Tissue Response Research Articles

Nonoperative and Operative Soft-Tissue, Cartilage, and Bony Regeneration and Orthopaedic Biologics of the Elbow and Upper Extremity: An Orthoregeneration Network Foundation Review

Orthoregeneration is defined as a solution for orthopaedic conditions that harnesses the benefits of biology to improve healing, reduce pain, improve function, and, optimally, provide an environment for tissue regeneration. Options include drugs, surgical intervention, scaffolds, biologics as a product of cells, and physical and electromagnetic stimuli. The goal of regenerative medicine is to enhance the healing of tissue after musculoskeletal injuries as both isolated treatment and adjunct to surgical management, using novel therapies to improve recovery and outcomes. Various orthopaedic biologics (orthobiologics) have been investigated for the treatment of pathology involving the elbow and upper extremity, including the tendons (lateral epicondylitis, medial epicondylitis, biceps tendonitis, triceps tendonitis), articular cartilage (osteoarthritis, osteochondral lesions), and bone (fractures, nonunions, avascular necrosis, osteonecrosis). Promising and established treatment modalities include hyaluronic acid; botulinum toxin; corticosteroids; leukocyte-rich and leukocyte-poor platelet-rich plasma; autologous blood; bone marrow aspirate comprising mesenchymal stromal cells (alternatively termed medicinal signaling cells and frequently mesenchymal stem cells [MSCs]) and bone marrow aspirate concentrate; MSCs harvested from adipose and skin (dermis) sources; vascularized bone grafts; bone morphogenic protein scaffold made from osteoinductive and conductive β-tricalcium phosphate and poly-ε-caprolactone with hydrogels, human MSCs, and matrix metalloproteinases; and collagen sponge. Autologous blood preparations such as autologous blood injections and platelet-rich plasma show positive outcomes for nonresponsive tendinopathy. In addition, cellular therapies such as tissue-derived tenocyte-like cells and MSCs show a promising ability to regulate degenerative processes by modulating tissue response to inflammation and preventing continuous degradation and support tissue restoration.

Thermoviscoelastic response of skin tissue via fractional Pennes bioheat and fractional viscoelasticity

In this paper, the thermoviscoelastic response of skin tissue, as a typical class of viscoelastic biological tissue, subject to thermal shock is studied based on the fractional Kelvin-Voigt model and fractional Pennes bioheat conduction. A time-fractional biothermoviscoelastic governing equation is derived and initial-boundary value conditions are given for monolayer skin tissue of finite thickness. The temperature change and thermal stress of viscoelastic skin tissue are obtained by the Laplace transform and its inversion using matlab software. The influences of viscosity coefficient, relaxation times, fractional-order viscosity/heat parameter, and blood perfusion rate of skin tissue on the temperature distribution and the elastic displacement are analyzed. The numerical results show that fractional-order viscosity does not affect temperature, whereas fractional-order heat flow does. Moreover, fractional-order heat flow affects the sensitivity of blood perfusion rate to the thermodynamic response.

Association of natriuretic peptides and receptor activity with cardio-metabolic health at middle age

Natriuretic peptides (NP) have multiple actions benefitting cardiovascular and metabolic health. Although many of these are mediated by Guanylyl Cyclase (GC) receptors NPR1 and NPR2, their role and relative importance in vivo is unclear. The intracellular mediator of NPR1 and NPR2, cGMP, circulates in plasma and can be used to examine relationships between receptor activity and tissue responses targeted by NPs. Plasma cGMP was measured in 348 participants previously recruited in a multidisciplinary community study (CHALICE) at age 50 years at a single centre. Associations between bio-active NPs and bio-inactive aminoterminal products with cGMP, and of cGMP with tissue response, were analysed using linear regression. Mediation of associations by NPs was assessed by Causal Mediation Analysis (CMA). ANP’s contribution to cGMP far exceed those of other NPs. Modelling across three components (demographics, NPs and cardiovascular function) shows that ANP and CNP are independent and positive predictors of cGMP. Counter intuitively, findings from CMA imply that in specific tissues, NPR1 responds more to BNP stimulation than ANP. Collectively these findings align with longer tissue half-life of BNP, and direct further therapeutic interventions towards extending tissue activity of ANP and CNP.

Comparing finite viscoelastic constitutive relations and variational principles in modeling gastrointestinal soft tissue deformation

The mechanical attributes of soft tissues within the gastrointestinal (GI) tract are crucial for the effective operation of the GI system, and alterations in these properties may play a role in motility-related disorders. Various constitutive modeling approaches have been suggested to comprehend the response of soft tissues to diverse loading conditions. Among these, hyperelastic constitutive models based on finite elasticity have gained popularity. However, these models fall short in capturing rate- and time-dependent tissue properties. In contrast, finite viscoelastic models offer a solution to overcome these limitations. Nevertheless, the development of a suitable finite viscoelastic model, coupled with a variational formulation for efficient finite element (FE) implementation, remains an ongoing challenge. This study aims to address this gap by developing diverse finite viscoelastic constitutive relations and applying them to characterize soft tissue. Furthermore, the research explores the creation of compressible, nearly incompressible, and incompressible versions of viscoelastic constitutive relations, along with their variational formulation, to facilitate efficient FE implementation. The proposed model demonstrates remarkable accuracy in replicating experimental results, achieving an R2 value exceeding 0.99.

Transcriptomic analyses provide new insights into immune response of the Procambarus clarkii intestines to Aeromonas hydrophila challenge

In recent years, the death rate of Procambarus clarkii increased sharply due to pathogenic bacterial infections, leading to huge economic losses. To determine the immune response of the intestinal tissues of P. clarkii to bacterial infections, we compared the immune indexes, histopathological damage, and transcriptome data of the control and Aeromonas hydrophila-infected P. clarkii. With the injection of A. hydrophila, it was found that intestinal mucosal folds increased, intestinal villi showed obvious vacuolation, and the tissue structure changed significantly. The results of non-specific immunoenzyme activity showed that the Total protein (TP) content was significantly lower than that of the control group at 24 h, and the Acid phosphatase (ACP) and Alkaline phosphatase (AKP) activities in the treatment group showed a significant increasing trend (p < 0.05). In terms of the transcriptome, an average of 22,927,523 clean reads and 27,866 genes were found in the control and treatment groups through gene assembly and annotation. Among these genes, 567 were identified as differentially expressed genes (DEGs), of which 501 were up-regulated and 66 were down-regulated. Quantitative-polymerase chain reaction (qPCR) analysis of six randomly selected genes was used to verify the RNA-sequencing results. The Gene Ontology enrichment analysis revealed that the DEGs were primarily involved in cell processes, metabolic processes, and biological regulation, while the Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that these DEGs were involved in tyrosine metabolism, glycosphingolipid biosynthesis—ganglionic series, and nitrogen metabolism. We studied the tyrosine metabolic pathway and found that it contributes to the immune defense mechanism of P. clarkii. The results of our study provide important insights into the intestinal immune response of P. clarkii to A. hydrophila infection.

Effects of feeding chicken egg yolk antibodies on intestinal cell apoptosis, oxidative stress and microbial flora of tilapia (Oreochromis niloticus) infected with Streptococcus agalactiae

Streptococcosis, the most common bacterial disease of fish in recent years, is highly infectious and lethal, and has become an important factor hindering the healthy and sustainable development of aquaculture. Chicken egg yolk antibody (IgY) has the advantages of high antigen specificity, inexpensive and easy to obtain, simple preparation, no toxic side effects, and in line with animal welfare, which is a green and safe alternative to antibiotics. In this study, the potential of specific IgY in the treatment of gastrointestinal pathogens was explored by observing the effects of specific IgY on intestinal flora, pathological tissue, apoptosis, oxidative stress, and inflammatory response of tilapia. We used the specific IgY prepared in the early stage to feed tilapia for 10 days, and then the tilapia was challenged with Streptococcus agalactiae. The results showed that feeding IgY before challenge had a small effect on the intestinal flora, and after challenge specific IgY decreased the proportion of Streptococcus and increased the diversity of the intestinal flora; in histopathology, specific IgY decreased tissue damage and maintained the integrity of tissue structure.Further study found that specific IgY can reduce intestinal epithelial cell apoptosis and reduce caspase activity; at the same time, the content of MDA was decreased, and the activities of SOD, CAT, GSH-Px and GR were increased. In addition, specific IgY can down-regulate the expression levels of IL-8 and TNF-α genes and up-regulate the expression levels of IL-10 and TGF-β. The results of this study showed that specific IgY could improve the intestinal flora of tilapia infected with Streptococcus agalactiae, reduce intestinal cell apoptosis, oxidative stress injury and inflammatory response, thereby reducing tissue damage and protecting the health of tilapia. Overall, specific IgY can be further explored as a potential antibiotic alternative for gastrointestinal pathogen infections.

Functional Optical Coherence Tomography of Rat Cortical Neurovascular Activation during Monopulse Electrical Stimulation with the Microelectrode Array

This paper presents a study to evoke rat cortical functional activities, including hemodynamic and neural tissue signal changes, by monopulse electrical stimulation with a microelectrode array using functional optical coherence tomography (fOCT). Based on the principal component analysis and fuzzy clustering method (PCA-FCM), the hemodynamic response of different size blood vessels in rat cortex are analyzed, showing that the hemodynamic response of the superficial large blood vessels is more concentrated. In the regions of neural tissue where blood vessels are removed, positive significant pixels (the intensity of the pixel for five consecutive frames is greater than the average value plus triple standard deviation) and negative significant pixels (the intensity of the pixel for five consecutive frames is less than the average value minus triple standard deviation) exist, and the averaged intensity signal responds rapidly with an onset time of ~20.8 ms. Furthermore, the hemodynamic response was delayed by ~3.5 s from the neural tissue response. fOCT can provide a label-free, large-scale and depth-resolved map of cortical neurovascular activation, which is a promising technology to monitor cortical small-scale neurovascular activities.

Differential Effects of HDAC6 Inhibition Versus Knockout During Hepatic Ischemia-reperfusion Injury Highlight Importance of HDAC6 C-terminal Zinc-finger Ubiquitin-binding Domain.

Ischemia-reperfusion injury (IRI) causes significant morbidity in liver transplantation among other medical conditions. IRI following liver transplantation contributes to poor outcomes and early graft loss. Histone/protein deacetylases (HDACs) regulate diverse cellular processes, play a role in mediating tissue responses to IRI, and may represent a novel therapeutic target in preventing IRI in liver transplantation. Using a previously described standardized model of murine liver warm IRI, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were assessed at 24 and 48 h after reperfusion to determine the effect of different HDAC inhibitors. Broad HDAC inhibition with trichostatin-A (TSA) was protective against hepatocellular damage (P < 0.01 for AST and P < 0.05 for ALT). Although HDAC class I inhibition with MS-275 provided statistically insignificant benefit, tubastatin-A (TubA), an HDAC6 inhibitor with additional activity against HDAC10, provided significant protection against liver IRI (P < 0.01 for AST and P < 0.001 for ALT). Surprisingly genetic deletion of HDAC6 or -10 did not replicate the protective effects of HDAC6 inhibition with TubA, whereas treatment with an HDAC6 BUZ-domain inhibitor, LakZnFD, eliminated the protective effect of TubA treatment in liver ischemia (P < 0.01 for AST and P < 0.01 for ALT). Our findings suggest TubA, a class IIb HDAC inhibitor, can mitigate hepatic IRI in a manner distinct from previously described class I HDAC inhibition and requires the HDAC6 BUZ-domain activity. Our data corroborate previous findings that HDAC targets for therapeutic intervention of IRI may be tissue-specific, and identify HDAC6 inhibition as a possible target in the treatment of liver IRI.

Stress and Heart in Remodeling Process: Multiple Stressors at the Same Time Kill.

Myocardial remodeling is developed by increased stress in acute or chronic pathophysiologies. Stressed heart morphology (SHM) is a new description representing basal septal hypertrophy (BSH) caused by emotional stress and chronic stress due to increased afterload in hypertension. Acute stress cardiomyopathy (ASC) and hypertension could be together in clinical practice. Therefore, there are some geometric and functional aspects regarding this specific location, septal base under acute and chronic stress stimuli. The findings by our and the other research groups support that hypertension-mediated myocardial involvement could be pre-existed in ASC cases. Beyond a frequently seen predominant base, hyperkinetic tissue response is detected in both hypertension and ASC. Furthermore, hypertension is the responsible factor in recurrent ASC. The most supportive prospective finding is BSH in which a hypercontractile base takes a longer time to exist morphologically than an acutely developed syndrome under both physiologic exercise and pressure overload by transaortic binding in small animals using microimaging. However, cardiac decompensation with apical ballooning could mask the possible underlying hypertensive disease. In fact, enough time for the assessment of previous hypertension history or segmental analysis could not be provided in an emergency unit, since ASC is accepted as an acute coronary syndrome during an acute episode. Additional supportive findings for SHM are increased stress scores in hypertensive BSH and the existence of similar tissue aspects in excessive sympathetic overdrive like pheochromocytoma which could result in both hypertensive disease and ASC. Exercise hypertension as the typical form of blood pressure variability is the sum of physiologic exercise and pathologic increased blood pressure and results in increased mortality. Hypertension is not rare in patients with a high stress score and leads to repetitive attacks in ASC supporting the important role of an emotional component as well as the potential danger due to multiple stressors at the same time. In the current review, the impact of multiple stressors on segmental or global myocardial remodeling and the hazardous potential of multiple stressors at the same time are discussed. As a result, incidentally determined segmental remodeling could be recalled in patients with multiple stressors and contribute to the early and combined management of both hypertension and chronic stress in the prevention of global remodeling and heart failure.

Comparison of different bone substitutes in the repair of rat calvaria critical size defects: questioning the need for alveolar ridge presentation.

This study aimed to evaluate the effectiveness of biomaterials in bone healing of critical bone defects created by piezoelectric surgery in rat calvaria. Histomorphologic analysis was performed to assess bone regeneration and tissue response. Fifty animals were randomized into five groups with one of the following treatments: Control group (n = 10), spontaneous blood clot formation with no bone fill; BO group (Bio-Oss, Geistlich Pharma; n = 10), defects were filled with bovine medullary bone substitute; BF group (Bonefill, Bionnovation; n = 10), defects were filled with bovine cortical bone substitute; hydroxyapatite group (n = 10), defects were filled with hydroxyapatite; calcium sulfate group (n = 10), defects were filled with calcium sulfate. Five animals from each group were euthanized at 30 and 45 days. The histomorphometry calculated the percentage of the new bone formation in the bone defect. All data obtained were evaluated statistically considering P < .05 as statistically significant. The results demonstrated the potential of all biomaterials for enhancing bone regeneration. The findings showed no statistical differences between all the biomaterials at 30 and 45 days including the control group without bone grafting. In conclusion, the tested biomaterials presented an estimated capacity of osteoconduction, statistically nonsignificant between them. In addition, the selection of biomaterial should consider the specific clinical aspect, resorption rates, size of the particle, and desired bone healing responses. It is important to emphasize that in some cases, using no bone filler might provide comparable results with reduced cost and possible complications questioning the very frequent use of ridge presentation procedures.

YL-109 attenuates sepsis-associated multiple organ injury through inhibiting the ERK/AP-1 axis and pyroptosis by upregulating CHIP

Sepsis is a severe inflammatory disorder that can lead to life-threatening multiple organ injury. Lipopolysaccharide (LPS)-induced inflammation is the leading cause of multiple organ failure in sepsis. This study aimed to explore the effect of a novel agent, 2-(4-hydroxy-3-methoxyphenyl)-benzothiazole (YL-109), on LPS-induced multiple organ injury and the molecular mechanisms underlying these processes. The results showed that YL-109 protected against LPS-induced high mortality, cardiac dysfunction, pulmonary and intestinal injury through inhibiting the proinflammatory response, NLRP3 expression and pyroptosis-associated indicators in mouse tissues. YL-109 suppressed LPS-initiated cytokine release, pyroptosis and pyroptosis-related protein expression in HL-1, IEC-6 and MLE-12 cells, which was consistent with the results of the in vivo experiments. Mechanistically, YL-109 reduces phosphorylated ERK (extracellular signal-regulated kinase) levels and NF-κB activation, which are achieved through upregulating CHIP (carboxy terminus of Hsc70-interacting protein) expression, thereby inhibiting c-Jun and c-Fos activation as well as NLRP3 expression. As an E3 ligase, CHIP overexpression obviously promoted the degradation of phosphorylated ERK and inhibited the expression of NF-κB-mediated NLRP3 in cells stimulated with LPS. The protective effects of YL-109 against cardiac, pulmonary and intestinal damage, inflammation and pyroptosis caused by LPS were eliminated in CHIP knockout mice. Our results not only reveal the protective effect and molecular mechanism of YL-109 against LPS-mediated organs damage but also provide additional insights into the effect of CHIP on negatively regulating pyroptosis and inflammatory pathways.

Dynamic mechanical response and functional mechanisms in rabbit pulmonary tissue

Dynamic mechanical response and functional mechanisms in rabbit pulmonary tissue

Role of transcriptional regulation in auxin-mediated response to abiotic stresses.

Global climate change (GCC) is posing a serious threat to organisms, particularly plants, which are sessile. Drought, salinity, and the accumulation of heavy metals alter soil composition and have detrimental effects on crops and wild plants. The hormone auxin plays a pivotal role in the response to stress conditions through the fine regulation of plant growth. Hence, rapid, tight, and coordinated regulation of its concentration is achieved by auxin modulation at multiple levels. Beyond the structural enzymes involved in auxin biosynthesis, transport, and signal transduction, transcription factors (TFs) can finely and rapidly drive auxin response in specific tissues. Auxin Response Factors (ARFs) such as the ARF4, 7, 8, 19 and many other TF families, such as WRKY and MADS, have been identified to play a role in modulating various auxin-mediated responses in recent times. Here, we review the most relevant and recent literature on TFs associated with the regulation of the biosynthetic, transport, and signalling auxin pathways and miRNA-related feedback loops in response to major abiotic stresses. Knowledge of the specific role of TFs may be of utmost importance in counteracting the effects of GCC on future agriculture and may pave the way for increased plant resilience.

High-fat diets induce inflammatory IMD/NFκB signaling via gut microbiota remodeling in Drosophila.

High-fat diets (HFDs), a prevailing daily dietary style worldwide, induce chronic low-grade inflammation in the central nervous system and peripheral tissues, promoting a variety of diseases including pathologies associated with neuroinflammation. However, the mechanisms linking HFDs to inflammation are not entirely clear. Here, using a Drosophila HFD model, we explored the mechanism of HFD-induced inflammation in remote tissues. We found that HFDs activated the IMD/NFκB immune pathway in the head through remodeling of the commensal gut bacteria. Removal of gut microbiota abolished such HFD-induced remote inflammatory response. Further experiments revealed that HFDs significantly increased the abundance of Acetobacter malorum in the gut, and the re-association of this bacterium was sufficient to elicit inflammatory response in remote tissues. Mechanistically, Acetobacter malorum produced a greater amount of peptidoglycan (PGN), a well-defined microbial molecular pattern that enters the circulation and remotely activates an inflammatory response. Our results thus show that HFDs trigger inflammation mediated by a bacterial molecular pattern that elicits host immune response.

The impact of Thiopeptide antibiotics on inflammatory responses in periodontal tissues through the regulation of the MAPK pathway

Periodontitis is a bacteria-induced inflammatory disease that damages the tissues supporting the teeth, gums, periodontal ligaments, and alveolar bone. Conventional treatments such as surgical procedures, anti-inflammatory drugs, and antibiotics, are somewhat effective; however, these may lead to discomfort and adverse events, thereby affecting patient outcomes. Therefore, this study aimed to find an effective method to prevent the onset of periodontal disease and explore the specific mechanisms of their action.The impact of thiostrepton on Porphyromonas gingivalis and periodontal ligament stem cells was evaluated in an inflammatory microenvironment. In vivo experiments were performed using a mouse periodontitis model to assess the effectiveness of locally applied thiostrepton combined with a silk fibroin hydrogel in impeding periodontitis progression. Thiostrepton exhibited significant antimicrobial effects against Porphyromonas gingivalis and anti-inflammatory properties by regulating the MAPK pathway through DUSP2. Locally applied thiostrepton effectively impeded the progression of periodontitis and reduced tissue damage. Thiostrepton treatment is a promising and tolerable preventive strategy for periodontitis, offering antimicrobial and anti-inflammatory benefits. These findings suggest the potential of thiostrepton as a valuable addition to periodontitis management, warranting further research and clinical exploration to improve patient outcomes.

Trauma-associated extracellular histones mediate inflammation via a MYD88-IRAK1-ERK signaling axis and induce lytic cell death in human adipocytes

Despite advances in the treatment and care of severe physical injuries, trauma remains one of the main reasons for disability-adjusted life years worldwide. Trauma patients often suffer from disturbances in energy utilization and metabolic dysfunction, including hyperglycemia and increased insulin resistance. White adipose tissue plays an essential role in the regulation of energy homeostasis and is frequently implicated in traumatic injury due to its ubiquitous body distribution but remains poorly studied. Initial triggers of the trauma response are mainly damage-associated molecular patterns (DAMPs) such as histones. We hypothesized that DAMP-induced adipose tissue inflammation contributes to metabolic dysfunction in trauma patients. Therefore, we investigated whether histone release during traumatic injury affects adipose tissue. Making use of a murine polytrauma model with hemorrhagic shock, we found increased serum levels of histones accompanied by an inflammatory response in white adipose tissue. In vitro, extracellular histones induced an inflammatory response in human adipocytes. On the molecular level, this inflammatory response was mediated via a MYD88-IRAK1-ERK signaling axis as demonstrated by pharmacological and genetic inhibition. Histones also induced lytic cell death executed independently of caspases and RIPK1 activity. Importantly, we detected increased histone levels in the bloodstream of patients after polytrauma. Such patients might benefit from a therapy consisting of activated protein C and the FDA-approved ERK inhibitor trametinib, as this combination effectively prevented histone-mediated effects on both, inflammatory gene activation and cell death in adipocytes. Preventing adipose tissue inflammation and adipocyte death in patients with polytrauma could help minimize posttraumatic metabolic dysfunction.

Bio-thermal response during laser haemorrhoidoplasty: an exclusive analytical and numerical approach for theoretical investigation.

Haemorrhoidal disease is identified by declension of the inflamed and bleeding of vascular tissues of the anal canal. Traditionally, haemorrhoids are associated with chronicconstipation and the most common symptoms are irritation in anus region, pain and discomfort, swelling around anus, tender lumps around the anus and rectal bleeding (depending upon the grade of haemorrhoid). Among the several conventional treatment procedures (commonly mentioned as, rubber band litigation, sclerotherapy and electrotherapy), laser haemorrhoidoplasty is an out-patient and less-invasive laparoscopic procedure. From literature survey it has been observed that an exclusive theoretical model depicting the impact of 1064nm wavelength laser wave on living tissues subjected to haemorrhoid therapy is not available. This research work is a pioneering attempt to develop a theoretical study attributing specifically on laser therapy of haemorrhoid treatment based on Pennes' biological heat transfer model. The corresponding mathematical model has been solved by analytical method to establish thermal response of tissue during the treatment and also the same has been solved a numerical approach based on finite difference method to validate the feasibility of former method due to unavailability of any theoretical model. Impact of variation of blood perfusion term, laser pulse time and optical penetration depth on temperature response of skin tissue is captured. The tissue temperature decreases along with time of laser exposure with increasing the blood perfusion rate as it carries away large amount of heat. With the increase in laser pulse time, tissue temperature declines due to shorter pulse time resulting in higher energy consumed by electrons. The research outcome is successfully validated with less than 1% of error observed between the appointed analytical and numerical scheme.

A telomere-to-telomere gap-free reference genome assembly of avocado provides useful resources for identifying genes related to fatty acid biosynthesis and disease resistance.

Avocado (Persea americana Mill.) is an economically valuable plant because of the high fatty acid content and unique flavor of its fruits. Its fatty acid content, especially the relatively high unsaturated fatty acid content, provides significant health benefits. We herein present a telomere-to-telomere gapless genome assembly (841.6Mb) of West Indian avocado. The genome contains 40 629 predicted protein-coding genes. Repeat sequences account for 57.9% of the genome. Notably, all telomeres, centromeres, and a nucleolar organizing region are included in this genome. Fragments from these three regions were observed via fluorescence in situ hybridization. We identified 376 potential disease resistance-related nucleotide-binding leucine-rich repeat genes. These genes, which are typically clustered on chromosomes, may be derived from gene duplication events. Five NLR genes (Pa11g0262, Pa02g4855, Pa07g3139, Pa07g0383, and Pa02g3196) were highly expressed in leaves, stems, and fruits, indicating they may be involved in avocado disease responses in multiple tissues. We also identified 128 genes associated with fatty acid biosynthesis and analyzed their expression patterns in leaves, stems, and fruits. Pa02g0113, which encodes one of 11 stearoyl-acyl carrier protein desaturases mediating C18 unsaturated fatty acid synthesis, was more highly expressed in the leaves than in the stems and fruits. These findings provide valuable insights that enhance our understanding of fatty acid biosynthesis in avocado.

Aryl Hydrocarbon Receptor Signalling in the Control of Gut Inflammation.

Aryl hydrocarbon receptor (AHR), a transcription factor activated by many natural and synthetic ligands, represents an important mediator of the interplay between the environment and the host's immune responses. In a healthy gut, AHR activation promotes tolerogenic signals, which help maintain mucosal homeostasis. AHR expression is defective in the inflamed gut of patients with inflammatory bowel diseases (IBD), where decreased AHR signaling is supposed to contribute to amplifying the gut tissue's destructive immune-inflammatory responses. We here review the evidence supporting the role of AHR in controlling the "physiological" intestinal inflammation and summarize the data about the therapeutic effects of AHR activators, both in preclinical mouse models of colitis and in patients with IBD.

Development of Mechanistic In Vitro-In Vivo Extrapolation to Support Bioequivalence Assessment of Long-Acting Injectables.

Long-acting injectable (LAI) formulations provide sustained drug release over an extended period ranging from weeks to several months to improve efficacy, safety, and compliance. Nevertheless, many challenges arise in the development and regulatory assessment of LAI drug products due to a limited understanding of the tissue response to injected particles (e.g., inflammation) impacting in vivo performance. Mechanism-based in silico methods may support the understanding of LAI-physiology interactions. The objectives of this study were as follows: (1) to use a mechanistic modeling approach to delineate the in vivo performance of DepoSubQ Provera® and formulation variants in preclinical species; (2) to predict human exposure based on the knowledge gained from the animal model. The PBPK model evaluated different elements involved in LAI administration and showed that (1) the effective in vivo particle size is potentially larger than the measured in vitro particle size, which could be due to particle aggregation at the injection site, and (2) local inflammation is a key process at the injection site that results in a transient increase in depot volume. This work highlights how a mechanistic modeling approach can identify critical physiological events and product attributes that may affect the in vivo performance of LAIs.