Two novel angiotensin I-converting enzyme inhibitory peptides from garlic protein: In silico screening, stability, antihypertensive effects in vivo and underlying mechanisms.

This study aimed to screen novel angiotensin I-converting enzyme (ACE) inhibitory peptides from garlic proteins and to explore their underlying antihypertensive mechanisms in vivo. After simulated hydrolysis and in silico screening, two novel peptides (MGR and HDCF) were obtained with the highest ACE inhibitory activity (IC50 of 4.50 µM and 26.38 µM) and acted as competitive inhibitors. They interacted with key residues in the ACE receptor mainly through hydrogen bonding and exhibited excellent stability against high temperature, extreme pH, and gastrointestinal digestion. In spontaneously hypertensive rats, MGR and HDCF effectively lowered blood pressure after single or continuous treatments. This was mainly achieved by balancing the renin-angiotensin system, improving renal and cardiac impairment, and regulating endothelial dysfunction. These findings suggested that garlic proteins were potentially suitable materials to prepare ACE inhibitory peptides and provided two promising candidates for ACE inhibition as functional food ingredients.

Health-promoting properties of bioactive proteins and peptides of garlic (Allium sativum).

Garlic is a popular food spice with diverse and well-established medicinal properties. Many research interests have been directed toward the biological activities of the phytochemical constituents of garlic. However, prospects of its bioactive proteins and peptides have been understudied to date. With the advances in food proteomics/peptide research, a review of studies on garlic bioactive proteins and peptides, especially on their nature, extraction, and biological activities, is timely. Garlic has been reported to express several proteins, endogenous and protein-derived peptides with interesting bioactivities, including antioxidant, anti-inflammatory, antibacterial, antifungal, anti-proliferative, antiviral, anti-hypertensive and immunomodulatory activities, suggesting their therapeutic and pharmacological potentials. Compared to legumes, the low protein contents of garlic bulbs and their low stability are possible limitations that would hinder future applications. We suggest adopting heterologous expression systems for peptide overproduction and stability enhancement. Therefore, we recommend increased scientific interest in the bioactive peptides of garlic and other spice plants.

Developing garlic polysaccharide-Fe (III) complexes using garlic pomace to provide enhanced iron-supplementing activity in vivo.

This study investigated the potential of garlic polysaccharides (GPs) from garlic pomace as iron carriers. The obtained GP-Fe (III) complexes had a higher molecular weight (5646 Da) and more fructose (90.46 %) than the GPs did and contained 9.7 % Fe (III). GPs were mainly composed of â†’ 2)-ß-d-Fruf (1 â†’ and â†’ 2)-ß-d-Fruf (6 â†’ residues, and their interactions with Fe (III) reduced the crystallinity, increased the thermal stability, and altered the morphological features through targeting the OH stretching vibrations of the hydroxyl groups and affecting the COC and OCO structures. The GP-Fe (III) complexes had high stability under simulated gastrointestinal digestion system and showed better therapeutic effects on iron deficiency anemia in mice than FeSO4 did, evidenced by improved hematological parameters, restored iron levels, and attenuated oxidative damage. Thus, GP-Fe (III) complexes are promising as novel Fe (III) supplements for Fe-deficient individuals, and promote the high-value utilization of garlic pomace.

Black carbon emissions inventory and scenario analysis for Pakistan.

Black carbon (BC) emissions, resulting from the incomplete combustion of carbonaceous fuels, have been extensively linked to adverse impacts on air quality, climate change, and public health. Nevertheless, there is currently a lack of a comprehensive analysis that integrates activity-based BC emissions inventory and scenario analysis at the national/regional, sectoral, and sub-sectoral levels in Pakistan. This study aims to fill this gap by conducting a comprehensive evaluation of Pakistan's BC emissions inventory for 2021 along projecting emissions until 2050 under the reference emission scenario (RES) and the accelerated reduction scenario (ARS) using the GAINS modeling framework to assess the potential impact of mitigation measures. This study takes a unique approach by considering commonly overlooked sources of BC emissions, such as kerosene lighting, brick kilns, diesel generator sets, and natural gas flaring, which are not typically included in conventional analyses. National BC emissions in 2021 were estimated at 181 kt, with residential combustion being the major contributor, accounting for more than half (108 kt) of the total emissions. The transport, industry, waste, agriculture, power plants, and fuel conversion sectors contributed 26.1 kt, 20.1 kt, 10.7 kt, 8.9 kt, 6.0 kt, and 0.9 kt, respectively. We anticipate that the total BC emissions in Pakistan will reach 201 kt under the RES and 41 kt under the ARS scenario by the year 2050. The ARS achieves substantial BC reductions by the adoption of cleaner fuels, improved biomass stoves, end-of-pipe emission control technologies with higher removal efficiencies, and implementing a ban on the open burning of waste and crop residues. This study underscores the considerable potential for reducing BC emissions across various sectors in Pakistan over the next three decades.

Effect of Crocus sativus L. (saffron) and crocin in the treatment of patients with type-2 diabetes mellitus: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Crocus sativus L. (saffron, Iridaceae) has been traditionally used for thousands of years as herbal medicine for many diseases, including type-2 diabetes mellitus (T2DM), especially in Sri Lanka. Systematic reviews and meta-analysis on C. sativus for T2DM value traditional knowledge about this species. AIM OF THE STUDY: To assess the effectiveness of C. sativus powdered plant, hydroethanolic extract and crocin in reducing fasting blood sugar (FBG), glycated hemoglobin (HbA1c), blood pressure, and other metabolic parameters in patients with T2DM. MATERIAL AND METHODS: Systematic review and meta-analysis based on searches in PubMed, Embase, and Cochrane, including all randomized clinical trials (RCTs) published before January 2, 2023. Two independent reviewers extracted the data and assessed the risks of bias. The effects of C. sativus and crocin were assessed on glycemic, metabolic, and blood pressure parameters. Weighted (WMD) or standardized (SMD) mean differences (before-after) and 95% confidence intervals (95%CI) of the outcomes were extracted or estimated and meta-analyses were conducted using RevMan 5.4 (Cochrane Collaboration). This protocol was registered in PROSPERO (#CRD42023390073). RESULTS: Fifteen of 29 studies were included. Saffron powdered plant decreased AST (WMD -1.19, 95%CI -2.24, -0.13), but increased BMI (WMD 0.56, 95%CI 0.07, 1.05); saffron extract decreased HbA1c (WMD -0.35, 95%CI -0.65, -0.06), FBG (WMD -26.90, 95%CI -38.87, -14.93), creatinine (WMD -0.12, 95%CI -0.19, -0.05), and total cholesterol (WMD -9.29, 95%CI -18.25, -0.33); and crocin decreased HbA1c (WMD -0.43, 95%CI -0.66, -0.20), FBG (WMD -14.10, 95%CI -22.91, -5.30), and systolic blood pressure (WMD -8.18, 95%CI -12.75, -3.61), but increased creatinine levels (WMD 0.24, 95%CI 0.17, 0.32). Of the 15 included studies, 14 had a moderate risk of bias, and one study had a low risk of bias. CONCLUSION: C. sativus (saffron) powdered plant, extract, and crocin have potential as an adjunct treatment for T2DM, improving control of metabolic and clinical parameters. However, C. sativus extract seems to be superior because it was effective in more parameters and did not induce adverse effects. Since many studies were at moderate risk of bias, further high-quality research is needed to firmly establish the clinical efficacy of this plant.

The interplay between chemical conjugation and biologic performance in the development of alginate-based 3D matrices to mimic neural microenvironments.

Biofunctionalization of polysaccharides is a widely used strategy for obtaining extracellular matrix (ECM)-mimicking biomaterials. Still, commonly employed chemistries present low reaction yields and the selection of the most adequate bioconjugation route can be challenging. Herein, we compared the performance of carbodiimide and reductive amination chemistries for the synthesis of tailored peptide-alginate hybrid hydrogels as neural tissue mimics. Reductive amination dramatically improved the peptide grafting efficiency, with yields of 50 % vs. 20 %, allowing 1.5 to 3-fold higher incorporation of cell-adhesive and matrix-metalloproteinases (MMP)-sensitive peptides, respectively. The conjugation of dual-end reactive MMP-sensitive peptides promoted a partial crosslinking, allowing adjusting gelation, stiffness, and degradability of hydrogels. Such parameters depended on the glycosidic position where the bioactive peptide binds, determined by the adopted chemical strategy, and this significantly impacted the biological response. Reductive amination provided softer (50-210 Pa) and fully degradable (60-100 % weight loss) hydrogels, depending on the amount of peptide in formulation, contrasting with the stiffer (400 Pa) and less degradable (40 % weight loss) carbodiimide-based hydrogels. Due to their opened polymer chain and increased peptide availability to cells, such hydrogels better supported the 3D culture of primary astrocytes, which present high complexity and process branching, allowing the development of improved brain ECM-mimicking systems.

Aloe-emodin destroys the biofilm of Helicobacter pylori by targeting the outer membrane protein 6.

Biofilm formation is one of the most important factors causing drug resistance of Helicobacter pylori. Therefore, it is necessary to explore the mechanism underlying the biofilm formation and its eradication methods. The outer membrane proteins (OMPs) play important roles in the formation of bacterial biofilms and are considered the essential targets for new drug discovery. Natural products play significant roles in anti-bacterial and anti-biofilm functions. This study explored the key OMPs involved in the biofilm formation of H. pylori and the natural products that target these OMPs. Transcriptome sequencing, gene knockout, and electrophoretic mobility shift assay (EMSA) were performed to reveal that OMP6 was involved in the biofilm formation of H. pylori, which was regulated by non-phosphorylated ArsR. Molecular docking suggested that aloe-emodin (AE) could target OMP6 and destroy the biofilms of H. pylori. Further exploration of its mechanism found that AE could also inhibit the expression of omp6 mRNA by binding to its regulator ArsR. In summary, we have discovered a novel molecular mechanism regulating the biofilm formation of H. pylori and identified a natural product against H. pylori biofilms, providing potential clues for clinical treatment of H. pylori.

Discovery of plant-derived anti-tumor natural products: Potential leads for anti-tumor drug discovery.

Natural products represent a paramount source of novel drugs. Numerous plant-derived natural products have demonstrated potent anti-tumor properties, thereby garnering considerable interest in their potential as anti-tumor drugs. This review compiles an overview of 242 recently discovered natural products, spanning the period from 2018 to the present. These natural products, which include 69 terpenoids, 42 alkaloids, 39 flavonoids, 21 steroids, 14 phenylpropanoids, 5 quinolines and 52 other compounds, are characterized by their respective chemical structures, anti-tumor activities, and mechanisms of action. By providing an essential reference and fresh insights, this review aims to support and inspire researchers engaged in the fields of natural products and anti-tumor drug discovery.

Accelerating the Discovery and Design of Antimicrobial Peptides with Artificial Intelligence.

Peptides modulate many processes of human physiology targeting ion channels, protein receptors, or enzymes. They represent valuable starting points for the development of new biologics against communicable and non-communicable disorders. However, turning native peptide ligands into druggable materials requires high selectivity and efficacy, predictable metabolism, and good safety profiles. Machine learning models have gradually emerged as cost-effective and time-saving solutions to predict and generate new proteins with optimal properties. In this chapter, we will discuss the evolution and applications of predictive modeling and generative modeling to discover and design safe and effective antimicrobial peptides. We will also present their current limitations and suggest future research directions, applicable to peptide drug design campaigns.

Rapid and selective removal of aristolochic acid I in natural products by vinylene-linked iCOF resins.

Rapid, efficient, and selective removal of toxicants such as aristolochic acid I (AAI) from complex natural product systems is of great significance for the safe use of herbal medicines or medicine-food plants. Addressing this challenge, we develop a high-performance separation approach based on ionic covalent organic frameworks (iCOFs) to separate and remove AAI. Two vinylene-linked iCOFs (NKCOF-46-Br- and NKCOF-55-Br-) with high crystallinity are fabricated in a green and scalable fashion via a melt polymerization synthesis method. The resulting materials exhibit a uniform morphology, high stability, fast equilibrium time, and superior affinity and selectivity for AAI. Compared to conventional separation media, NKCOF-46-Br- and NKCOF-55-Br- achieve the record high adsorption capacities of 246.0 mg g-1 and 178.4 mg g-1, respectively. Various investigations reveal that the positively charged framework and favorable pore microenvironment of iCOFs contribute to their high selectivity and adsorption efficiency. Moreover, the iCOFs exhibit excellent biocompatibility by in vivo toxicity assays. This study paves a new avenue for the rapid, selective and efficient removal of toxicants from complex natural systems.

Mechanism of Sophorae Flavescentis Radix (Kushen) in treating NSCLC: Insights from miRNA-mRNA network analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Sophorae Flavescentis Radix (Kushen) is the primary herb component of Compound Kushen Injection (CKI), an approved clinical treatment for tumors. Despite CKI's widespread use, the underlying mechanisms of Kushen regarding microRNA-target and pathway remain unclear in non-small cell lung cancer (NSCLC). AIM OF THE STUDY: This study aimed to elucidate the crucial miRNAs-targets and pathways responsible for the Kushen's impact on NSCLC. MATERIALS AND METHODS: CCK8, colony formation, and apoptosis assays were performed to assess the effects of Kushen on NSCLC cells. Subsequently, we treated the A549 cell line with varying concentrations of Kushen to obtain mRNA and miRNA expression profiles. A DE (differentially expressed) miRNAs-DEGs network was then constructed to identify the critical miRNA-mRNA interaction influenced by Kushen. Furthermore, we performed clinical significance and prognosis analyses of hub genes to narrow down key genes and their corresponding miRNAs. Finally, the effects of Kushen on critical miRNA-mRNA interaction and related pathway were verified by in vitro and in vivo experiments. RESULTS: In this study, we initially demonstrated that Kushen significantly inhibited cell proliferation, suppressed colony formation, and induced apoptosis in the A549 cells, PC9 cells, and the A549 zebrafish xenograft model. Through expression profile analysis, a DE miRs-DEGs network was constructed with 16 DE miRs and 68 DEGs. Through the network analysis and expression validation, we found Kushen could significantly down-regulate miR-183-5p expression and up-regulate EGR1 expression. Additionally, Kushen affected the PTEN/Akt pathway, increasing PTEN expression and decreasing pAkt expression. Finally, matrine, the essential active compound of Kushen, also inhibited cell growth, induced apoptosis, and regulated miR-183-5p/EGR1 and PTEN/AKT pathway. CONCLUSIONS: Altogether, these findings supported the critical role of miR-183-5p/EGR1 and the PTEN/AKT pathway in the beneficial effects of Kushen on NSCLC, highlighting the therapeutic potential of Kushen in NSCLC treatment.

Compound Kushen injection combined with transarterial chemoembolization for hepatocellular carcinoma: An evidence map and overview of systematic reviews.

ETHNOPHARMACOLOGICAL RELEVANCE: For the treatment of hepatocellular carcinoma (HCC), compound Kushen injection (CKi) is commonly used in combination with transarterial chemoembolization (TACE). AIMS OF THE STUDY: Our objective was to evaluate the reporting quality, methodological quality, risk of bias, and certainty of evidence for CKi combined with TACE for the treatment of patients with HCC by conducting systematic reviews (SRs). The purpose of this study was to improve the clinical application of CKis, strengthen clinical decision-making regarding CKis, and inform future research. MATERIALS AND METHODS: We used eight databases to systematically search SRs of CKi combined with TACE for HCC through February 21, 2023. The quality of reporting of SRs was evaluated using the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, methodological quality using A MeaSurement Tool to Assess systematic Reviews 2, risk of bias using the Risk of Bias in Systematic Review, and certainty of evidence using the Grading of Recommendations Assessment. Finally, the assessment results were visualized by the evidence mapping method. This overview has been registered on PROSPERO with the registration title "Compound Kushen injection for hepatocellular carcinoma: An overview of systematic reviews" and registration number CRD42022369120. RESULTS: A total of 12 SRs meeting the inclusion criteria were included. In terms of reporting quality, 42% of SRs reported relatively complete reports and 58% had certain deficiencies. The methodological quality of all SRs was " critically low". The risk of bias was evaluated as low in 33% of SRs and high in 67% of SRs. The results of the evidence synthesis showed that, in the "moderate" level of evidence, CKi combined with TACE resulted in a 12.7%-21.5% benefit for one-year survival rate, 11.7%-17.2% benefit for objective response rate (ORR), 20.5%-27.1% benefit for quality of life, 22.2% benefit for nausea and vomiting, and 24.7%-27.4% benefit for leukopenia in HCC patients. CONCLUSION: In conclusion, CKi combined with TACE improved survival, ORR and quality of life in patients with HCC, and reduced adverse events. The results should be interpreted with caution due to the low methodological quality of the included SRs. The clinical efficacy of CKis must be confirmed in a large number of randomized controlled trials.

Targeting ferroptosis with natural products in liver injury: new insights from molecular mechanisms to targeted therapies.

BACKGROUND: Ferroptosis is a brand-new type of controlled cell death that is distinguished by its reliance on iron and the production of lipid peroxidation. The role of ferroptosis in damaging liver disorders has attracted a lot of attention in recent years. One effective strategy to reduce liver damage is to target ferroptosis. PURPOSE: The purpose of this review is to clarify the connection between ferroptosis and liver damage and to look into the potential contribution of natural products to the clinical management of liver damage and the discovery of novel medications. METHODS: To study the methods by which natural products operate on ferroptosis to cure liver damage and their main signaling pathways, we searched databases from the time of initial publication to August 2023 in PubMed, EMBASE, Web of Science, Ovid, ScienceDirect, and China National Knowledge Infrastructure. The liver illness that each natural product treats is categorized and summarized. It's interesting to note that several natural compounds, such Artemether, Fucoidan sulfate, Curcumin, etc., have the benefit of having many targets and multiple pathways of action. RESULTS: We saw that in human samples or animal models of liver injury, ferroptosis indicators were activated, lipid peroxidation levels were elevated, and iron inhibitors had the ability to reduce liver damage. Liver damage can be treated with natural products by regulating ferroptosis. This is mostly accomplished through the modulation of Nrf2-related pathways (e.g., Conclusions and Astaxanthin), biological enzymes like GPX4 and the SIRT family (e.g., Chrysophanol and Decursin), and transcription factors like P53 (e.g., Artemether and Zeaxanthin). CONCLUSIONS: This review proposes a promising path for the therapeutic therapy of liver damage by providing a theoretical foundation for the management of ferroptosis utilizing natural ingredients.

VOC emitted by biopharmaceutical industries: Source profiles, health risks, and secondary pollution.

The biopharmaceutical industry contributes substantially to volatile organic compounds (VOCs) emissions, causing growing concerns and social developmental conflicts. This study conducted an on-site investigation of the process-based emission of VOCs from three biopharmaceutical enterprises. In the workshops of the three enterprises, 26 VOCs were detected, which could be sorted into 4 classes: hydrocarbons, aromatic hydrocarbons, oxygen-containing compounds, and nitrogen-containing compounds. Ketones were the main components of waste gases, accounting for 44.13%-77.85% of the overall VOCs. Process-based source profiles were compiled for each process unit, with the fermentation and extraction units of tiamulin fumarate being the main source of VOC emissions. Dimethyl heptanone, vinyl acetate, diethylamine, propylene glycol methyl ether (PGME), and benzene were screened as priority pollutants through a fuzzy comprehensive evaluation system. Ground level concentration simulation results of the Gauss plume diffusion model demonstrated that the diffusivity of VOCs in the atmosphere was relatively high, indicating potential non-carcinogenic and carcinogenic risks 1.5-2 km downwind. Furthermore, the process-based formation potentials of ozone and secondary organic aerosols (SOAs) were determined and indicated that N-methyl-2-pyrrolidone, dimethyl heptanone, and PGME should be preferentially controlled to reduce the ozone formation potential, whereas the control of benzene and chlorobenzene should be prioritized to reduce the generation of SOAs. Our results provide a basis for understanding the characteristics of VOC emission by biopharmaceutical industries and their diffusion, potentially allowing the development of measures to reduce health risks and secondary pollution.

Skin microbiota metabolism of natural products from comfrey root (Symphytum officinale L.).

ETHNOPHARMACOLOGICAL RELEVANCE: Comfrey root (Symphytum officinale L., Boraginaceae) has been used in folk medicine for a long time to treat different diseases. It is recommended for swellings, phlebitis, contusions, gastro-duodenal ulcers, respiratory diseases, and metrorrhagia. Currently, preparations from S. officinale are only topically used due to its wound-healing effects, and for reducing inflammation and the treatment of broken bones, tendon damage, painful joints and muscles. Although it is a widespread plant material, little is known about the interaction of externally applied preparations of comfrey with the human skin microbiome. AIM OF THE STUDY: The study aims to determine the interaction between human skin microbiota and the comfrey root extracts, by monitoring the biotransformation of the constituents present in the extract and evaluating changes in the population of the skin microbiota in an ex vivo setting. MATERIAL AND METHODS: The comfrey root extract was incubated with the human skin microbiota from ten healthy donors. The UHPLC-DAD-MSn analysis determined the composition of the raw extract and the microbial metabolites. Bacterial genomic DNA was extracted and examined by amplification sequencing of the 16S rDNA to determine changes in the bacterial composition. RESULTS: The hydroethanolic extract of comfrey root primarily consists of phenolic acids, pyrrolizidine alkaloids, and their derivatives, and lignans. The natural products present in the extract underwent biodegradation by the skin microbiota, leading to the formation of smaller molecules. It was observed that the skin microbial metabolism primarily focused on modifying the derivatives of pyrrolizidine alkaloids. It resulted in the production of deacetylated and deesterificated compounds. However, it did not lead to the conversion of these compounds into free alkaloids. CONCLUSIONS: The microbiota-triggered biotransformation of the comfrey root extract was observed. A few N-oxides were metabolized to deacetylated and deesterificated forms in ex vivo conditions. It suggests that the intermittent external applications of comfrey preparations perchance are unlikely to pose a substantial risk. While it even may serve as a potential factor influencing the extract activity in treating skin diseases.

Effect of garlic on the components of metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Metabolic diseases are the major causes of macrovascular and microvascular complications which lead to morbidity and mortality. Traditionally, garlic has been used as food and medicine for more than 5000 years. However, efficacy studies have shown conflicting results regarding the garlic effect. AIM OF THE STUDY: This study aims to evaluate the efficacy of garlic on the components of metabolic syndrome (MetS) in metabolic disease patients. MATERIALS AND METHODS: This study was a systematic review and meta-analysis of randomized controlled trials (RCTs). Pubmed, Cochrane Central Register of Controlled Trials (CENTRAL), and Google scholar were searched till December 25, 2021 for identifying the relevant studies that have shown the effects of garlic on components of metabolic syndrome in metabolic disease patients. The mean difference with 95% CI was calculated using fixed-effect or random-effect models. RESULTS: The effect of garlic has shown significant changes on waist circumference (p-value= <0.0001), total cholesterol (p < 0.0001), low density lipoprotein (p = 0.01), high density lipoprotein (p < 0.00001), triglycerides (p < 0.00001), systolic blood pressure (p < 0.00001), diastolic blood pressure (p < 0.00001), glucose (p < 0.00001), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (p = 0.04), C-reactive protein (p < 0.00001), tumor necrosis factor (TNF)-α (p = 0.002), interleukin (IL)-6 (p = 0.0001). Subgroup analysis has shown the favorable effects of garlic in metabolic disease patients. CONCLUSION: Our meta-analysis results confirm the findings that garlic could be useful as an anti-hyperlipidemic, anti-hyperglycemic, anti-hypertensive and anti-inflammatory drug.

Anti-inflammatory effects of Arnica montana (mother tincture and homeopathic dilutions) in various cell models.

ETHNOPHARMACOLOGICAL RELEVANCE: The plant Arnica montana L. has been shown to alleviate inflammation, pain and swelling associated with trauma, and post-operative clinical conditions, yet the mechanism of action is not well understood. AIM OF THE STUDY: The study was designed to investigate the effect of Arnica montana (A. montana) mother tincture and homeopathic dilutions on inflammation markers, oxidative stress and cell migration in diverse cell culture models. MATERIALS AND METHODS: We tested A. montana mother tincture and a range of homeopathic dilutions in different human and murine cell culture models to demonstrate their anti-inflammatory properties by measuring the inflammatory markers: tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule (ICAM-1), reactive oxygen species (ROS) and cell migration. The inflammatory markers were measured by ELISA assays. The intracellular oxidative stress (ROS) in microglial cells was measured using Deep Red CellROX probe. The cell migration was examined by wound healing using the Oris Cell migration assay. RESULTS: These data showed the ability of A. montana (mother tincture and mainly 1C dilution) to significantly reduce TNFα production in inflamed macrophages compared with vehicle (control). They significantly reduced both IL-6 and MCP-1 in inflamed human microglial cells and significantly decreased COX-2 expression in inflamed murine fibroblasts. Moreover, A. montana mother tincture reduced the cell migration whereas 9C dilution significantly enhanced the migration of fibroblast cells compared with vehicle. The expression of ICAM-1 was significantly reduced with A. montana mother tincture and 1C, 3C, 5C, and 9C dilutions in inflamed human endothelial cells compared with vehicle. A. montana mother tincture and 1C, 3C, 5C and 9C dilutions induced a significant and consistent effect on ROS production in inflamed murine microglial cells. A. montana 1C had the largest impact on ROS production. CONCLUSIONS: Mother tincture and 1C dilution of A. montana showed anti-inflammatory properties assessed by measurement of several markers (pro-inflammatory cytokines, adhesion molecule, ROS) in various human and murine cell models. In addition, A. montana 3C, 5C, 9C dilutions have anti-inflammatory and antioxidant effects as highlighted on both primary endothelial cells and murine microglial cells.

Safety and effectiveness of bDMARDs during pregnancy in patients with rheumatic diseases: Real-world data from the BIOBADASER registry / Seguridad y efectividad de los FAME biológicos durante el embarazo en pacientes con enfermedades reumáticas: datos del mundo real procedentes del registro BIOBADASER

Introduction: Inflammatory rheumatic diseases usually affect women of childbearing age treated with biologic drugs. However, there is a lack of literature on the efficacy and toxicity of biologic disease-modifying drugs during pregnancy. The aim of this study was to determine the presence of pregnant patients treated with bDMARDs in a real-world dataset and to examine the impact of pregnancy and lactation on the evolution of rheumatic disease in a registry of Spanish patients.Method: This was a multicentre prospective study with a real-world setting. Information was obtained from BIOBADASER registry. Patients included are women who got pregnant until November 2020 from 19 rheumatology units. We conducted proportions, means, and standard deviations (SD) to describe the study population and the use of treatments. T-test and Chi-square test were applied to assess differences between groups.Result: Ninety cases of pregnancy were registered (n=68 full-term pregnancies; n=22 spontaneous miscarriages). Most of the cases discontinued bDMARDs during pregnancy (78.9%) but 13 cases continued treatment during pregnancy, mainly using certolizumab pegol. These cases were obtaining better management of rheumatic disease, although the differences were not statistically significant [DAS28-CRP, 2.9 (SD: 1.6) vs. 2.0 (1.2), p=.255; DAS28-ESR, 2.2 (1.0) vs. 1.7 (.5), p=.266]. No serious adverse events were reported during pregnancy and lactation.Conclusion: Being pregnant is still an uncommon condition in patients with rheumatic diseases and using bDMARDs. Our results show that rheumatic disease tended to progress better during pregnancy in patients who continued to take bDMARDs.(AU)

Introducción: Las enfermedades reumáticas inflamatorias afectan normalmente a mujeres en edad fértil tratadas con fármacos biológicos. Sin embargo, escasea la literatura sobre la eficacia y la toxicidad de los fármacos modificadores de la enfermedad (FAME) biológicos durante el embarazo. El objetivo de este estudio fue determinar la presencia de pacientes embarazadas tratadas con FAME biológicos en un conjunto de datos del mundo real y examinar el impacto del embarazo y la lactancia en la evolución de la enfermedad reumática en un registro de pacientes españoles.Método: Estudio prospectivo multicéntrico en un entorno del mundo real. La información se obtuvo del registro BIOBADASER. Los pacientes fueron mujeres embarazadas hasta el mes de noviembre del 2020, de 19 unidades de Rreumatología. Obtuvimos proporciones, medias y desviaciones estándar (DE) para describir la población de estudio y el uso de tratamientos. Se realizaron las pruebas t y χ2 para evaluar las diferencias entre grupos.Resultado:Se registraron 90 casos de embarazo (n=68 embarazos a término; n=22 abortos espontáneos). La mayoría de los casos suspendieron el tratamiento con FAME biológicos durante el embarazo (78,9%), pero 13 casos prosiguieron el tratamiento durante el embarazo, utilizando principalmente certolizumab pegol. Dichos casos obtuvieron un mejor manejo de la enfermedad reumática, aunque las diferencias no fueron estadísticamente significativas (DAS28-CRP, 2,9 [DE 1,6] vs. 2 [1,2], p=0,255; DAS28-ESR, 2,2 [1] vs. 1,7 [0,5], p=0,266). No se reportaron episodios adversos graves durante el embarazo y la lactancia.Conclusión: La situación de embarazo sigue siendo infrecuente en las pacientes con enfermedades reumáticas que utilizan FAME biológicos. Nuestros resultados reflejan que la enfermedad reumática tendió a progresar mejor durante el embarazo en las mujeres tratadas con FAME biológicos.(AU)

Biological treatment interruption in inflammatory bowel disease: Motivation and predictive factors / Interrupción del tratamiento biológico en la enfermedad inflamatoria intestinal: causas y factores predictores

Background: Loss-of-response and adverse events (AE) to biologics have been linked to HLA-DQA1*05 allele. However, the clinical factors or biologic used may influence treatment duration. Our objective was to evaluate the influence of clinical and therapeutic factors, along with HLA, in biological treatment discontinuation. Methods: A retrospective study of consecutive IBD patients treated with biologics between 2007 and 2011 was performed. Main outcome was treatment discontinuation due to primary non-response (PNR), secondary loss of response (SLR) or AE. HLA-DQA1 genotyping was done in all patients. Regression analyses were used to assess risk factors of treatment discontinuation. Results: One hundred fifty patients (61% male) with 312 biologic treatments were included. 147 (47%) were discontinued with a cumulative probability of 30%, 41% and 56% at 1, 2 and 5 years. The use of infliximab (p=0.006) and articular manifestations (p<0.05) were associated with treatment discontinuation. Considering cause of withdrawal, Ulcerative Colitis (UC) had a higher proportion of PNR (HR=4.99; 95% CI=1.71–14.63; p=0.003), SLR was higher if biologics had been indicated due to disease flare (HR=2.32; 95% CI=1.05–5.09; p=0.037) while AE were greater with infliximab (HR=2.46; 95% CI=1.48–4.08; p<0.001) or spondylitis (HR=2.46; 95% CI=1.78–6.89; p<0.001). According to the biological drug, HLA-DQA1*05 with adalimumab showed more SLR in cases with Crohn's disease (HR=3.49; 95% CI=1.39–8,78; p=0.008) or without concomitant immunomodulator (HR=2.8; 95% CI=1.1–6.93; p=0.026). Conclusions: HLA-DQ A1*05 was relevant in SLR of IBD patients treated with adalimumab without immunosupression. In patients treated with other biologics, clinical factors were more important for treatment interruption, mainly extensive UC or extraintestinal manifestations and having indicated the biologic for flare. (AU)

Introducción: Estudios previos han observado una asociación entre el HLA-DQA1*05 y la pérdida de respuesta a biológicos y el desarrollo de efectos adversos (EA). Hay factores clínicos y biológicos que podrían influir en la duración del tratamiento. El objetivo del estudio fue evaluar la influencia del HLA, de factores clínicos y terapéuticos en la interrupción del tratamiento biológico. Métodos: Se realizó un estudio retrospectivo de pacientes con enfermedad inflamatoria intestinal (EII) tratados con biológicos entre 2007 y 2011. Los principales eventos analizados fueron la suspensión del tratamiento por fallo de respuesta primaria (PRP), secundaria (PRS) o EA. Se realizó un tipaje del HLA-DQA1*05 y se evaluaron los factores de riesgo de interrupción del tratamiento mediante un análisis de regresión logística. Resultados: Se incluyeron 150 pacientes y 312 tratamientos, de los cuales se suspendieron 147 (47%) en el seguimiento. El infliximab (p=0,006) y las manifestaciones articulares (p<0,05) se relacionaron con la interrupción del tratamiento. La colitis ulcerosa (CU) presentó mayor PRP (HR: 4,99; IC 95%: 1,71-14,63; p=0,003), el brote como indicación de tratamiento se asoció a más PRS (HR: 2,32; IC 95%: 1,05-5,09; p=0,037); el uso de infliximab (HR: 2,46; IC 95%: 1,48-4,08; p<0,001) y la espondilitis (HR: 2,46; IC 95%: 1,78-6,89; p<0,001) a la suspensión por EA. El HLA-DQA1*05 fue un factor de riesgo de PRS en los pacientes tratados con adalimumab (ADA) con enfermedad de Crohn (HR: 3,49; IC 95%: 1,39-8,78; p=0,008) o con EII sin inmunosupresor asociado (HR: 2,8; IC 95%: 1,1-6,93; p=0,026). Conclusiones: El HLA-DQA1*05 se asoció al cese del tratamiento con ADA por PRS en los pacientes con EII sin inmunosupresor asociado. Respecto a otros biológicos, la suspensión se debió más a factores como la CU, las manifestaciones articulares y la indicación para remisión de brote intestinal. (AU)

Neurodevelopment among children exposed to HIV and uninfected in sub-Saharan Africa.

INTRODUCTION: The population of 16 million children exposed to HIV and uninfected (CHEU) under 15 years of age continues to expand rapidly, and the estimated prevalence of CHEU exceeds 20% in several countries in sub-Saharan Africa with high HIV prevalence. Some evidence suggests that CHEU experience suboptimal neurodevelopmental outcomes compared to children born to women without HIV. In this commentary, we discuss the latest research on biologic and socio-behavioural factors associated with neurodevelopmental outcomes among CHEU. DISCUSSION: Some but not all studies have noted that CHEU are at risk of poorer neurodevelopment across multiple cognitive domains, most notably in language and motor skills, in diverse settings, ages and using varied assessment tools. Foetal HIV exposure can adversely influence infant immune function, structural brain integrity and growth trajectories. Foetal exposure to antiretrovirals may also influence outcomes. Moreover, general, non-CHEU-specific risk factors for poor neurodevelopment, such as preterm birth, food insecurity, growth faltering and household violence, are amplified among CHEU; addressing these factors will require multi-factorial solutions. There is a need for rigorous harmonised approaches to identify children at the highest risk of delay. In high-burden HIV settings, existing maternal child health programmes serving the general population could adopt structured early child development programmes that educate healthcare workers on CHEU-specific risk factors and train them to conduct rapid neurodevelopmental screening tests. Community-based interventions targeting parent knowledge of optimal caregiving practices have shown to be successful in improving neurodevelopmental outcomes in children and should be adapted for CHEU. CONCLUSIONS: CHEU in sub-Saharan Africa have biologic and socio-behavioural factors that may influence their neurodevelopment, brain maturation, immune system and overall health and wellbeing. Multidisciplinary research is needed to disentangle complex interactions between contributing factors. Common environmental and social risk factors for suboptimal neurodevelopment in the general population are disproportionately magnified within the CHEU population, and it is, therefore, important to draw on existing knowledge when considering the socio-behavioural pathways through which HIV exposure could impact CHEU neurodevelopment. Approaches to identify children at greatest risk for poor outcomes and multisectoral interventions are needed to ensure optimal outcomes for CHEU in sub-Saharan Africa.