Cross-Sectional Variations of Illiquidity on Stock Returns,Idiosyncratic Volatility Biases in the Shanghai A’Share Stock Market

Under the NTS Reform(Non-Tradable Share Reform),this paper explores the cross-sectional relations between illiquidity and stock returns by considering the idiosyncratic volatility biases in the Shanghai A’Share stock market.Differing from prior studies,stock returns are decreasing in a stock’s illiquidity both before and after the NTS Reform.Regarding the negative relation between illiquidity and stock returns,we find that stock returns show no clear relation with illiquidity after controlling for idiosyncratic volatility biases.Furthermore,we use residual approach to eliminate the effect of idiosyncratic volatility,and find there exists a positive relation between illiquidity and stock returns after the NTS Reform.

Compatibility with Fructus Ligustri Lucidi Effectively Mitigates Idiosyncratic Liver Injury of Epimedii Folium by Modulating NOD-like Receptor Family Pyrin Domain Containing 3 Inflammasome Activation

Background: Idiosyncratic drug-induced liver injury(IDILI) is a serious side effect of drugs, Epimedii Folium(EF) is unequivocally implicated in idiosyncratic liver injury onset, potentially due to its ability to perturb the NOD-like receptor family pyrin domain containing 3(NLRP3) inflammasome. Fructus Ligustri Lucidi(FLL), a frequently used medicinal combination with EF, has not yet been investigated for its ability to ameliorate EF-associated hepatotoxicity. Aims and Objectives: Study on the mechanism of compatibility of FLL to alleviate liver injury caused by EF. Materials and Methods: Western blot was used to determine the expression of related proteins, ELISA was used to detect the secretion of related inflammatory factors IL-1β, IL-18, IL-6 and TNF-α, liver injury indexes were detected and liver pathological tissue staining was used to evaluate the liver injury. Results: Our results demonstrated that EF exerted a particular augmenting effect on the stimulation of the NLRP3 inflammasome mediated by nigericin or ATP, whereas FLL suppressed the NLRP3 inflammasome stimulation. Furthermore, an equal EF to FLL ratio significantly reduced the stimulatory effects of EF. Moreover, EF has the potential to induce hepatic injury and augment pro-inflammatory cytokine synthesis in rats subjected to LPS. However, when combined with FLL, the detrimental effects of EF were mitigated. Conclusions: FLL possesses the capacity to attenuate EF-associated hepatotoxicity by suppressing EF-triggered NLRP3 inflammasome activation. Thus, FLL holds promise for improving the clinical safety profile of EF, shedding light on the potential of compatibility and detoxification theories in traditional Chinese medicine.

New incompatible pair of TCM:Epimedii Folium combined with Psoraleae Fructus induces idiosyncratic hepatotoxicity under immunological stress conditions

Epimedii Folium(EF)combined with Psoraleae Fructus(PF)is a common modern preparation,but liver injury caused by Chinese patent medicine preparations containing EF and PF has been frequently reported in recent years.Zhuangguguanjiewan pills(ZGW),which contain EF and PF,could induce immune idiosyncratic liver injury according to clinical case reports and a nonhepatotoxic dose of lipopolysaccharide(LPS)model.This present study evaluated the liver injury induced by EF or PF alone or in combination and investigated the related mechanism by using the LPS model.Liver function indexes and pathological results showed that either EF or PF alone or in combination led to liver injury in normal rats;however,EF or PF alone could lead to liver injury in LPS-treated rats.Moreover,EF combined with PF could induce a greater degree of injury than that caused by EF or PF alone in LPS-treated rats.Furthermore,EF or PF alone or in combination enhanced the LPS-stimulated inflammatory cytokine production,implying that IL-1β,which is processed and released by activating the NLRP3 inflammasome,is a specific indicator of EF-induced immune idiosyncratic hepatotoxicity.Thus,EF may induce liver injury through enhancing the LPS-mediated proinflammatory cytokine production and activating the NLRP3 inflammasome.In addition,the metabolomics analysis results showed that PF affected more metabolites in glycerophospholipid and sphingolipid metabolic pathways compared with EF in LPS model,suggesting that PF increased the responsiveness of the liver to LPS or other inflammatory mediators via modulation of multiple metabolic pathways.Therefore,EF and PF combination indicates traditional Chinese medicine incompatibility,considering that it induces idiosyncratic hepatotoxicity under immunological stress conditions.

Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum

The main constituents of a typical medicinal herb, Polygonum multiflorum （Heshouwu in Chinese）, that induces idiosyncratic liver injury remain unclear. Our previous work has shown that cotreatment with a nontoxic dose of lipopolysaccharide （LPS） and therapeutic dose of Heshouwu can induce liver injury in rats, whereas the solo treatment cannot induce observable injury. In the present work, using the constituent ＂knock-out＂ and ＂knock-in＂ strategy, we found that the ethyl acetate （EA） extract of Heshouwu displayed comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Results indicated a significant elevation of plasma alanine aminotransferase, aspartate aminotransferase, and liver histologic changes, whereas other separated fractions failed to induce liver injury. The mixture of EA extract with other separated fractions induced comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Chemical analysis further revealed that 2,3,5,4＇-tetrahydroxy trans-stilbene-2-O-p-glucoside （trans-SG） and its cis-isomer were the two major compounds in EA extract. Furthermore, the isolated cis-, and not its trans-isomer, displayed comparable idiosyncratic hepatotoxicity to EA extract in LPS-treated rats. Higher contents of cis-SG were detected in Heshouwu liquor or preparations from actual liver intoxication patients associated with Heshouwu compared with general collected samples. In addition, plasma metabolomics analysis showed that cis-SG-disturbing enriched pathways remarkably differed from trans-SG ones in LPS-treated rats. All these results suggested that cis-SG was closely associated with the idiosyncratic hepatotoxicity of Heshouwu. Considering that the cis-trans isomerization oftrans- SG was mediated by ultraviolet light or sunlight, our findings serve as reference for controlling photoisomerization in drug discovery and for the clinical use of Heshouwu and stilbene-related medications.

Icariside Ⅱ, a main compound in Epimedii Folium, induces idiosyncratic hepatotoxicity by enhancing NLRP3 inflammasome activation

Idiosyncratic drus-induced liver injury(IDILI)is an intrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs.Epimedii Folium(EF),the widely used herbal medicine,has shown to cause idiosyncratic liver injury,but the underlying mechanisms are poorly understood.Increasing evidence has indicated that most cases of IDILI are immune mediated.Here,we report that icarisideⅡ(ICSⅡ),the major active and metabolic constituent of EF,causes idiosyncratic liver injury by promoting NLRP3 inflammasome activation.ICSⅡexacerbates NLRP3 inflammasome activation triggered by adenosine triphosphate(ATP)and nigericin,but not silicon dioxide(SiO2),monosodium urate(MSU)crystal or cytosolic lipopolysaccharide(LPS).Additionally,the activation of NLRC4 and AIM2 inflammasomes is not affected by ICSⅡ.Mechanistically,synergistic induction of mitochondrial reactive oxygen species(mtROS)is a crucial contributor to the enhancing effect of ICSⅡon ATP-or nigericin-induced NLRP3 inflammasome activation.Importantly,in vivo data show that a combination of non-hepatotoxic doses of LPS and ICSⅡcauses the increase of aminotransferase activity,hepatic inflammation and pyroptosis,which is attenuated by Nlrp3 deficiency or pretreatment with MCC950(a specific NLRP3 inflammasome inhibitor).In conclusion,these findings demonstrate that ICSⅡcauses idiosyncratic liver injury through enhancing NLRP3 inflammasome activation and suggest that ICSⅡmay be a risk factor and responsible for EF-induced liver injury.

Bavachin enhances NLRP3 inflammasome activation induced by ATP or nigericin and causes idiosyncratic hepatotoxicity

Psoraleae Fructus(PF)is a well-known traditional herbal medicine in China,and it is widely used for osteoporosis,vitiligo,and other diseases in clinical settings.However,liver injury caused by PF and its preparations has been frequently reported in recent years.Our previous studies have demonstrated that PF could cause idiosyncratic drug-induced liver injury(IDILI),but the mechanism underlying its hepatotoxicity remains unclear.This paper reports that bavachin isolated from PF enhances the specific stimuli-induced activation of the NLRP3 inflammasome and leads to hepatotoxicity.Bavachin boosts the secretion of IL-ip and caspase-1 caused by ATP or nigericin but not those induced by poly(I:C),monosodium urate crystal,or intracellular lipopolysaccharide.Bavachin does not affect AIM2 or NLRC4 inflammasome activation.Mechanistically,bavachin specifically increases the production of nigericin-induced mitochondrial reactive oxygen species among the most important upstream events in the activation of the NLRP3 inflammasome.Bavachin increases the levels of aspartate transaminase and alanine aminotransferase in serum and hepatocyte injury accompanied by the secretion of IL-ip via a mouse model of lipopolysaccharide-mediated susceptibility to IDILI.These results suggest that bavachin specifically enhances the ATP-or nigericin-induced activation of the NLRP3 inflammasome.Bavachin also potentially contributes to PF-induced idiosyncratic hepatotoxicity.Moreover,bavachin and PF should be evaded among patients with diseases linked to the ATP-or nigericin-mediated activation of the NLRP3 inflammasome,which may be a dangerous factor for liver injury.

Idiosyncratic Drug-Induced Liver Injury Linked to Polygonum multiflorum:A Case Study by Pharmacognosy

The use of Chinese medicinal herbs（CMH）continues to expand rapidly across the world with a deep belief that herbs are safe because they are＂natural＂.（1）However,a survey of the literature indicates that CMH related hepatotoxicity is increasing and has been a worldwide problem.（2,3）Polygonum multiflorum Thunb.（P.multiflorum）,officially listed in the Pharmacopoeia of the People＇s Republic of China.

Acute hepatitis after amiodarone infusion

Acute hepatitis is a very rare, but potentially fatal, adverse effect of intravenous amiodarone. We present a case of an 88-year-old man with history of ischemic dilated cardiomyopathy and severely depressed left ventricular function that was admitted to our coronary care unit with diagnosis of decompensated heart failure and non-sustained ventricular tachycardia. A few hours after the beginning of intravenous amiodarone he developed an acute hepatitis. There was a completely recovery within the next days after amiodarone withdrawn and other causes of acute hepatitis have been ruled out. This case highlights the need for close monitoring of hepatic function during amiodarone infusion in order to identify any potential hepatotoxicity and prevent a fatal outcome. Oral amiodarone is, apparently, a safe option in these patients.

Systematic review and meta-analysis: Comparing hepatocellular and cholestatic patterns of drug-induced liver injury

Background and aims:Drug-induced liver injury(DILI)is a leading cause of death from acute liver failure(ALF).Hy's law warns that a hepatocellular pattern of injury accompanied by jaundice and normal alkaline phosphatase(ALP)levels is associated with a 10%or greater chance of progression to transplant or liver-related death.This meta-analysis of DILI studies evaluates acute and chronic outcomes of DILI according to clinical pattern of injury.Methods:We conducted a systematic search using electronic databases PubMed and EMBASE through to 8 March 2022.Our primary outcome was to compare acute outcomes including ALF,liver-related death,and liver transplant between patients experiencing hepatocellular,cholestatic,and mixed patterns of DILI.Our secondary outcome was to compare the rate of DILI chronicity between patients of these three differing patterns of injury.Pooled odds ratios(ORs)and 95%confidence intervals(CIs)were calculated using a random-effects model.Results:Overall,12 studies comprising 4290 patients were included.Patients with cholestatic DILI demonstrated similar rates of ALF(OR:0.80,95%CI:0.46–1.40,p=0.429)and liver-related death(OR:0.92,95%CI:0.50–1.69,p=0.792)compared to patients with hepatocellular DILI.Patients with cholestatic DILI were significantly more likely to experience chronicity compared to patients with hepatocellular DILI(OR:2.53,95%CI:1.34–4.79,p=0.004).

Hepatic macrophages in drug-induced liver injury

Drug-induced liver injury(DILI)is a major public health concern.Intrinsic DILI,for example,acetaminophen overdose accounts for half of acute liver failure in the United States.However,the most problematic type of DILI affecting drug development and health care is idiosyncratic DILI,which occurs unpredictably in a small population of patients taking the drug and the latency could be several weeks to months.Recent knowledge on the pathogenesis of DILI suggest that hepatic macrophages play a central role in the initiation,progression and restoration stages of DILI,which make hepatic macrophages attractive as therapeutic targets.Hepatic macrophages consist of liver resident macrophages(also known as Kupffer cells,KCs)and infiltrating monocyte-derived macrophages(MoMF).There is a growing appreciation that hepatic macrophage is very plastic,and assumes diverse phenotypes and functions in response to micro-environmental cues.In this review,we will summarize studies on the role of hepatic macrophages in both intrinsic DILI and idiosyncratic DILI,followed by discussing the prognostic and therapeutic potentials of targeting hepatic macrophages and the obstacles in studying hepatic macrophages.

Progress in the Clinical Features and Pathogenesis of Abnormal Liver Enzymes in Coronavirus Disease 2019

With the rapid development of research on coronavirus disease 2019(COVID-19),more and more attention has been drawn to its damage to extrapulmonary organs.There are increasing lines of evidence showing that liver injury is closely related to the severity of COVID-19,which may have an adverse impact on the progression and prognosis of the patients.What is more,severe acute respiratory syndrome coronavirus-2 infection,cytokine storm,ischemia/hypoxia reperfusion injury,aggravation of the primary liver disease and drug-induced liver injury may all contribute to the hepatic damage in COVID-19 patients;although,the drug-induced liver injury,especially idiosyncratic drug-induced liver injury,requires further causality confirmation by the updated Roussel Uclaf Causality Assessment Method published in 2016.Up to now,there is no specific regimen for COVID-19,and COVID-19-related liver injury is mainly controlled by symptomatic and supportive treatment.Here,we review the clinical features of abnormal liver enzymes in COVID-19 and pathogenesis of COVID-19-related liver injury based on the current evidence,which may provide help for clinicians and researchers in exploring the pathogenesis and developing treatment strategies.

Disease-based Toxicology on Safety Assessment Strategy and Application for Herbal and Traditional Medicines

The safety issue on herbal and traditional medicines(H&TM) is one of the most challenging problems and serious concern worldwide. With scientific endeavor and further exploration, we came to realize that there are great differences between H&TM and synthetic drugs in many aspects, such as medical theory, medication experience, compatibility, processing, toxicological characteristics, and safety evaluating requirements. In the current preclinical models for synthetic drugs, the safety assessment results of some conventional deemed 'nontoxic' H&TM were not well consistent with clinical situations, which resulted in major difficulties to understand the mechanisms and guide the safe and rational uses of these H&TM. Thus, based on the traditional Chinese medicine toxicity theory called You Gu Wu Yun, this paper introduces a novel safety assessment strategy for H&TM, named as disease-based toxicology. It aims to cognize the relativity and susceptibility of the toxicity of H&TM, and then to enhance controllability in new drug development and clinical applications. It also provides a theoretical practice for the traditional Chinese medicine toxicity theory and a methodological promotion for the future development of the precision toxicology for H&TM.

The Relationship between Firm-Specific Return Variation and Price Informativeness:Some Cross-Sectional Evidence

The progressive removal of short-selling constraints in the Chinese stock market provides us with a natural experiment to investigate the relationship between firm-specific return variation(FSRV)and price informativeness.Based on the empirical finding that idiosyncratic volatility is a satisfied proxy for FSRV when the information environment for individual firms improves,we mainly find that the FSRV is negatively related to price informativeness.This negative relationship is robust to alternative model specifications,alternative proxies for price informativeness,and alternative estimation windows.Generally speaking,our results complement the extant literature on the mixed relationships between FSRV and price informativeness by providing cross-sectional evidence.