Scientific Reports - Combined in vivo and silico assessment of melatonin’s protective effects on rifampicin-induced liver damage in rats

Read the full paper: Beyond Inhibition: Sublethal Rifampicin-Induced Molecular Adaptations Confer Phenotypic Drug Tolerance in Mycobacteria

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World Health Organization (WHO) tuberculosis (TB) screening guidelines recommend computer-aided detection (CAD) software for chest radiograph (CXR) interpretation. However, studies evaluating their diagnostic and prognostic accuracy are limited.MethodsWe conducted a prospective cohort study of household contacts of rifampicin-resistant TB in South Africa. Participants underwent baseline CXR and sputum investigation (routine [single spontaneous] and enhanced [additionally 2–3 induced]) for prevalent TB and follow-up for incident TB. Three CXR-CAD software products (CAD4TBv7.0, qXRv3.0.0, and Lunit INSIGHT v3.1.4.111) were compared. We evaluated their performance to detect routine and enhanced prevalent and incident TB, comparing performance with blood tests (Xpert MTB host-response, erythrocyte sedimentation rate, C-reactive protein, QuantiFERON) in a subgroup.Results483 participants were followed up for 4.6 years (median). There were 23 prevalent (7 routinely diagnosed) and 38 incident TB cases. The AUC ROCs (95% CIs) to identify prevalent TB for CAD4TBv7.0, qXRv3.0.0, and Lunit INSIGHT v3.1.4.111 were .87 (.77–.96), .88 (.79–.97), and .91 (.83–.99), respectively. More than 30% with scores above recommended CAD thresholds who were bacteriologically negative on routine baseline sputum were subsequently diagnosed by enhanced sputum investigation or during follow-up. The AUC performance of baseline CAD to identify incident cases ranged between .60 and .65. Diagnostic performance of CAD for prevalent TB was superior to blood testing.ConclusionsOur findings suggest that the potential of CAD-CXR screening for TB is not maximized as a high proportion of those above current thresholds, but with a negative routine confirmatory sputum, have true TB disease that may benefit intervention.

Read the full paper: Protective Effects of Rifampicin and Its Analog Rifampicin Quinone in a Mouse Model of Obesity-Induced Type 2 Diabetes

Antibiotic-induced disruptions of the gut microbiota have been linked to behavioral alterations, but the mechanisms underlying these effects remain poorly understood. Here, we demonstrate that combined vancomycin and rifampicin (VR) treatment in male C57BL/6 mice impairs female odor preference and reduces interaction time with female conspecifics in favor of males, without affecting general locomotion or anxiety-like behavior. VR-induced effects on the intestinal microbiome persisted for weeks after antibiotic withdrawal. Metabolomic profiling revealed brain ATP depletion upon vancomycin treatment, while intranasal administration of the electron transport chain uncoupler dinitrophenol (DNP) partially recapitulated antibiotics-induced social deficits. Microbiome analysis and functional tests identified Akkermansia muciniphila and short chain fatty acids acetate and propionate as key mediators of the behavioral phenotype. Strikingly, this VR-induced behavioral phenotype was reproducible in BALB/c mice, suggesting broad applicability. Our findings establish VR treatment as a model for microbiotadependent social deficits, implicating mitochondrial metabolism and specific bacterial taxa in sexually dimorphic behaviors. These results highlight the need to consider neuroactive antibiotic effects in clinical and translational research.

Antibiotic-induced disruptions of the gut microbiota have been linked to behavioral alterations, but the mechanisms underlying these effects remain poorly understood. Here, we demonstrate that combined vancomycin and rifampicin (VR) treatment in male C57BL/6 mice impairs female odor preference and reduces interaction time with female conspecifics in favor of males, without affecting general locomotion or anxiety-like behavior. VR-induced effects on the intestinal microbiome persisted for weeks after antibiotic withdrawal. Metabolomic profiling revealed brain ATP depletion upon vancomycin treatment, while intranasal administration of the electron transport chain uncoupler dinitrophenol (DNP) partially recapitulated antibiotics-induced social deficits. Microbiome analysis and functional tests identified Akkermansia muciniphila and short chain fatty acids acetate and propionate as key mediators of the behavioral phenotype. Strikingly, this VR-induced behavioral phenotype was reproducible in BALB/c mice, suggesting broad applicability. Our findings establish VR treatment as a model for microbiotadependent social deficits, implicating mitochondrial metabolism and specific bacterial taxa in sexually dimorphic behaviors. These results highlight the need to consider neuroactive antibiotic effects in clinical and translational research.

We report case who suffered from acute renal failure twice (second time with hepatitis) induced by rifampicin. Hepatitis associated with the renal toxicity may be a manifestation of general hypersensitivity. Both the hepatic and renal toxic...

We report case who suffered from acute renal failure twice (second time with hepatitis) induced by rifampicin. Hepatitis associated with the renal toxicity may be a manifestation of general hypersensitivity. Both the hepatic and renal toxic...

This study demonstrates that the significant reduction of hepatic FGF1 in response to isoniazid(INH) and rifampicin(RIF) leads to aberrant accumulation of hepatic bile acids (BAs), ultimately causing drug-induced liver injury, by inducing FGFR4-ERK1/2 mediated hepatocyte nuclear factor 4 α (HNF4 α ) expression, which triggers the transcription of key enzymes for BAs biosynthesis. Abstract Isoniazid and rifampicin co-therapy are the main causes of anti-tuberculosis drug-induced liver injury (ATB-DILI) and acute liver failure, seriously threatening human health. However, its pathophysiology is not fully elucidated. Growing evidences have shown that fibroblast growth factors (FGFs) play a critical role in diverse aspects of liver pathophysiology. The aim of this study is to investigate the role of FGFs in the pathogenesis of isoniazid (INH) and rifampicin (RIF)-induced liver injury. Through systematic screening, this study finds that hepatic FGF1 expression is significantly downregulated in both mouse model and human patients challenged with INH and RIF. Hepatocyte-specific Fgf1 deficiency exacerbates INH and RIF-induced liver injury resulted from elevated bile acids (BAs) synthases and aberrant BAs accumulation. Conversely, pharmacological administration of the non-mitogenic FGF1 analog – FGF1 ΔHBS significantly alleviated INH and RIF-induced liver injury via restoring BAs homeostasis. Mechanically, FGF1 repressed hepatocyte nuclear factor 4 α ( Hnf4α ) transcription via activating FGF receptor 4 (FGFR4)-ERK1/2 signaling pathway, thus reducing BAs synthase. The findings demonstrate hepatic FGF1 functions as a negative regulator of BAs biosynthesis to protect against INH and RIF-induced liver injury via normalizing hepatic BAs homeostasis, providing novel mechanistic insights into the pathogenesis of ATB-DILI and potential therapeutic strategies for treatment of ATB-DILI.