Background: Influenza A virus (IAV) is a negative-sense RNA virus of the Orthomyxoviridae family and is the etiological agent of a highly contagious acute respiratory disease that can lead to acute lung injury. Objective: To elucidate the molecular mechanisms of IAV infection, an integrative research approach combining gene expression profiling, multinetwork analysis, and in vivo experimental validations was employed. Methods: First, a series of network-based analyses were performed, including protein-protein interaction network construction, weighted gene co-expression network analysis, and subsequent gene set enrichment analysis, to identify the major underlying mechanisms of IAV infection. Following gene expression analysis, core targets, both direct and indirect regulators, were screened. An IAV (H1N1) strain A/PR/8/34-induced acute lung injury mouse model was constructed for in vivo validations. Batch one included two groups to evaluate findings from the multi-network analysis: Mock (n = 10; 5 males and 5 females) and IAV (n = 10; 5 males and 5 females). Batch two included three groups to assess the role of toll-like receptor 3 (TLR3) in IAV infection: Mock (n = 6; 3 males and 3 females), IAV (n = 6; 3 males and 3 females), and TLR3 inhibitor (n = 6; 3 males and 3 females). Body weight was measured on days 0, 3, and 5 after infection. On day 5, lung tissues were collected to assess viral load and histopathological changes. Key targets were examined using enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence staining, both in sera and lung tissues. Results: IAV infection was significantly associated with dysregulation of the immune-inflammation system, such as the LTR, nucle-otide-binding oligomerization domain-(NOD) like receptor, retinoic acid-inducible gene I-like receptor, and nuclear factor kappa-B signaling pathways. Gene set enrichment analysis further indicated that the TLR and necroptosis signaling pathways played crucial roles in the progression of IAV infection (TLR signaling pathway normalized enrichment score = 2.3941, P = 1.00 × 10 ⁻¹⁰; necroptosis normalized enrichment score = 1.9421, P = 6.21 × 10 ⁻⁷). Among the core targets, TLR3 and mixed lineage kinase domain-like protein (MLKL) may regulate gene expression at the transcriptional level (all P < 0.05). In vivo validation using an IAV (PR8) infected acute lung injury mouse model demonstrated increased viral load and lung index, alveolar structural damage, and inflammatory cell infiltration. Immunofluorescence staining exhibited large gaps in Lamin B1 staining and breaches in Emerin signals following IAV-PR8 infection. Expression levels of TLR3, p-receptor-interacting serine/threonine-protein kinase 3 (RIPK3)/RIPK3, and p-mixed lineage kinase domain-like protein (MLKL)/MLKL proteins in lung tissues, as well as proinflammatory factors and mediators in sera, were significantly elevated after IAV infection. Moreover, enhanced neutrophil infiltration (myeloperoxidase) and citrullinated histone H3 (a neutrophil extracellular trap-specific marker), both established indicators of neutrophil extracellular trap formation, were observed. Notably, treatment with a TLR3 inhibitor significantly ameliorated IAV-induced acute lung injury by regulating necroptosis-related targets. Conclusion: Our study provides network-based in vivo evidence that TLR3-receptor-interacting serine/threonine-protein kinase 3-MLKL-mediated necroptosis may underlie IAV-induced acute lung injury and could serve as a potential therapeutic target in severe influenza cases.

Malignant tumor metastasis is the key factor leading to poor prognosis of patients， and it is a difficult problem to be overcome in the field of tumor therapy. Metabolic reprogramming， as a key link in the regulation of tumor metastasis activity， affects the growth， invasion， and metastasis of tumor cells by changing the metabolic pathways of intracellular substances （such as glucose， amino acids， lipids， and nucleotides）. In particular， metabolic reprogramming plays a key role in the multistage linked steps related to tumor metastasis and can play a crucial role in several key stages of tumor tissue dissociation in situ， hematogenous metastasis， and remote colonization. Malignant tumor cells can selectively adjust their own metabolic state to adapt to the growth conditions of different metastatic microenvironments and colonization sites and then choose the most favorable growth and metabolism strategy. According to the holistic concept of traditional Chinese medicine （TCM）， the metastasis of malignant tumors is generally closely related to the metabolic state of the whole body. One of the advantages of TCM in the treatment of malignant tumors is systemic regulation. With its multi-pathway， multi-target， and multi-component therapeutic characteristics， TCM can effectively control the metastasis of malignant tumors by regulating the degradation of tumor epithelial mesenchymal transformation （EMT） and extracellular matrix （ECM）， anchoring the independent growth of tumor cells and the tumor microenvironment. In this paper， the potential regulatory effects of metabolic reprogramming on the metastasis of malignant tumors were discussed， and the latest research progress of the regulation of metabolic reprogramming by TCM on tumor metastasis was reviewed. At the same time， the key targets of TCM and its bioactive components in the process of tumor metastasis intervention were reviewed. This study aims to provide a more valuable basis and clearer idea for the treatment of malignant tumor metastasis by regulating metabolic reprogramming with TCM.

Portal hypertensive biliopathy is a secondary condition of intrahepatic and extrahepatic bile duct abnormalities caused by portal hypertension, especially in extrahepatic portal venous obstruction. Most patients may remain asymptomatic for a long time, while a few may present with symptomatic portal hypertensive biliopathy, such as obstructive jaundice, cholelithiasis with or without cholangitis, gastrointestinal bleeding, and others. Such disease is rare in clinical practice and is prone to misdiagnosis and missed diagnosis. Improper treatment can lead to serious adverse consequences. We report a case of unexpected discovery of bile duct dilation due to abdominal pain, which was ultimately diagnosed as portal hypertensive biliopathy based on the medical history, manifestations of portal hypertension, and imaging examinations, especially intraductal ultrasonography.

Portal hypertensive biliopathy is a secondary condition of intrahepatic and extrahepatic bile duct abnormalities caused by portal hypertension, especially in extrahepatic portal venous obstruction. Most patients may remain asymptomatic for a long time, while a few may present with symptomatic portal hypertensive biliopathy, such as obstructive jaundice, cholelithiasis with or without cholangitis, gastrointestinal bleeding, and others. Such disease is rare in clinical practice and is prone to misdiagnosis and missed diagnosis. Improper treatment can lead to serious adverse consequences. We report a case of unexpected discovery of bile duct dilation due to abdominal pain, which was ultimately diagnosed as portal hypertensive biliopathy based on the medical history, manifestations of portal hypertension, and imaging examinations, especially intraductal ultrasonography.

Objective: The R language was used to quantitatively compare the medication patterns of Mongolian medicines used for the treatment of liver diseases between China and Mongolia, with a view to provide a reference for the research and clinical application of Mongolian medicines in the treatment of liver diseases. Methods: The Mongolian medicinal prescriptions used for treating liver disease in Mongolia were collected from the Mongolian Pharmacy and Mongolian Treatment Guide for Common diseases in Mongolian Medicine, and those used in China were collected from the Inner Mongolia Standard for Mongolian Proprietary Medicine and Annotation of Mongolian Medicine Preparation Specifications. After the database was established, the frequency, properties, and tastes of the Mongolian medicines were analyzed, and R studio was used for the association rules analysis and cluster analysis. Results: A total of 27 prescriptions used in Inner Mongolia, China, were collected involving 105 Mongolian medicines, with a total frequency of 284. Among them, there were 18 high-frequency medicines (frequency ≥5), which had a frequency of 147, accounting for 51.76% of the total frequency. The medicine with the highest frequency (14, 4.93%) was Carthamus tinctorius L.. The analysis of the medicine data in China revealed 15 association rules. A total of 21 prescriptions used in Mongolia were collected, involving 92 Mongolian medicines, with a total frequency of 254. Among them, there were 17 high-frequency (frequency ≥5) medicines, with a total frequency of 124 (48.82%). The medicine with the highest frequency (13, 5.12%) was Carthamus tinctorius L.. The analysis of the medicine data in Mongolia revealed 79 association rules. In both regions, the high-frequency medicines used for treating liver disease commonly had cool or warm property with bitter or sweet taste. Conclusions: Carthamus tinctorius L., Terminalia chebula Retz., and other Mongolian medicines are commonly used to treat liver diseases in Inner Mongolia and Mongolia. The Mongolian medicines with cool or warm property and bitter, sweet, or astringent taste are commonly used to protect the liver.

Objective:To investigate the effects of different intensity of lighting on normal refractive development and form deprivation myopia (FDM) in guinea pigs.Methods:A total of 108 healthy 3-week-old guinea pigs were divided into normal refractive development guinea pigs ( n=54) and FDM guinea pigs ( n=54). FDM models were prepared in FDM animals by occlusion of the left eyes using an opaque mask, and the bilateral eyes were open in the normal refractive development guinea pigs.The guinea pigs were randomized to low (20 lx), normal(300 lx), and high intensity-lighting (5 000 lx) groups with a 12-hour light/12-hour dark cycle for 6 consecutive weeks under LED light.The ocular biometry was performed in a two-week interval.Axial length (AL) and dilated diopter were measured by A-scan ultrasonography and retinoscopy, respectively, and were compared after different lighting durations, and the change trends of them in normal refractive development and FDM guinea pigs were evaluated. Results:The AL values were not significantly different among low, normal and high intensity-lighting groups ( Fgroup=0.365, P=0.697), and the AL was gradually prolonged over the lighting duration ( Ftime=353.750, P<0.001). The diopters showed a statistically significant difference among different intensity-lighting groups ( Fgroup=3.576, P=0.034). The diopter in high intensity-lighting for 4 weeks was (+ 2.75±2.15) D, which was significantly higher than (0.41±3.07) D in the normal refrective development guinea pigs ( P<0.001). In the FDM guinea pigs, both AL and diopter were not significantly different among low, normal and high intensity-lighting groups ( Fgroup=0.105, P=0.900; Fgroup=0.973, P=0.387), and significant differences were seen in AL and diopter among three groups ( Ftime=408.302, 27.407; both at P<0.001). The diopter in FDM eyes of low intensity-lighting for 2 weeks was (+ 2.35±1.95) D, which was higher than (+ 1.90±0.97) D before lighting, with no statistically significant difference between them ( P>0.05). The AL was shortest and the AL change was smallest in normal refractive development guinea pigs of high intensity-lighting group.The diopter change in FDM guinea pigs of the low intensity-lighting group was significantly smaller than that in the normal intensity-lighting group ( P<0.001), with a transient hyperopia drift. Conclusions:The 5 000 lx lighting can slow down the development toward myopia in the normal refractive development eyes, and 20 lx lighting tends to delay the progression FDM eyes with a hyperopic shift after lighting for 2 weeks.

Nicotinamide phosphoribosyl transferase (NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation. However, therapeutic benefit of NAMPT enzymatic inhibitors appears very limited, likely due to the failure to intervene non-enzymatic functions of NAMPT. Herein, we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells (MDSCs) via a mechanism independent of its enzymatic activity. Using proteolysis-targeting chimera (PROTAC) technology, PROTAC A7 is identified as a potent and selective degrader of NAMPT, which degrades intracellular NAMPT (iNAMPT) via the ubiquitin-proteasome system, and in turn decreases the secretion of extracellular NAMPT (eNAMPT), the major player of the non-enzymatic activity of NAMPT. In vivo, PROTAC A7 efficiently degrades NAMPT, inhibits tumor infiltrating MDSCs, and boosts antitumor efficacy. Of note, the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on MDSCs. Together, our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment, and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT, pointing out a new direction for the development of NAMPT-targeted therapies.

OBJECTIVE：To study the effects of Modified liuwei dihuang decoction on kidney/bone injury of chronic kidney disease-mineral and bone disorder（CKD-MBD）model rats. METHODS ：The male SD rats were randomly divided into normal group（n＝10），high phosphorus group （n＝30），model group （n＝30），calcitriol group （positive control ，0.09 μg/kg，n＝30）， Modified liuwei dihuang decoction group （10 g/kg by crude drug ，n＝30）. CKD-MBD model was established by high phosphorus and adenine diet for 6 weeks. After modeling ，normal group and model group were given normal diet/high phosphorus diet and intragastric administration of water. Administration groups were fed with normal diet and given corresponding solution intragastrically（water as solvent ），0.1 mL/kg，once a day ，for consecutive 6 weeks. Blood sample of rats in the normal group were collected ，and they were sacrificed after the last administration. Blood sample of 10 rats in each other group were collected ， and they were sacrificed at 2，4 and 6 weeks after administration. The contents of blood urea nitrogen （BUN），serum creatinine （Scr），calcium，phosphorus，iPTH，FGF-23，RANKL and osteocalcin in serum were detected in each group. The bone mineral density（BMD）of femoral was measured ，the morphological changes of renal tissue and bone tissue were observed ，and the percentage of renal tubular injury and the score of renal interstitial fibrosis were calculated. RESULTS ：Compared with normal group，above indexes in high phosphorus group had no significant change at different time points （P＞0.05）. There was no abnormal change in renal/bone tissue. Compared with high phosphorus group at the same time point ，the contents of BUN ，Scr， phosphorus，iPTH，FGF-23，RANKL and osteocalcin in serum ，the percentage of renal tubular injury and the score of renal interstitial fibrosis in the model group were significantly increased ，while the contents of calcium in serum and the BMD of femoral were significantly decreased （P＜0.05 or P＜0.01）. The renal tissue showed diffuse fibrosis. The width of trabecular bone was increased and the number of osteoblasts was decreased. Compared with the model group at the same time point ，the contents of BUN（except for Modified liuwei dihuang decoction group after 2 weeks of administration ），Scr，serum phosphorus ，iPTH， FGF-23，RANKL and osteocalcin ，the percentage of renal tubular injury and the score of renal interstitial fibrosis in Modified liuwei dihuang decoction group and calcitriol group were decreased significantly at each time point ；serum calcium content and BMD（except for 2 weeks of administration ）were significantly increased （P＜0.05 or P＜0.01），and the pathological changes of renal/bone tissue were significantly improved ；there was no statistical significance in above indexes between Modified liuwei dihuang decoction group and calcitriol group （P＞0.05）. CONCLUSIONS ：Modified liuwei dihuang decoction can improve kidney/ bone injury of CKD-MBD model rats ，and improve BMD and regulate disorder of calcium and phosphorus metabolism.

Objective To evaluate the position of the fetal conus medullaris during pregnancy and its value in detecting tethered cord syndrome(TCS). Methods Nine hundred and seventy-four normal fetuses and 46 fetuses with TCS between 15 and 41 weeks gestation were involved in the study.Parameters D 1 (the distance between the end of the conus medullaris and the caudal edge of last vertebral body ossification center) and D2 (the distance from the end of the conus medullaris to the caudal skin namely the intersection point of the extending line of D1 and the skin) were measured in the caudal midsagittal plane of the spine. Sixty normal fetuses were chosed randomly for interobserver variability.Correlation analysis between these two parameters and gestational age(GA) were conducted and the normal reference value of these parameters were calculated in normal group. The ratios of growth parameters ( Biparietal diameter, Head circumference,Abdominal circumference,Femur length) to D1 and D2 were calculated separately to observe the difference of the ratios between two groups. All the parameters and ratios of normal fetuses were compared with that of TCS cases.Results There was no significant difference in D1 and D2 between two observers.A significant linear correlation between the parameters and GA was found in normal group,linear regression equations were D1=0.251 GA -2.265 cm (R2=0.926,P <0.01) and D2=0.267 GA -1.812 cm(R2=0.928,P <0.01),respectively.D1 and D2 were much lower in normal group than in abnormal group (all P <0.01). The ratios of the growth parameters to D1 and D2 were relatively stable and had statistically differences between two groups in different gestational age. Conclusions The methods that determination of D1 and D2 are simple and feasible,and could help to the prenatal diagnosis of TCS.

Objective To explore the effects of leukoaraiosis on cognitive function in elderly patients after acute cerebral infarction.Methods From May 2010 to August 2011,a total of 147 elderly patients with acute cerebral infarction were enrolled,including 96 patients with leukoaraiosis and 51 patients without leukoaraiosis.The Montreal Cognitive Assessment (MOCA) and the correlative factors of cognitive function were assessed in all patients.Results There was no statistical difference in general information between patients with and without leukoaraiosis.There were significant differences in the MoCA scores between patients with and without leukoaraiosis (x2 =19.15,P＜0.01),as well as between the vital and non-vital positions of cerebral infarction (x2=21.41,P＜0.01).The Logistic regression analysis showed that the vital position of infarction and leukoaraiosis were related to the cognitive impairment (OR=12.27,6.60,both P＜0.01),while the area of infarction and the type of cerebral infarction in Oxford County Community Stroke Project (OCSP) had no effects on cognitive impairment.Pearson correlation analysis showed that there was a positive relationship between the degree of white matter lesions and the decline in cognitive function (r=-0.87,P＜0.01).Conclusions The position of acute cerebral infarction and leukoaraiosis are independent risk factors for cognitive function after acute cerebral infarction,and the former plays a more important role than does the latter.