Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

Drug-induced liver injury (DILI) can broadly be divided into predictable and dose dependent such as acetaminophen (APAP) and unpredictable or idiosyncratic DILI (IDILI). Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable) results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis) of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER) and mitochondrial stress) leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI) is usually the result of engagement of the innate and adaptive immune system (likely apoptotic), involving death receptors (DR). Here, we review the hepatocyte cell death pathways both in direct hepatotoxicity such as in APAP DILI as well as in IDILI. We examine the known signaling pathways in APAP toxicity, a model of necrotic liver cell death. We also explore what is known about the genetic basis of IDILI and the molecular pathways leading to immune activation and how these events can trigger hepatotoxicity and cell death

Hydroxycut hepatotoxicity: A case series and review of liver toxicity from herbal weight loss supplements

Dietary supplements represent an increasingly common source of drug-induced liver injury. Hydroxycut is a popular weight loss supplement which has previously been linked to hepatotoxicity, although the individual chemical components underlying liver injury remain poorly understood. We report two cases of acute hepatitis in the setting of Hydroxycut exposure and describe possible mechanisms of liver injury. We also comprehensively review and summarize the existing literature on commonly used weight loss supplements, and their individual components which have demonstrated potential for liver toxicity. An increased effort to screen for and educate patients and physicians about supplement-associated hepatotoxicity is warranted

PERBANDINGAN ANTARA MODEL ATURAN LEPASAN BERDASARKAN TAMPUNGAN DAN MODEL RULE CURVE UNTUK WADUK PENGGA

Abstrak : Penelitian ini untuk membandingkan an­ta­ra 2 alternatif aturan operasi waduk Pengga dalam mengatur debit lepasan guna memenuhi kebutuhan sepanjang tahun.  Waduk Pengga beroperasi dengan periode ½ bulanan.  Ada 2 alternatif yang disarankan untuk waduk Pengga, yaitu (1) aturan lepasan yang berdasarkan status tampungan waduk pada awal periode operasi, dan (2) rule curve sebagai batas bawah tampungan wa­duk pada setiap periode operasi.  A­tur­an operasi lepasan waduk dari masing-masing alternatif di­op­timasi untuk me­ning­kat­kan kinerjanya sampai mencapai batas maksimum, lalu dilakukan perbandingan antara kedua alternatif tersebut.  Sebelum dilakukan optimasi, dilakukan revisi terhadap struktur daripada ma­sing-masing aturan operasi untuk meningkatkan potensi perbaikan kinerja da­lam optimasi.  Pada aturan lepasan berdasarkan tampungan, revisi struktur di­pu­sat­kan pada peningkatan jumlah grid tampungan, sementara juga dicoba alternatif bentuk garis lepasan yang kontinyu disamping bentuk diskrit.  Sedangkan pada rule curve, re­vi­si struktur dipusatkan pada penambahan kurva-kurva sebagai batas bawah pelepasan bertingkat.  Untuk melakukan optimasi di­gu­nakan prosedur Evolutionary Solver yang ada pa­da perangkat Add-Ins Solver dari MS-Excel 2010. Kata kunci: aturan lepasan, status tampungan, rule curve.   Abstract : This research is the comparison of two alternatives of operating rule of the Pengga Reservoir for regulating the releases to fulfill the annual water demand.  The Pengga Reservoir operate in half-month periods.  Two alternatives being proposed for the release operating rule of Pengga Reservoir, (1) the release rule based on the reservoir storage state at the beginning of operating period, and (2) the Rule Curve as the lower boundary of reservoir storage at every operating period.  The reservoir release operating rule of each alternative is optimized to improve its performance until attain the maximum limit, then the comparison is conducted between the two alternatives.  Before the optimization, structural revisions are done on each operating rule to enhance the potency of performance improvement in the optimization.  In the Release Rule based on storage, the revisions are focused on the expansion of number of storage grid, beside also the  trial shape of continuous release line instead of discrete.  As for the Rule Curve, the revisions are focused on the additional curves as the lower bounds of stepped release.  The undertaking of this optimization study will use the Evolutionary Solver procedure in Add-Ins Solver package of the MS-Excel 2010. Keywords: release rule, storage state, rule curve

Innate and adaptive immune cell interaction drives inflammasome activation and hepatocyte apoptosis in murine liver injury from immune checkpoint inhibitors

Abstract Immune checkpoints (CTLA4 & PD-1) are inhibitory pathways that block aberrant immune activity and maintain self-tolerance. Tumors co-opt these checkpoints to avoid immune destruction. Immune checkpoint inhibitors (ICIs) activate immune cells and restore their tumoricidal potential, making them highly efficacious cancer therapies. However, immunotolerant organs such as the liver depend on these tolerogenic mechanisms, and their disruption with ICI use can trigger the unintended side effect of hepatotoxicity termed immune-mediated liver injury from ICIs (ILICI). Learning how to uncouple ILICI from ICI anti-tumor activity is of paramount clinical importance. We developed a murine model to recapitulate human ILICI using CTLA4+/- mice treated with either combined anti-CTLA4 + anti-PDL1 or IgG1 + IgG2. We tested two forms of antisense oligonucleotides to knockdown caspase-3 in a total liver (parenchymal and non-parenchymal cells) or in a hepatocyte-specific manner. We also employed imaging mass cytometry (IMC), a powerful multiplex modality for immunophenotyping and cell interaction analysis in our model. ICI-treated mice had significant evidence of liver injury. We detected cleaved caspase-3 (cC3), indicating apoptosis was occurring, as well as Nod-like receptor protein 3 (NLRP3) inflammasome activation, but no necroptosis. Total liver knockdown of caspase-3 worsened liver injury, and induced further inflammasome activation, and Gasdermin-D-mediated pyroptosis. Hepatocyte-specific knockdown of caspase-3 reduced liver injury and NLRP3 inflammasome activation. IMC-generated single-cell data for 77,692 cells was used to identify 22 unique phenotypic clusters. Spatial analysis revealed that cC3+ hepatocytes had significantly closer interactions with macrophages, Kupffer cells, and NLRP3hi myeloid cells than other cell types. We also observed zones of three-way interaction between cC3+ hepatocytes, CD8 + T-cells, and macrophages. Our work is the first to identify hepatocyte apoptosis and NLRP3 inflammasome activation as drivers of ILICI. Furthermore, we report that the interplay between adaptive and innate immune cells is critical to hepatocyte apoptosis and ILICI

Biodiversity monitoring for a just planetary future

Data that influence policy and major investment decisions risk entrenching social and political inequities