Xuebijing Injection Maintains GRP78 Expression to Prevent Candida albicans–Induced Epithelial Death in the Kidney

Abstract

Sepsis and septic shock threaten the survival of millions of patients in the intensive care unit. Secondary fungal infections significantly increased the risk of mortality in sepsis patients. Chinese medicine Xuebijing injection (XBJ) has been routinely used as an add-on treatment to sepsis and septic shock in China. Our network pharmacology analysis predicted that XBJ also influences fungal infection, consisting with results of pioneer clinical studies. We conducted in vivo and in vitro experiments to verify this prediction. To our surprise, XBJ rescued mice from lethal Candida sepsis in a disseminated Candida albicans infection model and abolished the colonization of C. albicans in kidneys. Although XBJ did not inhibit the growth and the virulence of C. albicans in vitro, it enhanced the viability of 293T cells upon C. albicans insults. Further RNA-seq analysis revealed that XBJ activated the endoplasmic reticulum (ER) stress pathway upon C. albicans infection. Western blot confirmed that XBJ maintained the expression of GRP78 in the presence of C. albicans. Interestingly, key active ingredients in XBJ (C0127) mirrored the effects of XBJ. C0127 not only rescued mice from lethal Candida sepsis and prevented the colonization of C. albicans in kidneys, but also sustained the survival of kidney epithelial cells partially by maintaining the expression of GRP78. These results suggested that XBJ may prevent fungal infection in sepsis patients. Pre-activation of ER stress pathway is a novel strategy to control C. albicans infection. Network pharmacology may accelerate drug development in the field of infectious diseases.

Paeoniflorin and Hydroxysafflor Yellow A in Xuebijing Injection Attenuate Sepsis-Induced Cardiac Dysfunction and Inhibit Proinflammatory Cytokine Production

“…The animals were randomly divided into five groups, sham group, CLP group, CLP + Xuebijing group, CLP + C0127 group, and CLP + C0127-2 group. C0127 was defined as the combination of paeoniflorin (2 mg/ml, CAS #:23180-57-6), hydroxysafflor yellow A (0.5 mg/ml, CAS #: 78281-02-4), ferulic acid (0.02 mg/ml, CAS # 537-98-4), and protocatechuic aldehyde (0.01 mg/ml, CAS #: 139-85-5) at the indicated concentrations (Shang et al, 2019). C0127-2 was defined as the combination of paeoniflorin (2 mg/ml, CAS #:23180-57-6) and hydroxysafflor yellow A (0.5 mg/ml, CAS #: 78281-02-4) at the indicated concentration.…”

“…Paeoniflorin claims the highest concentration and hydroxysafflor yellow A claims the 2 nd highest concentration among all detectable compounds in Xuebijing injection (Cheng et al, 2016;Shang et al, 2019;Li et al, 2020a). A series of studies indicated these two compounds are promising Xuebijing constituents of therapeutic importance (Cao et al, 2011;Zhai and Guo, 2016b;Cheng et al, 2016;Zou et al, 2018;Shang et al, 2019). Paeoniflorin improved survival and cardiac function in LPS-treated rodents (Cao et al, 2011;Zhai and Guo, 2016b;Liu et al, 2016).…”

“…Showing promising clinical effect in managing severe COVID-19 and saving thousands of lives in China, it was recently approved to treat moderate and severe CVOID-19 in China (Fan et al, 2020). Activating circulation and remove stasis, XBJ maintains the balance of the immune system and renders organ protections during systemic infection (Liu et al, 2014a;Chen et al, 2018;Shang et al, 2019). Paeoniflorin claims the highest concentration and hydroxysafflor yellow A claims the 2 nd highest concentration among all detectable compounds in Xuebijing injection (Cheng et al, 2016;Shang et al, 2019;Li et al, 2020a).…”

“…Activating circulation and remove stasis, XBJ maintains the balance of the immune system and renders organ protections during systemic infection (Liu et al, 2014a;Chen et al, 2018;Shang et al, 2019). Paeoniflorin claims the highest concentration and hydroxysafflor yellow A claims the 2 nd highest concentration among all detectable compounds in Xuebijing injection (Cheng et al, 2016;Shang et al, 2019;Li et al, 2020a). A series of studies indicated these two compounds are promising Xuebijing constituents of therapeutic importance (Cao et al, 2011;Zhai and Guo, 2016b;Cheng et al, 2016;Zou et al, 2018;Shang et al, 2019).…”

Endoplasmic reticulum stress regulates cell injury in lipopolysaccharide-induced nerve cells

“…8 Thus, the maintenance of ER stress at normal levels plays a vital role in reducing the tissue injury caused by sepsis. 9 Glucose-regulated protein 78 (GRP78), which belongs to the HSP70 family of molecular chaperones, is constitutively expressed in the ER lumen and is involved in the folding and trafficking of secretory and transmembrane proteins. 10 Overall, GRP78 plays a key role in regulating UPR response in cells during ER stress.…”