Formation of Hyperprogression of Immunotherapy from Perspective of "Yang Deficiency and Toxin Knot" and Role of "Five Views on Differentiation and Treatment" Intervention / 中国实验方剂学杂志

Immune checkpoint inhibitors （ICIs） have shown good efficacy in tumor treatment and have changed the landscape of tumor treatment. However， some patients treated with ICIs have not only failed to achieve the desired therapeutic effect， but also developed an atypical response pattern of abnormally accelerated tumor growth， namely hyperprogressive disease （HPD）. The pathogenesis of HPD is still unclear and it is difficult to diagnose， which poses a challenge for clinical identification and treatment decisions. Exploring the underlying mechanism of HPD is important to improve the effect of immunotherapy. Based on the theory of "Yang deficiency and toxic knot"， this paper discussed the mechanism of HPD in immunotherapy from the perspective of "spleen and kidney Yang deficiency and hefty toxic pathogens". It was concluded that the inactivation of p53 oncogene and immunosuppressive microenvironment were the manifestations of the deficiency of healthy qi in the body and declined yang in the spleen and kidney， serving as an important basis for the occurrence of HPD. Adverse reactions caused by ICIs belong to the category of "drug toxicity". The occurrence and development of murine double minute 2 （MDM2）/murine double minute 4 （MDM4） activation， epidermal growth factor receptor （EGFR） mutation， and tumor inflammatory microenvironment are the manifestations of the hyperactivity of pathogenic Qi， conflict of cancer toxicity and drug toxicity， and being hefty by virtue of deficiency， which can promote the abnormal proliferation of tumor cells， and they are the core pathogenic elements of HPD and are closely related to disease prognosis. In terms of treatment， under the guidance of the theory of "five views on differentiation and treatment" （time-space view， core view， symptom view， precision view， and disease-before-onset view）， which was summarized according to the clinical practice of this research team， this paper， taking the prevention and treatment of HPD as the entry point， formulated traditional Chinese medicine （TCM） compounds to reinforce healthy Qi and warm Yang and realize the dynamic management of the whole spatiotemporal cycle， and removed toxins and resisted cancer to realize the all-round systemic intervention of the specimen. Additionally， targets were enriched in the macro-clinical manifestations and microscopic pathological changes of HPD to improve the targeting of drug selection and the precision of prevention and treatment， giving full play to the unique therapeutic advantages of TCM， and providing new ideas for the clinical application of TCM in the prevention and treatment of HPD.

Vitamin D receptor (VDR) mediates the quiescence of activated hepatic stellate cells (aHSCs) by regulating M2 macrophage exosomal smooth muscle cell-associated protein 5 (SMAP-5) / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism. Hepatic fibrosis is characterized by activated hepatic stellate cells (aHSCs) with an excessive production of extracellular matrix. Although promoted activation of HSCs by M2 macrophages has been demonstrated, the molecular mechanism involved remains ambiguous. Herein, we propose that the vitamin D receptor (VDR) involved in macrophage polarization may regulate the communication between macrophages and HSCs by changing the functions of exosomes. We confirm that activating the VDR can inhibit the effect of M2 macrophages on HSC activation. The exosomes derived from M2 macrophages can promote HSC activation, while stimulating VDR alters the protein profiles and reverses their roles in M2 macrophage exosomes. Smooth muscle cell-associated protein 5 (SMAP-5) was found to be the key effector protein in promoting HSC activation by regulating autophagy flux. Building on these results, we show that a combined treatment of a VDR agonist and a macrophage-targeted exosomal secretion inhibitor achieves an excellent anti-hepatic fibrosis effect. In this study, we aim to elucidate the association between VDR and macrophages in HSC activation. The results contribute to our understanding of the pathogenesis mechanism of hepatic fibrosis, and provide potential therapeutic targets for its treatment.

Liver injury induced by hydrodynamic injection and natural repair of liver in mice / 吉林大学学报(医学版)

Objective:To observe the morphological features of liver injury induced by hydrodynamic injection, and to explore the procedure and mechanism of liver repair. Methods:Twenty-five female Balb/c mice were intravenously injected with large volume of saline solution(1.8-2.0 mL)in 3 s. The mice were divided into 30 min,8 h,1 d,3 d,and 7 d groups according to the post-injection time.Each group contained 5 mice.Six non-injected mice were used as control group.The blood samples from angular vein of the mice were collected to detect the levels of alanine transaminase(ALT).The morphological features of liver tissue of the mice in various groups were observed with HE staining.The proliferating cell nuclear antigen(PCNA)protein expressions in liver tissue of the mice in various groups were detected by immunohistochemical saining.The expression levels of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),epidermal growth factor(EGF),hepatocyte growth factor (HGF),transforming growth factor-α(TGF-α),Cyclin D1,vascular endothelial growth factor(VEGF),Bax and Bcl-2 mRNA were determined by Real-time PCR.Results:Compared with control group,the ratio of liver weight/original body weight in 8 h group was significantly decreased(P<0.05),but there was no significant difference in 7 d group(P>0.05).Compared with control group,the serum ALT level in 1 d group was significantly elevated (P<0.01),but there was no significant difference in 7 d group(P>0.05).Compared with control group,the liver tissue of the mice in 30 min group showed hepatocyte swollen and small hemorrhagic area,and the number of hepatocytes per high power field was significantly declined(q=4.760,P<0.05)under microscope.Compared with 30 min group,the number of swollen cells was decreased in 8 h group,the hemorrhagic and necrotic area enlarged, both of the hepatocyte number and binuclear hepatocyte number per high power field were significantly increased (q=7.310,P<0.01;q=7.200,P<0.01).Compared with 8 h group,the hemorrhagic and necrotic areas in 1 d group were reduced,both of the hepatocyte number and binuclear hepatocyte number per high power field were significantly decreased(q=4.966,P<0.05;q=6.596,P<0.01);there were no significant differences compared with control group(P>0.05).The hemorrhagic and necrotic areas almost disappeared in 3 d group.The histological appearance of liver tissue of the mice in 7 d group was same as control group.Compared with control group,the PCNA indexes in hepatocytes in 8 h and 1 d groups were significantly increased(t=4.458,P<0.01;t=15.557,P<0.01);there was no significant difference in 7 d group(P>0.05).Compared with control group, the PCNA index in cholangiocytes in 30 min group was increased significantly(t=3.985,P<0.01);there was no significant difference in 7 d group(P>0.05).The mRNA expression levels of TNF-α,IL-6,EGF,and VEGF in liver tissue of the mice in 30 min group were significantly higher than those in 8 h group(q=4.952,P<0.05;q=14.750,P<0.01;q=14.750,P<0.01;q=13.551,P<0.01).The HGF mRNA expression level in liver tissue of the mice in 3 d group was significantly higher than those in 30 min group and 8 h group(q=5.031,P<0.05;q=4.631,P<0.05).The TGF-αmRNA expression levels in liver tissue of the mice in 8 h group and 1 d group were higher than that in 30 min group(q=4.592,P<0.05;q=8.137,P<0.01).The Cyclin D1 mRNA expression levels in liver tissue of the mice in 8 h group and 1 d group were higher than that in 7 d group(q=4.736, q=5.213,P<0.05).The Bax/Bcl-2 ratio of the mice in 1 d group was higher than that in 30 min group(q=5.731,P<0.01).Conclusion:Acute liver injury induced by hydrodynamic injection mainly shows the hepatocyte swelling and hemorrhagic necrosis.The injury could be repaired naturally in a week.The various cytokines and growth factors related with liver regeneration are involved in the repair procedure.