Resistance Enzymes Research Articles

Supramolecular Assembly of Multifunctional Collagen Nanocomposite Film via Polyphenol-Coordinated Clay Nanoplatelets.

Functional bionanocomposites have evoked immense research interests in many fields including biomedicine, food packaging, and environmental applications. Supramolecular self-assembled bionanocomposite materials fabricated by biopolymers and two-dimensional (2D) nanomaterials have particularly emerged as a compelling material due to their biodegradable nature, hierarchical structures, and designable multifunctions. However, construction of these materials with tunable properties has been still challenging. Here, we report a self-assembled, flexible, and antioxidative collagen nanocomposite film (CNF) via regulating supramolecular interactions of type I collagen and tannic acid (TA)-functionalized 2D synthetic clay nanoplatelets Laponite (LAP). Specifically, TA-coordinated LAP (LAP-TA) complexes were obtained via chelation and hydrogen bonding between TA and LAP clay nanoplatelets and further used to stabilize the triple-helical confirmation and fibrillar structure of the collagen via hydrogen bonding and electrostatic interactions, forming a hierarchical microstructure. The obtained transparent CNF not only exhibited the reinforced thermal stability, enzymatic resistance, tensile strength, and hydrophobicity but also good water vapor permeability and antioxidation. For example, the tensile strength was improved by over 2000%, and the antioxidant property was improved by 71%. Together with the simple fabrication process, we envision that the resulting CNF provides greater opportunities for versatile bionanocomposites design and fabrication serving as a promising candidate for emerging applications, especially food packaging and smart wearable devices.

Chitosan as an Adjuvant to Improve Isopyrazam Azoxystrobin against Leaf Spot Disease of Kiwifruit and Enhance Its Photosynthesis, Quality, and Amino Acids

Leaf spot disease caused by Lasiodiplodia theobromae is one of the most serious fungal diseases of kiwifruit production. In this work, the co-application of isopyrazam·azoxystrobin and chitosan against leaf spot disease in kiwifruit and its effects on disease resistance, photosynthesis, yield, quality, and amino acids of kiwifruit were investigated. The results show that isopyrazam·azoxystrobin exhibited a superior bioactivity against L. theobromae with an EC50 value of 0.1826 mg kg−1. The foliar application of chitosan could effectively enhance isopyrazam·azoxystrobin against leaf spot disease with a field control efficacy of 86.83% by spraying 29% isopyrazam·azoxystrobin suspension concentrate (SC) 1500 time + chitosan 100-time liquid, which was significantly (p < 0.05) higher than 78.70% of 29% isopyrazam·azoxystrobin SC 1000-time liquid. The co-application of isopyrazam·azoxystrobin and chitosan effectively enhanced soluble protein, resistance enzymes’ activity in kiwifruit leaves, and reduced their malonaldehyde (MDA), as well as reliably improved their photosynthetic characteristics. Simultaneously, their co-application was more effective in promoting growth, quality, and amino acids of kiwifruit fruits compared to isopyrazam·azoxystrobin or chitosan alone. This study highlights that the co-application of isopyrazam·azoxystrobin and chitosan can be used as a green, safe, and efficient approach for controlling leaf spot disease of kiwifruit and reducing the application of chemical fungicides.

A New Method to Address the Importance of Detoxified Enzyme in Insecticide Resistance - Meta-Analysis.

Insect-borne diseases, such as malaria, and plant pathogens, like the tobacco mosaic virus, are responsible for human deaths and poor crop yields in communities around the world. The use of insecticides has been one of the major tools in pest control. However, the development of insecticide resistance has been a major problem in the control of insect pest populations that threaten the health of both humans and plants. The overexpression of detoxification genes is thought to be one of the major mechanisms through which pests develop resistance to insecticides. Hundreds of research papers have explored how overexpressed detoxification genes increase the resistance status of insects to an insecticide in recent years. This study is, for the first time, a synthesis of these resistance and gene expression data aimed at (1) setting up an example for the application of meta-analysis in the investigation of the mechanisms of insecticide resistance and (2) seeking to determine if the overexpression detoxification genes are responsible for insecticide resistance in insect pests in general. A strong correlation of increased levels of insecticide resistance has been observed in tested insects with cytochrome P450 (CYP), glutathione-S-transferase (GST), and esterase gene superfamilies, confirming that the overexpression of detoxification genes is indeed involved in the insecticide resistance through the increased metabolism of insecticides of insects, including medically (e.g., mosquito and housefly) and agriculturally (e.g., planthopper and caterpillar) important insects.

Functional and Structural Characterization of Diverse NfsB Chloramphenicol Reductase Enzymes from Human Pathogens.

ABSTRACTPhylogenetically diverse bacteria can carry out chloramphenicol reduction, but only a single enzyme has been described that efficiently catalyzes this reaction, the NfsB nitroreductase from Haemophilus influenzae strain KW20. Here, we tested the hypothesis that some NfsB homologs function as housekeeping enzymes with the potential to become chloramphenicol resistance enzymes. We found that expression of H. influenzae and Neisseria spp. nfsB genes, but not Pasteurella multocida nfsB, allows Escherichia coli to resist chloramphenicol by nitroreduction. Mass spectrometric analysis confirmed that purified H. influenzae and N. meningitides NfsB enzymes reduce chloramphenicol to amino-chloramphenicol, while kinetics analyses supported the hypothesis that chloramphenicol reduction is a secondary activity. We combined these findings with atomic resolution structures of multiple chloramphenicol-reducing NfsB enzymes to identify potential key substrate-binding pocket residues. Our work expands the chloramphenicol reductase family and provides mechanistic insights into how a housekeeping enzyme might confer antibiotic resistance.IMPORTANCE The question of how new enzyme activities evolve is of great biological interest and, in the context of antibiotic resistance, of great medical importance. Here, we have tested the hypothesis that new antibiotic resistance mechanisms may evolve from promiscuous housekeeping enzymes that have antibiotic modification side activities. Previous work identified a Haemophilus influenzae nitroreductase housekeeping enzyme that has the ability to give Escherichia coli resistance to the antibiotic chloramphenicol by nitroreduction. Herein, we extend this work to enzymes from other Haemophilus and Neisseria strains to discover that expression of chloramphenicol reductases is sufficient to confer chloramphenicol resistance to Es. coli, confirming that chloramphenicol reductase activity is widespread across this nitroreductase family. By solving the high-resolution crystal structures of active chloramphenicol reductases, we identified residues important for this activity. Our work supports the hypothesis that housekeeping proteins possessing multiple activities can evolve into antibiotic resistance enzymes.

Frequency of Pyrethroid Insecticide Resistance kdr Gene and Its Associated Enzyme Modulation in Housefly, Musca domestica L. Populations From Jhang, Pakistan

Housefly, Musca domestica, is considered responsible for transmitting a wide variety of human and veterinary diseases. Mostly, insecticides are being used for their control and more commonly, pyrethroid insecticides worldwide. However, resistance has been reported against various pyrethroid insecticides. Houseflies become resistant by two major mechanisms, i.e., target site insensitivity through knockdown resistance gene mutation (kdr) and enzyme detoxification. Thus, the current study was designed to monitor the frequency of pyrethroid resistance gene kdr in housefly populations of District Jhang. The flies were collected from seven sampling sites and then reared in the lab for molecular and biochemical assays. The amplification of template DNA was performed for knockdown resistance gene through the outer primers kdr1 and kdr4, and the inner primers kdr1 and kdr2 using PASA (PCR Amplification of Specific Alleles) method which specifically amplify the domain-II of kdr gene. Three populations were found homozygous susceptible (+/+; 42.85%), whereas two populations were found genetically homozygous resistant (−/−; 28.57%) which are insensitive to pyrethroid insecticides. Similarly, two populations were found heterozygous (+/−; 28.57%) for kdr suggesting thereby that at least 1/4th homozygous-resistant (−/−) housefly populations with insensitivity to pyrethroids would be produced in the future keeping in view the Mendelian ratio. Biochemical assay showed that homozygous-resistant populations had increased activity of Acetylcholinesterase (AChE), α-Carboxylesterases (α-Carboxyl), β-Carboxylesterase (β-Carboxyl), Alkaline Phosphatase (AkP), and Acidic Phosphatase (AcP) enzymes. In addition, heterozygous populations also showed increased activities of these enzymes. The current results would not only help avoid the indiscriminate load of insecticides onto the environment but also serve as a hallmark for the management of housefly populations in target areas in the future.

Do serum vitamin D levels affect liver enzymes in insulin resistance and obesity patients?

article: Do serum vitamin D levels affect liver enzymes in insulin resistance and obesity patients? - Gazzetta Medica Italiana - Archivio per le Scienze Mediche 2021 October;180(10):613-21 - Minerva Medica - Journals

Structural basis for context-specific inhibition of translation by oxazolidinone antibiotics.

The antibiotic linezolid, the first clinically approved member of the oxazolidinone class, inhibits translation of bacterial ribosomes by binding to the peptidyl transferase center. Recent work has demonstrated that linezolid does not inhibit peptide bond formation at all sequences but rather acts in a context-specific manner, namely when alanine occupies the penultimate position of the nascent chain. However, the molecular basis for context-specificity has not been elucidated. Here we show that the second-generation oxazolidinone radezolid also induces stalling with a penultimate alanine, and we determine high-resolution cryo-EM structures of linezolid- and radezolid-stalled ribosome complexes to explain their mechanism of action. These structures reveal that the alanine side chain fits within a small hydrophobic crevice created by oxazolidinone, resulting in improved ribosome binding. Modification of the ribosome by the antibiotic resistance enzyme Cfr disrupts stalling due to repositioning of the modified nucleotide. Together, our findings provide molecular understanding for the context-specificity of oxazolidinones.

Enhancement of enzymatic resistance in V-type starch inclusion complexes by hydrothermal treatments

Resistant starch (RS) is well known for its health beneficial effects for glycemic control and gut health. In addition to some commonly reported RS types, such as raw high amylose maize starch (HAMS), potato starch, retrograded starch, and cross-linked starch, formation of starch inclusion complexes could also contribute to an increase in RS content. In this study, V type starch inclusion complexes with two guest compounds, ascorbyl palmitate (AP) and palmitic acid (PA), were formed using the novel “empty” V type method, and hydrothermal treatments were performed to further enhance the RS contents. Complimentary X-ray diffraction (XRD) and differential scanning calorimetry (DSC) techniques were conducted to assess the crystalline structure and thermal properties of the raw and treated inclusion complexes, and simulated in vitro enzymatic digestion was performed to study the structure-digestibility relationship in the treated samples. Although the raw inclusion complex samples exhibited minimal RS contents, all the treatments retarded starch digestion by increasing RS or SDS levels. For both V6h-AP and V6h-PA inclusion complexes, annealing followed by long-term strong acid hydrolysis treatment (ANN-ACH) resulted in the greatest increase in RS content, followed by strong ACH treatments alone. In addition, while presenting a comparable RS level as traditional RS2, the ANN-ACH treated V6h-AP inclusion complex retained a V type crystalline structure, indicating its great potential as a novel type of RS, i.e., RS5. The study findings could have practical implications for the design and modification of RS-containing food for the control and modulation of glycemic response.

Pharmacokinetics and neurotropic effects of cyclo-L-prolylglycine and its modified analogues

The review presents the results of studies on the pharmacokinetics, metabolism, and bioavailability of new neurotropic dipeptide cyclo-Lprolilglycine (CPG) and their pharmacological activity. It was shown that the pharmacologically active metabolite of the nootropic drug noopept cyclo-Lprolilglycine (CPG) is an endogenous dipeptide, it is a fragment of the terminal Tripeptide of the insulin-like nerve growth factor IGF-1. Much attention is paid both in Russia and abroad to the development of modified CPG analogues with improved pharmacokinetic properties, enzymatically more stable, better penetrating the BBB, and highly effective when used in micromolar doses. CPG shows neuroprotective activity in ischemic-hypoxic and other brain injuries, in addition, it has a complex of other pharmacological effects and therefore CPG can be considered not only as a potential drug, but also as a basic structure for the development of new neurotropic drugs – analogs of CPG with improved pharmacokinetic properties, greater enzymatic resistance and higher bioavailability for the central nervous system.

Occurrence of L1014F and L1014S mutations in insecticide resistant Culex quinquefasciatus from filariasis endemic districts of West Bengal, India.

IntroductionLymphatic filariasis causes long term morbidity and hampers the socio-economic status. Apart from the available treatments and medication, control of vector population Culex quinquefasciatus Say through the use of chemical insecticides is a widely applied strategy. However, the unrestrained application of these insecticides over many decades has led to resistance development in the vectors.MethodsIn order to determine the insecticide susceptibility/resistance status of Cx. quinquefasciatus from two filariasis endemic districts of West Bengal, India, wild mosquito populations were collected and assayed against six different insecticides and presence of L1014F; L1014S kdr mutations in the voltage-gated sodium channel gene was also screened along with the use of synergists to evaluate the role of major detoxifying enzymes in resistance development.ResultsThe collected mosquito populations showed severe resistance to insecticides and the two synergists used–PBO (piperonyl butoxide) and TPP (triphenyl phosphate), were unable to restore the susceptibility status of the vector thereupon pointing towards a minor role of metabolic enzymes. kdr mutations were present in the studied populations in varying percent with higher L1014F frequency indicating its association with the observed resistance to pyrethroids and DDT. This study reports L1014S mutation in Cx. quinquefasciatus for the first time.

Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding.

Antimicrobial resistance in Gram-negative bacteria is one of the greatest threats to global health. New antibacterial strategies are urgently needed, and the development of antibiotic adjuvants that either neutralize resistance proteins or compromise the integrity of the cell envelope is of ever-growing interest. Most available adjuvants are only effective against specific resistance proteins. Here, we demonstrate that disruption of cell envelope protein homeostasis simultaneously compromises several classes of resistance determinants. In particular, we find that impairing DsbA-mediated disulfide bond formation incapacitates diverse β-lactamases and destabilizes mobile colistin resistance enzymes. Furthermore, we show that chemical inhibition of DsbA sensitizes multidrug-resistant clinical isolates to existing antibiotics and that the absence of DsbA, in combination with antibiotic treatment, substantially increases the survival of Galleria mellonella larvae infected with multidrug-resistant Pseudomonas aeruginosa. This work lays the foundation for the development of novel antibiotic adjuvants that function as broad-acting resistance breakers.

Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding

Antimicrobial resistance in Gram-negative bacteria is one of the greatest threats to global health. New antibacterial strategies are urgently needed, and the development of antibiotic adjuvants that either neutralize resistance proteins or compromise the integrity of the cell envelope is of ever-growing interest. Most available adjuvants are only effective against specific resistance proteins. Here we demonstrate that disruption of cell envelope protein homeostasis simultaneously compromises several classes of resistance determinants. In particular, we find that impairing DsbA-mediated disulfide bond formation incapacitates diverse β-lactamases and destabilizes mobile colistin resistance enzymes. Furthermore, we show that chemical inhibition of DsbA sensitizes multidrug-resistant clinical isolates to existing antibiotics and that the absence of DsbA, in combination with antibiotic treatment, substantially increases the survival of Galleria mellonella larvae infected with multidrug-resistant Pseudomonas aeruginosa. This work lays the foundation for the development of novel antibiotic adjuvants that function as broad-acting resistance breakers.

Mitigation of vanillic acid‐promoted faba bean Fusarium wilt by faba bean–wheat intercropping

AbstractLong‐term continuous monocropping of faba beans increases the incidence of faba bean wilt, while faba bean–wheat intercropping can effectively control it. This study aimed to understand the underlying mechanism of faba bean–wheat intercropping for the control of Fusarium oxysporum and vanillic acid (VA)‐promoted occurrence of faba bean wilt. The occurrence of faba bean wilt was investigated among the monocropped and intercropped plants of faba beans in a field experiment. The contents and types of phenolic acids were examined in the rhizosphere soil. Monocropped and intercropped faba beans were examined under the dual stress of F. oxysporum and different concentrations of VA (0, 50, 100, 200 mg/L) to understand the alleviating mechanism of faba bean–wheat intercropping. Exogenous addition of high concentrations of VA significantly inhibited the growth and reproduction of F. oxysporum, but under the dual stress of F. oxysporum and different concentrations of VA, it significantly inhibited the defence enzymes of faba bean roots, stems, and leaves, and rhizosphere soil enzymes. Interestingly, faba bean–wheat intercropping alleviated VA stress and thereby the incidence and disease index of faba bean Fusarium wilt by improving plant resistance and soil enzyme activity. The dual stress of F. oxysporum and VA promotes the occurrence of Fusarium wilt by damaging the defence system of the faba bean root system and rhizosphere soil environment. However, faba bean–wheat intercropping effectively alleviates the autotoxicity of VA by improving the physiological and biochemical resistance of faba beans and soil enzyme activities, and thus controls the occurrence of Fusarium wilt.

The Apolipoprotein B/A1 Ratio is Associated With Metabolic Syndrome Components, Insulin Resistance, Androgen Hormones, and Liver Enzymes in Women With Polycystic Ovary Syndrome.

AimTo evaluate the association between the apolipoprotein B/A1 ratio (ApoB/ApoA1) and metabolic and endocrine parameters in women with polycystic ovary syndrome (PCOS).MethodsThis study was a secondary analysis of the Acupuncture and Clomiphene for Chinese Women with Polycystic Ovary Syndrome trial (PCOSAct), and 957 subjects with available ApoB and ApoA1 measurements were included. Tests for linear trends and linear regression were used to assess the relation between the ApoB/ApoA1 ratio and metabolic and endocrine parameters. Logistic regression was used to estimate the association between the ratio and risk of metabolic syndrome (MetS) and insulin resistance (IR). The receiver operating characteristics (ROC) curve was used to determine the predictive value of the ApoB/ApoA1 ratio for MetS and IR.ResultsThe results showed that the ApoB/ApoA1 ratio was positively associated with waist circumference, systolic blood pressure, total cholesterol, triglycerides, low-density lipoprotein, fasting plasma glucose, fasting insulin, homeostatic model assessment-insulin resistance, high free testosterone, high free androgen index, alanine transferase, aspartate transferase, and higher prevalence of MetS and IR, but was negatively correlated with high-density lipoprotein and sex hormone-binding globulin after adjusting for age and body mass index. Logistic regression showed that compared with the ApoB/ApoA1 ratio in first quartile, those in the fourth quartile demonstrated a higher risk of MetS (OR: 24.48, 95%CI: 8.54–70.15, P trend <0.001) and IR (OR: 1.78, 95%CI: 1.10–2.87, P trend <0.05) after adjusting for confounding factors. ROC curve results showed that the AUCMetS was 0.84 (95%CI: 0.81–0.86) and had 86.8% sensitivity and 70.3% specificity with a threshold value of 0.64, and the AUCIR was 0.68 (95%CI: 0.64–0.71) and had 74.3% sensitivity and 58.2% specificity with a threshold value of 0.56.ConclusionsIncreased ApoB/ApoA1 ratio was associated with worse MetS components, IR, and elevated androgen hormones and liver enzymes. The ratio might be a useful tool to screen for MetS and IR in PCOS patients.

Gellan gum modified hyaluronic acid hydrogels as viscosupplements with lubrication maintenance and enzymatic resistance.

Osteoarthritis (OA) is a common disease caused by damage to articular cartilage and underlying bone tissues. Early OA can be treated by intra-articular injection of viscosupplements to restore the lost viscoelasticity and lubricity of synovial fluid. Hyaluronic acid (HA), as a most standard synovial fluid supplementation, can be easily degraded in vivo, bringing about lower viscoelasticity and increased injection frequency. In this study, we focus on products with reasonable viscoelasticity and long-lasting action time and develop a kind of polysaccharide-based hydrogel viscosupplement (HEG) based on HA chemically modified gellan gum (GG), which can maintain stable viscoelasticity with hyaluronidase for 1 week owing to the fact that the main component of GG still maintains a stable three-dimensional network structure after enzyme treatment. The as-developed injectable HEG hydrogel possesses good biocompatibility, excellent injectability, suitable viscoelasticity, satisfactory lubricity, and enzymatic resistance, demonstrating great potential to intervene in the development of OA.

Relative Time Inference Using Lateral Gene Transfers.

Many organisms are able to incorporate exogenous DNA into their genomes. This process, called lateral gene transfer (LGT), has the potential to benefit the recipient organism by providing useful coding sequences, such as antibiotic resistance genes or enzymes which expand the organism's metabolic niche. For evolutionary biologists, LGTs have often been considered a nuisance because they complicate the reconstruction of the underlying species tree that many analyses aim to recover. However, LGT events between distinct organisms harbor information on the relative divergence time of the donor and recipient lineages. As a result transfers provide a novel and as yet mostly unexplored source of information to determine the order of divergence of clades, with the potential for absolute dating if linked to the fossil record.

Control of starch-lipid interactions on starch digestibility during hot-extrusion 3D printing for starchy foods.

The nutritional design of personalized starchy foods has become a research hotspot in the field of food science. Driven by the immense functional and nutritional implications of starch-lipid binary interactions, this study is aimed at designing starch digestibility by controlling the interaction between starch and glycerol monostearate (GMS)/stearic acid (SA) using a hot-extrusion 3D printing (HE-3DP) environment. The results indicated that the thermal shear force in the HE-3DP environment promoted hydrophobic interactions between starch and lipids, forming a V-type starch-lipid complex with a compact and ordered structure, thus enhancing enzymatic resistance. Compared with GMS, SA with linear hydrophobic chains was inclined to compound with starch to form a more ordered structure. Interestingly, the slowly digestible starch (SDS) and resistant starch (RS) content reached 25.06% when the added SA content was 10%. Besides, correlations between the structural parameters and digestibility were established, which provided crucial information for designing nutritional starchy food systems using HE-3DP.

Structural and functional characterization of fosfomycin resistance conferred by FosB from Enterococcus faecium.

The Gram-positive pathogen Enterococcus faecium is one of the leading causes of hospital-acquired vancomycin resistant enterococci (VRE) infections. E. faecium has extensive multidrug resistance and accounts for more than two million infections in the United States each year. FosB is a fosfomycin resistance enzyme found in Gram-positive pathogens like E. faecium. Typically, the FosB enzymes are Mn2+ -dependent bacillithiol (BSH) transferases that inactivate fosfomycin through nucleophilic addition of the thiol to the antibiotic. However, our kinetic analysis of FosBEf shows that the enzyme does not utilize BSH as a thiol substrate, unlike the other well characterized FosB enzymes. Here we report that FosBEf is a Mn2+ -dependent L-cys transferase. In addition, we have determined the three-dimensional X-ray crystal structure of FosBEf in complex with fosfomycin at a resolution of 2.0Å. A sequence similarity network (SSN) was generated for the FosB family to investigate the unexpected substrate selectivity. Three non-conserved residues were identified in the SSN that may contribute to the substrate selectivity differences in the family of enzymes. Our structural and functional characterization of FosBEf establishes the enzyme as a potential target and may prove useful for future structure-based development of FosB inhibitors to increase the efficacy of fosfomycin.

Efficient saccharification of ionic liquid-pretreated rice straw in a one-pot system using novel metagenomics derived cellulases

Ionic liquids (ILs)-resistant cellulase enzymes can facilitate the saccharification of IL- pretreated biomass in a one-pot wash-free method. Using a bioinformatics approach, two cellulases, Persicel7 and Persicel8, with convincing evidence for ionic liquid tolerance were identified. Subsequently, these enzymes were heterologously expressed and biochemically characterized. Persicel7 and Persicel8 exhibited endo-β-1, 4-glucanase activity and were resistant to inhibitors and several organic solvents. Their activity in 10% (v/v) 1-ethyl-3-methylimidazolium chloride and 1-butyl-3-methylimidazolium chloride were 130% higher compared with IL-free control. The half-life of cellulases was improved up to 11-fold when incubated with 20% (v/v) solution of ion liquids. In addition, a one-pot IL-pretreatment and enzymatic saccharification of rice straw enhanced the saccharification rate by 33% compared to the untreated reaction. The Persicel7 and Persicel8 unique properties make them attractive candidates for industrial applications, particularly hydrolyzing ion liquid activated biomass in a one-pot system.

Fibrogenesis Marker PRO-C3 Is Higher in Advanced Liver Fibrosis and Improves in Patients Undergoing Bariatric Surgery.

Serum propeptides of type III and type VI collagen (PRO-C3 and PRO-C6) are elevated in advanced nonalcoholic fatty liver disease (NAFLD), but their value in patients with severe obesity and their evolution after bariatric surgery (BS) is unknown. It is unclear if these markers of fibrogenesis are affected by adipose tissue fibrosis (ATF). We studied the association of PRO-C3 and PRO-C6 with liver fibrosis before BS, examined their evolution after BS, and evaluated how much patients' ATF contribute to their levels. Serum PRO-C3 and PRO-C6 were measured in 158 BS patients and compared with liver, subcutaneous, and omental adipose tissue histology obtained during surgery. PRO-C3 and PRO-C6 levels of 63 patients were determined in follow-up at 3 and 12 months post-BS. Patients in the highest quartile of PRO-C3 had a higher risk of advanced liver fibrosis (stage F3-4; odds ratio 5.8; 95% CI [1.5-29.9]; P = 0.017) vs the lowest quartile (adjustment for age, gender, and BMI). PRO-C3 was positively correlated with markers of insulin resistance and liver enzymes. After BS, PRO-C3 levels decreased in patients with high baseline liver fibrosis. This decrease correlated with improvement of metabolic and liver parameters. PRO-C6 was not related to stage of liver fibrosis. ATF did not correlate with PRO-C3 or PRO-C6 levels at baseline or after BS. PRO-C3 was associated with advanced liver fibrosis in patients with severe obesity, and decreased after BS, without being affected by ATF. These data suggest that BS prominently eliminates drivers of hepatic fibrogenesis in NAFLD.