA expression levels of integrinβ1， and YAP （P＜0.05 or P＜0.01）. Furthermore， protein expression levels of integrinβ1， p-FAK， and YAP in the high-dose HSF group were significantly lower than those in the model group （P＜0.05 or P＜0.01）. Pearson correlation analysis demonstrated a significant negative correlation between tumor tissue Young's modulus and apoptosis rate （r =-0.93， P＜0.01）. In contrast， the protein expression levels of integrinβ1， p-FAK， and YAP were positively correlated with Young's modulus （r=0.88， 0.97， and 0.98， respectively； P＜0.05） and negatively correlated with apoptosis rate （r=-0.93，-0.97， and -0.93， respectively； P＜0.05）. ConclusionHSF can significantly inhibit tumor growth in TNBC model mice. Its antitumor effect may be associated with reducing tumor tissue stiffness through suppression of the integrinβ1/FAK/YAP mechanotransduction signaling pathway.

Macrophages are innate immune cells connected with the development of inflammation. Retinoic acid has previously been proved to have anti-inflammatory and anti-arthritic properties. However, the exact mechanism through which retinoic acid modulates arthritis remains unclear. This study aimed to investigate whether retinoic acid ameliorates rheumatoid arthritis by modulating macrophage polarization. This study used retinoic acid to treat mice with adjuvant arthritis and evaluated anti-inflammatory effects by arthritis score, thermal nociceptive sensitization test, histopathologic examination and immunofluorescence assays. In addition, its specific anti-arthritic mechanism was investigated by flow cytometry, cell transfection and inflammatory signaling pathway assays in RAW264.7 macrophages in vitro. Retinoic acid significantly relieved joint pain and attenuated inflammatory cell infiltration in mice. Furthermore, this treatment modulated peritoneal macrophage polarization, increased levels of arginase 1, as well as decreased inducible nitric oxide synthase expression. In vitro, we verified that retinoic acid promotes macrophage transition from the M1 to M2 type by upregulating mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) expression and inhibiting P38, JNK and ERK phosphorylation in lipopolysaccharide-stimulated RAW264.7 cells. Notably, the therapeutic effects of retinoic acid were inhibited by MKP-1 knockdown. Retinoic acid exerts a significant therapeutic effect on adjuvant arthritis in mice by regulating macrophage polarization through the MKP-1/MAPK pathway, and play an important role in the treatment of rheumatic diseases.

Macrophages are innate immune cells connected with the development of inflammation. Retinoic acid has previously been proved to have anti-inflammatory and anti-arthritic properties. However, the exact mechanism through which retinoic acid modulates arthritis remains unclear. This study aimed to investigate whether retinoic acid ameliorates rheumatoid arthritis by modulating macrophage polarization. This study used retinoic acid to treat mice with adjuvant arthritis and evaluated anti-inflammatory effects by arthritis score, thermal nociceptive sensitization test, histopathologic examination and immunofluorescence assays. In addition, its specific anti-arthritic mechanism was investigated by flow cytometry, cell transfection and inflammatory signaling pathway assays in RAW264.7 macrophages in vitro. Retinoic acid significantly relieved joint pain and attenuated inflammatory cell infiltration in mice. Furthermore, this treatment modulated peritoneal macrophage polarization, increased levels of arginase 1, as well as decreased inducible nitric oxide synthase expression. In vitro, we verified that retinoic acid promotes macrophage transition from the M1 to M2 type by upregulating mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) expression and inhibiting P38, JNK and ERK phosphorylation in lipopolysaccharide-stimulated RAW264.7 cells. Notably, the therapeutic effects of retinoic acid were inhibited by MKP-1 knockdown. Retinoic acid exerts a significant therapeutic effect on adjuvant arthritis in mice by regulating macrophage polarization through the MKP-1/MAPK pathway, and play an important role in the treatment of rheumatic diseases.

Objective To measure radiation filed distribution in the treatment room of the Varian Halcyon medical linear accelerator, and to provide a basis for shielding design and potential exposure analysis of treatment rooms for this type of accelerator. Methods Under the 6 MV X-ray (FFF) mode at a maximum dose rate of 800 MU/min and a maximum irradiation field of 28.00 cm × 28.00 cm, a total of 540 MU was delivered during gantry rotation. Radiation field distribution was measured using thermoluminescence dosimeters located at multiple points in the room. The measured data were then applied to shielding calculations, and the results were compared with those obtained using empirical formulas. Results The overall radiation levels in the treatment room were in the range of 12.2 µGy/540 MU to 5.520 Gy/540 MU, with the highest dose (5.520 Gy/540 MU) observed at the isocenter, and the lowest dose (12.2 µGy/540 MU) recorded at approximately 6.5 m from the gantry head. The radiation levels at most points were within the range of 100-1000 µGy/540 MU. At heights of 0.5, 1.1, and 1.7 m, the radiation field exhibited a rapid attenuation from the beam center outward, with a faster decay along the treatment couch direction (Y-axis) than along the perpendicular direction (X-axis). Shielding calculations based on the measured radiation field yielded required wall thicknesses of 1219 mm (east wall), 949 mm (south wall), 1235 mm (west wall), and 1252 mm (north wall), all of which were smaller than those calculated using empirical formulas. Conclusion Thermoluminescence dosimeter is suitable for multi-point in situ measurement of radiation field distribution in Halcyon accelerator treatment rooms. The measurement results can be used to optimize the shielding design of Halcyon accelerator treatment rooms.

A 36-year-old male developed unconsciousness and no response to voice stimuli after taking approximately 2 050 mg felodipine (the specific time was unknown). Two hours later, he was sent to the department of emergency by his family and admitted to the hospital. His vital signs showed body temperature 35.1 ℃, pulse 148 times/min, respiration 32 times/min, and blood pressure 65/34 mmHg. Acute drug poisoning, acute toxic cardiomyopathy, acute toxic shock, acute type Ⅱ respiratory failure, acute toxic encephalopathy, and acute renal failure were diagnosed based on the patient′s clinical manifestations combined with laboratory tests results, cardiac ultrasound, chest and abdominal CT scans. Endotracheal intubation connected to a ventilator for invasive assisted ventilation, pressure boosting, and fluid resuscitation were given. At the same time, repeated gastric lavage and enema were performed to remove toxins. Blood perfusion was intermittently and repeatedly administered, and continuous renal replacement therapy was used. The blood concentration of felodipine was 1 298 μg/L at 2 hours after admission, and cardiac arrest occurred at 4 hours. Venous-arterial extracorporeal membrane oxygenation (V-A ECMO) treatment was administered immediately. After 48 hours of ECMO operation, sedatives were discontinued and the patient′s consciousness was improved after 4 hours. On the 5th day of ECMO treatment, his heart rate was 72 beats per minute, and blood pressure was 127/65 mmHg. The blood concentration of felodipine decreased to 2 μg/L. The patient′s vital signs were significantly improved and ECMO supportive treatment was withdrawn. After 26 days of hospitalization, the patient recovered and was discharged.

Objective To explore the mechanism of Lidan Huatan Huoxue Decoction improving cognitive impairment caused by obesity based on metabolomics.Methods Twenty-four 6-week-old male SD rats were randomly divided into a normal group fed with regular diet(Con,n=6)and a modeling group fed with high-fat and high-sugar diet(n=18).Rats with a body mass that is 20%higher than the standard body mass of their age-matched peers fed with ordinary diet were considered to have a successful obese model established.The presence of cognitive impairment was assessed by Morris water maze and Barnes maze tests.After the obese-induced cognitive impairment(OICI)model was established,the modeling rats were randomly divided into a model group(Model,n=6),a donepezil group(Donepezil,n=6),and a Lidan Huatan Huoxue Decoction group(LHH,n=6).Drugs were administered to the donepezil and LHH groups by gastric intubation.The donepezil group was administered with a dose of 0.45 mg·(kg·d)-1,while the LHH group was administered with a dose of 25 g·(kg·d)-1.The normal and model groups were given the same volume of normal saline by gastric intubation for 8 weeks.Before the rats were sacrificed,water maze and Barnes maze experiments were conducted to assess cognitive function.After sacrifice,specimens were collected for biochemical and histological examination of liver tissue and brain tissue.Non-targeted metabolomic analysis using liquid chromatography-mass spectrometry(LC-MS)was performed on feces,serum,and brain tissue to analyze changes in differential metabolites in rats.Results Compared with the model group,the intervention of Donepezil and LHH effectively improved the learning and memory ability of OICI rats(P<0.05 or P<0.01),inhibited the overactivation of hippocampal microglia,and increased the number of hippocampal synaptic proteins.LHH improved metabolic-related indicators in OICI rats(P<0.05 or P<0.01).Metabolomic analysis showed significant differences in metabolites in feces,serum,and brain tissue between the model group and the normal group.The main affected pathways in fecal metabolites included steroid biosynthesis,caffeine metabolism,lysosome,vitamin B6 metabolism,phenylalanine,tyrosine,and tryptophan biosynthesis.The main affected pathways in serum metabolites included central carbon metabolism in cancer,pentose phosphate pathway,mineral absorption,protein digestion and absorption,and aminoacyl-tRNA biosynthesis.The main affected pathways in brain tissue metabolites included glycerophospholipid metabolism,β-alanine metabolism,propionic acid metabolism,niacin and nicotinamide metabolism,and caffeine metabolism.After LHH intervention,fecal metabolites showed the most significant changes,mainly involving vitamin B6 metabolism,vitamin digestion and absorption,histidine metabolism,fructose and mannose metabolism,and steroid biosynthesis.Conclusion LHH can improve cognitive impairment in obese rats mainly by regulating fecal metabolites.The main pathways involved include vitamin B6 metabolism,vitamin digestion and absorption,histidine metabolism,fructose and mannose metabolism,and steroid biosynthesis.Among them,vitamin B6 metabolism and vitamin digestion and absorption may be the most important pathways.

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.