The burden of cannabis use disorder (CUD) in the context of its prevalence and subsequent cardiopulmonary outcomes among cancer patients with severe sepsis is unclear.

To address this knowledge gap, especially due to rising patterns of cannabis use and its emerging pharmacological role in cancer.

By applying relevant International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes to the National Inpatient Sample database between 2016-2020, we identified CUD(+) and CUD(-) arms among adult cancer admissions with severe sepsis. Comparing the two cohorts, we examined baseline demographic characteristics, epidemiological trends, major adverse cardiac and cerebrovascular events, respiratory failure, hospital cost, and length of stay. We used the Pearson χ² d test for categorical variables and the Mann-Whitney U test for continuous, non-normally distributed variables. Multivariable regression analysis was used to control for potential confounders. A P value ≤ 0.05 was considered for statistical significance.

We identified a total of 743520 cancer patients admitted with severe sepsis, of which 4945 had CUD. Demographically, the CUD(+) cohort was more likely to be younger (median age = 58 vs 69, P < 0.001), male (67.9% vs 57.2%, P < 0.001), black (23.7% vs 14.4%, P < 0.001), Medicaid enrollees (35.2% vs 10.7%, P < 0.001), in whom higher rates of substance use and depression were observed. CUD(+) patients also exhibited a higher prevalence of chronic pulmonary disease but lower rates of cardiovascular comorbidities. There was no significant difference in major adverse cardiac and cerebrovascular events between CUD(+) and CUD(-) cohorts on multivariable regression analysis. However, the CUD(+) cohort had lower all-cause mortality (adjusted odds ratio = 0.83, 95% confidence interval: 0.7-0.97, P < 0.001) and respiratory failure (adjusted odds ratio = 0.8, 95% confidence interval: 0.69-0.92, P = 0.002). Both groups had similar median length of stay, though CUD(+) patients were more likely to have higher hospital cost compared to CUD(-) patients (median = 94574 dollars vs 86615 dollars, P < 0.001).

CUD(+) cancer patients with severe sepsis, who tended to be younger, black, males with higher rates of substance use and depression had paradoxically significantly lower odds of all-cause in-hospital mortality and respiratory failure. Future research should aim to better elucidate the underlying mechanisms for these observations.

• Cannabis/marijuana
• Sepsis
• Cardiovascular outcomes
• Major adverse cardiac and cerebrovascular events
• Pulmonological complications
• Cancer

• Oxidative stress
• Parotid gland
• Proteomics
• Salivary glands
• Submandibular gland

• Ag NPs
• Earthworm extract
• Faeces
• Mice
• Nanoparticles
• Sepsis

• Animals
• Sepsis/drug therapy
• Sepsis/metabolism
• Mice
• Silver/chemistry
• Male
• Metal Nanoparticles/chemistry
• Oligochaeta/chemistry
• Disease Models, Animal
• Kidney/drug effects
• Kidney/metabolism
• Kidney/pathology
• Liver/drug effects
• Liver/metabolism
• Liver/pathology

• Cairo University

• Alanine
• Amino acid profile
• Children
• Diagnostic biomarker
• Sepsis

• Humans
• Sepsis/blood
• Sepsis/diagnosis
• Biomarkers/blood
• Male
• Pilot Projects
• Female
• Child, Preschool
• Alanine/blood
• Child
• Infant
• Intensive Care Units, Pediatric
• ROC Curve
• Amino Acids/blood
• Tandem Mass Spectrometry

• 20171928 Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant
• 82171729 National Natural Science Foundation of China
• 19ZR1442500 Natural Science Foundation of Shanghai

• glutathione
• immune modulation
• organ dysfunction
• oxidative stress
• sepsis
• therapeutic intervention

• critical illness
• drug dosing
• metabolomics
• precision medicine

• Humans
• Cystatin C
• Carnitine
• Shock, Septic/drug therapy
• Creatinine
• Glomerular Filtration Rate/physiology
• Renal Insufficiency, Chronic
• Kidney

• K23 GM113041 NIGMS NIH HHS
• NIH HHS
• R01 GM111400 NIGMS NIH HHS
• R01 GM103799 NIGMS NIH HHS
• R35 GM136312 NIGMS NIH HHS

• Adult
• Humans
• Shock, Septic
• Sepsis
• Critical Care
• Intensive Care Units
• Hospital Mortality
• Retrospective Studies

• National Natural Science Foundation of China

• bioinformatics
• cd247
• cd3d
• prognosis
• septic shock

• Humans
• Shock, Septic/genetics
• Gene Regulatory Networks
• Protein Interaction Mapping
• Receptors, IgE/genetics
• Gene Expression Profiling
• Sepsis/genetics
• Receptors, Antigen, T-Cell
• Computational Biology

The profound effects of and distress caused by the global COVID-19 pandemic highlighted what has been known in the health sciences a long time ago: that bacteria, fungi, viruses, and parasites continue to present a major threat to human health. Infectious diseases remain the leading cause of death worldwide, with antibiotic resistance increasing exponentially due to a lack of new treatments. In addition to this, many pathogens share the common trait of having the ability to modulate, and escape from, the host immune response. The challenge in medical microbiology is to develop and apply new experimental approaches that allow for the identification of both the microbe and its drug susceptibility profile in a time-sensitive manner, as well as to elucidate their molecular mechanisms of survival and immunomodulation. Over the last three decades, proteomics has contributed to a better understanding of the underlying molecular mechanisms responsible for microbial drug resistance and pathogenicity. Proteomics has gained new momentum as a result of recent advances in mass spectrometry. Indeed, mass spectrometry-based biomedical research has been made possible thanks to technological advances in instrumentation capability and the continuous improvement of sample processing and workflows. For example, high-throughput applications such as SWATH or Trapped ion mobility enable the identification of thousands of proteins in a matter of minutes. This type of rapid, in-depth analysis, combined with other advanced, supportive applications such as data processing and artificial intelligence, presents a unique opportunity to translate knowledge-based findings into measurable impacts like new antimicrobial biomarkers and drug targets. In relation to the Research Topic “Proteomic Approaches to Unravel Mechanisms of Resistance and Immune Evasion of Bacterial Pathogens,” this review specifically seeks to highlight the synergies between the powerful fields of modern proteomics and microbiology, as well as bridging translational opportunities from biomedical research to clinical practice.

• AKI
• H2O2
• TBSA
• burn injury
• hydrogen peroxide
• hypermetabolism
• mortality
• sepsis
• shock

Patients with sepsis have a wide range of respiratory disorders that can be treated with oxygen therapy. Experimental data in animal sepsis models show that oxygen therapy significantly increases survival, while clinical data on the use of different oxygen therapy protocols are ambiguous. Oxygen therapy, especially hyperbaric oxygenation, in patients with sepsis can aggravate existing oxidative stress and contribute to the development of disseminated intravascular coagulation. The purpose of this article is to compare experimental and clinical data on oxygen therapy in animals and humans, to discuss factors that can influence the results of oxygen therapy for sepsis treatment in humans, and to provide some recommendations for reducing oxidative stress and preventing disseminated intravascular coagulation during oxygen therapy.

Critically ill patients with COVID-19 are at an increased risk of developing secondary bacterial infections. These are both difficult to diagnose and are associated with an increased mortality. Metabolomics may aid clinicians in diagnosing secondary bacterial infections in COVID-19 through identification and quantification of disease specific biomarkers, with the aim of identifying underlying causative microorganisms and directing antimicrobial therapy.

This is a multi-centre prospective diagnostic observational study. Patients with COVID-19 will be recruited from critical care units in three Scottish hospitals. Three serial blood samples will be taken from patients, and an additional sample taken if a patient shows clinical or microbiological evidence of secondary infection. Samples will be analysed using LC–MS and subjected to bioinformatic processing and statistical analysis to explore the metabolite changes associated with bacterial infections in COVID-19 patients. Comparisons of the data sets will be made with standard microbiological and biochemical methods of diagnosing infection.

Metabolomics analyses may provide additional strategies for identifying secondary infections, which might permit faster initiation of specific tailored antimicrobial therapy to critically ill patients with COVID-19.

• COVID-19
• Critical care
• Metabolomics
• Secondary infection

• Acinetobacter
• Eravacycline
• colistin
• combination
• polymyxin
• synergy
• tigecycline

• biomarker
• metabolic profiling
• metabolomics
• pediatric sepsis
• sampling time

Sepsis can develop during the body’s response to a critical illness leading to multiple organ failure, irreversible shock, and death. Sepsis has been vexing health care providers for centuries due to its insidious onset, generalized metabolic dysfunction, and lack of specific therapy. A common factor underlying sepsis is the characteristic hypermetabolic response as the body ramps up every physiological system in its fight against the underlying critical illness. A hypermetabolic response requires supraphysiological amounts of energy, which is mostly supplied via oxidative phosphorylation generated ATP. A by-product of oxidative phosphorylation is hydrogen peroxide (H₂O₂), a toxic, membrane-permeable oxidizing agent that is produced in far greater amounts during a hypermetabolic state. Continued production of mitochondrial H₂O₂ can overwhelm cellular reductive (antioxidant) capacity leading to a build-up within cells and eventual diffusion into the bloodstream. H₂O₂ is a metabolic poison that can inhibit enzyme systems leading to organ failure, microangiopathic dysfunction, and irreversible septic shock. The toxic effects of H₂O₂ mirror the clinical and laboratory abnormalities observed in sepsis, and toxic levels of blood H₂O₂ have been reported in patients with septic shock. This review provides evidence to support a causal role for H₂O₂ in the pathogenesis of sepsis, and an evidence-based therapeutic intervention to reduce H₂O₂ levels in the body and restore redox homeostasis, which is necessary for normal organ function and vascular responsiveness.

• Sepsis
• Septic shock
• Redox homeostasis
• Thiosulfate
• Hydrogen peroxide

• cecal ligation and puncture
• echinochrome
• inflammation
• oxidative stress
• sepsis

• Biomarker
• Extracellular mitochondria
• Immunoregulation
• Inflammation
• Sepsis
• Therapeutic agent

• Humans
• Immune System/physiology
• Mitochondria/physiology

• apoptosis
• hyperbaric oxygenation
• microcirculation
• sepsis
• survival rate

• Caspase
• Glutamate cysteine ligase
• Glutathione
• Inflammation
• Macrophage

• Caspases/metabolism
• Down-Regulation
• Glutamate-Cysteine Ligase/genetics
• Glutamate-Cysteine Ligase/metabolism
• Glutathione/metabolism
• Humans
• Macrophages/metabolism

• R01 ES003598 NIEHS NIH HHS
• R01 ES023864 NIEHS NIH HHS
• R56 ES003598 NIEHS NIH HHS
• T32 AG052374 NIA NIH HHS
• R56 ES023864 NIEHS NIH HHS

• critical care
• pharmacometabolomics
• septic shock
• systems pharmacology

• RuO2 nanoparticles
• acute kidney injury
• in vivo clearance
• multienzyme-like activity
• ultrasmall

• Acute Kidney Injury/drug therapy
• Animals
• Catalase/metabolism
• Catalysis
• Glutathione Peroxidase/metabolism
• Humans
• Mice
• Nanoparticles/chemistry
• Oxidative Stress/drug effects
• Peroxidase/metabolism
• Reactive Oxygen Species/metabolism
• Ruthenium Compounds/chemistry
• Ruthenium Compounds/therapeutic use
• Superoxide Dismutase/metabolism

Although the immune response has a prominent role in the pathophysiology of ulcerative colitis, sepsis, and systemic lupus erythematosus, a primary immune causation has not been established to explain the pathogenesis of these diseases. However, studies have reported significantly elevated levels of colonic epithelial hydrogen peroxide (a known colitic agent) in ulcerative colitis prior to the appearance of colitis. And patients with sepsis are reported to have toxic levels of blood hydrogen peroxide, whose pathologic effects mirror the laboratory and clinical abnormalities observed in sepsis. More recently, evidence supports a causal role for cellular hydrogen peroxide (a potent apoptotic agent) in the enhanced apoptosis believed to be the driving force behind auto-antigenic exposure and chronic immune activation in systemic lupus erythematosus. The different biological properties of hydrogen peroxide exert distinct pathologic effects depending on the site of accumulation within the body resulting in a unique disease patho-phenotype. On a cellular level, the build-up of hydrogen peroxide triggers apoptosis resulting in systemic lupus erythematosus, on a tissue level (colonic epithelium) excess hydrogen peroxide leads to inflammation and ulcerative colitis, and on a systemic level the pathologic effects of toxic concentrations of blood hydrogen peroxide result in bioenergetic failure and microangiopathic dysfunction leading to multiple organ failure and circulatory shock, characteristic of advanced sepsis. The aim of this paper is to provide a unified evidence-based common causal role for hydrogen peroxide in the pathogenesis of ulcerative colitis, sepsis, and systemic lupus erythematosus. Based on this new theory of pathogenesis, a novel evidence-based treatment of sepsis is also discussed.

• Glutathione
• Hydrogen peroxide
• Redox balance
• Redox homeostasis
• Sepsis
• Systemic lupus erythematosus
• Ulcerative colitis

• biomarker
• early diagnose
• mass spectrometry
• proteomics
• sepsis-induced acute kidney injury

• LPS
• TLR4
• endotoxemia
• mass spectrometry
• sepsis
• serum proteomics

• Cellular stress
• DNAdamage response
• autophagy
• low-grade inflammation
• mitochondrial stress
• oxidative stress
• systemic inflammation
• tissue stress.

• CBD
• THC
• cannabinoids
• cannabis sativa
• endocannabinoid system
• sepsis

• Cannabis/chemistry
• Critical Illness
• Endocannabinoids/metabolism
• Humans
• Inflammation/genetics
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Oxidative Stress/genetics
• Sepsis/genetics
• Sepsis/pathology
• Sepsis/physiopathology

• Fibroblast growth factor 21
• Mortality
• Sepsis
• Thyroid hormone

Autophagy, lipophagy, and mitophagy are considered to be the major recycling processes for protein aggregates, excess fat, and damaged mitochondria in adipose tissues in response to nutrient status-associated stress, oxidative stress, and genotoxic stress in the human body. Obesity with increased body weight is often associated with white adipose tissue (WAT) hypertrophy and hyperplasia and/or beige/brown adipose tissue atrophy and aplasia, which significantly contribute to the imbalance in lipid metabolism, adipocytokine secretion, free fatty acid release, and mitochondria function. In recent studies, hyperactive autophagy in WAT was observed in obese and diabetic patients, and inhibition of adipose autophagy through targeted deletion of autophagy genes in mice improved anti-obesity phenotypes. In addition, active mitochondria clearance through activation of autophagy was required for beige/brown fat whitening – that is, conversion to white fat. However, inhibition of autophagy seemed detrimental in hypermetabolic conditions such as hepatic steatosis, atherosclerosis, thermal injury, sepsis, and cachexia through an increase in free fatty acid and glycerol release from WAT. The emerging concept of white fat browning–conversion to beige/brown fat–has been controversial in its anti-obesity effect through facilitation of weight loss and improving metabolic health. Thus, proper regulation of autophagy activity fit to an individual metabolic profile is necessary to ensure balance in adipose tissue metabolism and function, and to further prevent metabolic disorders such as obesity and diabetes. In this review, we summarize the effect of autophagy in adipose tissue browning in the context of obesity prevention and its potential as a promising target for the development of anti-obesity drugs.

• autophagy
• beige/brown adipose tissue
• browning
• lipophagy
• mitophagy
• obesity
• white adipose tissue
• whitening

• CARS
• PICS
• inflammation
• metabolic stress
• multiple organ dysfunction syndrome
• systemic inflammatory response syndrome

• Acute Disease
• Humans
• Immune Tolerance
• Inflammation/metabolism
• Multiple Organ Failure/etiology
• Systemic Inflammatory Response Syndrome

The aim of our research was to study sex differences and the severity of inflammatory changes in target organs and the peculiarities of immunological disorders when low and high doses of lipopolysaccharide (LPS) were administered to rats.

Male and female 2- to 3-month-old Wistar rats (200–250 g) were injected intraperitoneally with Escherichia coli LPS in one of two doses: 1.5 or 15 mg/kg. In a day after the LPS injection, we studied endotoxin, corticosterone, sex steroids, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity levels in the serum; morphological disorders in the lung, liver, thymus, and spleen; ex vivo production of IL-2, IL-4, tumor necrosis factor (TNF), and interferon γ (IFNγ) by splenic cells activated by ConA; and relative amount of T- and B-lymphocytes in the peripheral blood.

After the injection of low-dose LPS, the serum endotoxin level increased only in males and was combined with a more pronounced inflammatory response in the lungs and thymus and an increase in ALT and AST activity levels without any changes in corticosterone level. After the injection of high-dose LPS, the inflammatory and pathological changes in the target organs manifested as severe endotoxemia and sex differences of pathological changes in the lungs and liver were not revealed. The level of production of IL-2, IL-4, IFNγ, and TNF by splenic cells and the number of T-lymphocytes, including cytotoxic cells, in the peripheral blood, decreased in males, which is an evidence of a pronounced suppression of the immune response.

We have shown that the morphofunctional changes in the organs of the immune system in females and males, as well as the intensity of the sex differences of inflammation, depend on the severity of systemic inflammatory response, induced by different doses of LPS.

• SIRS
• endotoxinemia
• female rats
• male rats
• spleen
• thymus

• Endotoxemia
• bovine serum albumin
• inflammation
• lipopolysaccharide
• manganese dioxide

• Albumins/chemistry
• Albumins/pharmacology
• Animals
• Brain/drug effects
• Brain/metabolism
• Brain/pathology
• Cognitive Dysfunction/chemically induced
• Cognitive Dysfunction/drug therapy
• Cognitive Dysfunction/genetics
• Cognitive Dysfunction/pathology
• Endotoxemia/chemically induced
• Endotoxemia/drug therapy
• Endotoxemia/genetics
• Gene Expression Regulation/drug effects
• Humans
• Hydrogen Peroxide/toxicity
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Inflammation/chemically induced
• Inflammation/drug therapy
• Inflammation/genetics
• Inflammation/pathology
• Lipopolysaccharides/toxicity
• Macrophages/drug effects
• Macrophages/pathology
• Manganese Compounds/chemistry
• Manganese Compounds/pharmacology
• Mice
• Nanocomposites/administration & dosage
• Nanocomposites/chemistry
• Oxidative Stress/drug effects
• Oxides/chemistry
• Oxides/pharmacology
• Peroxidase/chemistry
• Peroxidase/genetics
• Peroxides/chemistry
• Peroxides/pharmacology
• Reactive Oxygen Species/toxicity
• Signal Transduction/drug effects
• Tumor Necrosis Factor-alpha/genetics

During sepsis, the alarmin HMGB1 is released from tissues and promotes systemic inflammation that results in multi-organ damage, with the kidney particularly susceptible to injury. The severity of inflammation and pro-damage signaling mediated by HMGB1 appears to be dependent on the alarmin's redox state. Therefore, we examined HMGB1 redox in kidney cells during sepsis. Using intravital microscopy, CellROX labeling of kidneys in live mice indicated increased ROS generation in the kidney perivascular endothelium and tubules during lipopolysaccharide (LPS)-induced sepsis. Subsequent CellROX and MitoSOX labeling of LPS-stressed endothelial and kidney proximal tubule cells demonstrated increased ROS generation in these cells as sepsis worsens. Consequently, HMGB1 oxidation increased in the cytoplasm of kidney cells during its translocation from the nucleus to the circulation, with the degree of oxidation dependent on the severity of sepsis, as measured in in vivo mouse samples using a thiol assay and mass spectrometry (LC-MS/MS). The greater the oxidation of HMGB1, the greater the ability of the alarmin to stimulate pro-inflammatory cyto-/chemokine release (measured by Luminex Multiplex) and alter mitochondrial ATP generation (Luminescent ATP Detection Assay). Administration of glutathione and thioredoxin inhibitors to cell cultures enhanced HMGB1 oxidation during sepsis in endothelial and proximal tubule cells, respectively. In conclusion, as sepsis worsens, ROS generation and HMGB1 oxidation increases in kidney cells, which enhances HMGB1's pro-inflammatory signaling. Conversely, the glutathione and thioredoxin systems work to maintain the protein in its reduced state.

•

Endotoxins (LPS) increase cellular oxidative stress during sepsis.

• Cytokines
• HMGB1
• Oxidative stress
• Redox
• Sepsis

Sepsis is an often lethal syndrome resulting from maladaptive immune and metabolic responses to infection, compromising host homeostasis. Disease tolerance is a defense strategy against infection that preserves host homeostasis without exerting a direct negative impact on pathogens. Here, we demonstrate that induction of the iron-sequestering ferritin H chain (FTH) in response to polymicrobial infections is critical to establish disease tolerance to sepsis. The protective effect of FTH is exerted via a mechanism that counters iron-driven oxidative inhibition of the liver glucose-6-phosphatase (G6Pase), and in doing so, sustains endogenous glucose production via liver gluconeogenesis. This is required to prevent the development of hypoglycemia that otherwise compromises disease tolerance to sepsis. FTH overexpression or ferritin administration establish disease tolerance therapeutically. In conclusion, disease tolerance to sepsis relies on a crosstalk between adaptive responses controlling iron and glucose metabolism, required to maintain blood glucose within a physiologic range compatible with host survival.

•

Ferritin is required to establish disease tolerance to sepsis

• disease tolerance
• ferritin
• gluconeogenesis
• glucose-6-phosphatase
• heme
• infection
• inflammation
• iron
• metabolism
• sepsis

• Microarray
• Microarray modelling
• Predictive modelling
• Septic shock
• Singular value decomposition

• multiple organ dysfunction syndrome
• pediatrics
• nutrition
• bacterial translocation
• microbiome
• extracorporeal membrane oxygenation
• therapeutic plasma exchange
• continuous renal replacement therapy
• hemophagocytic lymphohistiocytosis
• macrophage activation syndrome
• anti-cytokine therapy
• bacterial toxin-mediated disease
• anti-toxin therapy
• corticosteroids
• hydrocortisone
• mineralocorticoids
• aldosterone
• gonadocorticoids
• oxandrolone
• tight glucose control
• anti-oxidant therapy

• Anti-Inflammatory Agents/therapeutic use
• Antioxidants/therapeutic use
• Antitoxins/therapeutic use
• Child
• Combined Modality Therapy
• Critical Care/methods
• Extracorporeal Circulation
• Humans
• Hypoglycemic Agents/therapeutic use
• Multiple Organ Failure/therapy
• Nutrition Therapy/methods
• Pediatrics
• Steroids/therapeutic use
• Treatment Outcome

• K23 DK106462 NIDDK NIH HHS
• R01 AI097434 NIAID NIH HHS
• R01 GM113838 NIGMS NIH HHS

• Humans
• Inflammation/etiology
• Sepsis/complications
• Signal Transduction

• APACHE II
• Antioxidants
• ICU
• Oxidants
• Sepsis

Ethyl pyruvate (EP) is a derivative of pyruvic acid that has been demonstrated to be a potential scavenger of reactive oxygen species as well as an anti-inflammatory agent. In this study, we investigated the protective effects of EP and its role in regulating the energy metabolism in the livers of cecal-ligation-and-puncture-induced septic mice.

The animals were treated intraperitoneally with 0.2 mL of Ringer’s lactate solution or an equivalent volume of Ringer’s lactate solution containing EP immediately after cecal ligation and puncture. Each mouse in the Sham group was only subjected to a laparotomy. At 30-, 60-, 180-, and 360-minute time points, we measured the histopathological alterations of the intestines, and the plasma levels of interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor-α, and the total antioxidative capacity, malondialdehyde content, and lactate and lactate/pyruvate levels in livers. Furthermore, we detected the levels of adenosine triphosphate, total adenylate, and energy charge in the livers.

Our results demonstrated that the administration of EP significantly improved the survival rate and reduced intestinal histological alterations. EP inhibited the plasma levels of IL-1β, IL-6, and tumor necrosis factor-α and increased the IL-10 level. EP significantly inhibited the elevation of the malondialdehyde, lactate, and lactate/pyruvate levels and enhanced the total antioxidative capacity levels in the liver tissues. The downregulation of the adenosine triphosphate, total adenylate, and energy charge levels in the liver tissues was reversed in the septic mice treated with EP.

The results suggest that EP administration effectively modulates the energy metabolism, which may be an important component in treatment of sepsis.

• energy metabolism
• ethyl pyruvate
• inflammation
• reactive oxygen species
• sepsis