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Open Access Publications from the University of California

Scholarly Works (23 results)

  • Article
  • Peer Reviewed
UC Irvine Previously Published Works (2023)
The effects of global warming are not limited to rising global temperatures and have set in motion a complex chain of events contributing to climate change. A consequence of global warming and the resultant climate change is the rise in cyanobacterial harmful algal blooms (cyano-HABs) across the world, which pose a threat to public health, aquatic biodiversity, and the livelihood of communities that depend on these water systems, such as farmers and fishers. An increase in cyano-HABs and their intensity is associated with an increase in the leakage of cyanotoxins. Microcystins (MCs) are hepatotoxins produced by some cyanobacterial species, and their organ toxicology has been extensively studied. Recent mouse studies suggest that MCs can induce gut resistome changes. Opportunistic pathogens such as Vibrios are abundantly found in the same habitat as phytoplankton, such as cyanobacteria. Further, MCs can complicate human disorders such as heat stress, cardiovascular diseases, type II diabetes, and non-alcoholic fatty liver disease. Firstly, this review describes how climate change mediates the rise in cyanobacterial harmful algal blooms in freshwater, causing increased levels of MCs. In the later sections, we aim to untangle the ways in which MCs can impact various public health concerns, either solely or in combination with other factors resulting from climate change. In conclusion, this review helps researchers understand the multiple challenges brought forth by a changing climate and the complex relationships between microcystin, Vibrios, and various environmental factors and their effect on human health and disease.
    Cover page: Cyanobacterial Harmful Algal Bloom Toxin Microcystin and Increased Vibrio Occurrence as Climate-Change-Induced Biological Co-Stressors: Exposure and Disease Outcomes via Their Interaction with Gut–Liver–Brain AxisCreative Commons 'BY' version 4.0 license
    • Thesis
    • Peer Reviewed
    UC Irvine Electronic Theses and Dissertations (2024)

    Understanding the complex pathology of Gulf War Illness (GW), with its multisymptomatic condition, and identifying an efficient treatment has been a longstanding challenge for researchers. Researchers have made significant efforts in conducting mechanistic studies using different combinations of representative Gulf War (GW) chemicals in various experimental animal models in an attempt to create a translatable GWI pre-clinical model. However, there remain confounding factors like paucity of information regarding the actual amount of exposure among the GW Veterans, route, and duration of exposure impede the process.Our lab has been pioneering GWI research for the past decade. From the very first report about the association of altered gut microbiome in GWI pathology, we have attempted to approach the condition considering the translatable impact of the results on present-day Veterans. In the first study, the impact of metabolic disorders in underlying GWI conditions has been studied. GW Veterans living in a sedentary lifestyle now have an increased risk of xii developing conditions like obesity. The results showed that administration of a Western diet in a mouse model pre-exposed to GW chemicals decreased the abundance of beneficial gut bacteria. A decrease in bacterial diversity is strongly associated with gastrointestinal, hepatic, and systemic inflammation along with increased neurodegeneration. This study further provides cues of pleiotropic marker IL-6 being responsible for GWI pathology via the microbiome-gut-brain axis. In the second study, the alteration of gut resistome profile due to GW chemical exposure is long-lasting and closely associated with bacterial dysbiosis. In this study, a similar trend in resistome profile has been observed in an experimental murine model and GW Veterans. It was also observed that the altered antibiotic resistance genes were associated with gastrointestinal and systemic inflammation and decreased synaptic plasticity in the brain. In the third study, a double humanized mouse model have been designed in an approach to have a more translatable GWI murine model. The model has been designed to have both human microbiome and immune system. Exposure to GW chemicals resulted in alteration of gut microbiome and expression of host immune markers which were similar to the results observed in GW Veterans in an earlier study.

      Cover page: Unraveling the Genomic Crosstalk of Host Microbiome in Human and Humanized Preclinical Models of Gulf War Illness
      • Thesis
      • Peer Reviewed
      UC Irvine Electronic Theses and Dissertations (2024)

      Climate change and its associated stressors have significantly impacted the freshwater and marine ecosystems worldwide. Increased cases of moderate to extreme weather conditions like heavy rainfalls, warmer coastal temperatures, warmer seawater temperature, decreased salinity, etc., in combination with anthropogenic contributions, have led to increased occurrences of cyanotoxin-producing harmful algal blooms in freshwater and a rising number of non-cholera vibriosis cases. Exposure to these climate change-associated stressors has a significant influence on public health but is presumed to be more severe towards susceptible individuals, including children, the aged population, immunocompromised individuals, and patients with pre-existing chronic disease conditions.Several published studies from our research group have shown that environmental toxins and contaminants can greatly affect the liver, causing the worsening of the so-called silent and benign steatosis stage to a more inflammatory steatohepatitis stage with the onset of scar tissue formation. However, we also found significant knowledge gaps in the existing literature. Moreover, we also wanted to explore the role of the gut microbiota and whether these cyanotoxin exposures had any significant impact on it. In the first study, we established a murine model of early life exposure to the cyanotoxin microcystin-LR and also parallelly used a separate humanized mice model to translate our findings. Our results showed that early-life MC exposure could impart significant changes in the gut microbiota and increase the abundance of antibiotic-resistance genes. Furthermore, this early-life MC exposure further augmented significant changes in intestinal immunosurveillance and showed elevated systemic inflammation with increased immunosenescence. Therefore, the study provided a breakthrough in cyanotoxin-mediated changes in the gut resitome and its association with the immune markers. In the second study, we wanted to explore the role of another subchronic cyanotoxin (cylindrospermopsin) exposure on gut microbiota by using a murine model of subchronic exposure. Our data detected that the toxin exposures significantly reshaped the gut bacteriome profile and increased endotoxemia levels that further contributed to the overall hepatotoxicity. These findings were the first proof that established the role of cylindrospermopsin in mediating gut microbiome alterations. In the third study, we further wanted to follow up on these findings and aimed to explore CYN-mediated toxicity in underlying chronic liver disease conditions. For these purposes, we used a diet-induced murine model to mimic the conditions in humans and subjected the mice to a similar subchronic cylindrospermopsin exposure. The study results showed that CYN treatment caused a significantly increased formation of peroxynitrite, a major cellular oxidant species, leading to increased inflammasome activation, inflammation, and early onset of fibrosis similar to steatohepatitis-like pathology. Administration of different redox inhibitors in these obese mice showed improved pathophysiological outcomes, further confirming the role of peroxynitrite formation and providing a novel mechanistic insight regarding cylindropsermopsin-mediated hepatotoxicity in underlying chronic liver disease conditions. In the fourth study, we wanted to establish the role of gut microbiota and intestinal homeostasis in causing increased non-cholera vibriosis in a susceptible population like individuals with underlying steatotic liver disease. Similar to the third study, we used another diet-induced murine model to mimic the underlying disease conditions. Our results implicated those mice with underlying obesity had severe vibriosis compared to the lean counterparts, which was further linked to an altered gut microbiota and resistome profile and dysregulation of intestinal homeostasis.

        Creative Commons 'BY-ND' version 4.0 license
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2023)
        The rapid increase in drug-resistant and multidrug-resistant infections poses a serious challenge to antimicrobial therapies, and has created a global health crisis. Since antimicrobial peptides (AMPs) have escaped bacterial resistance throughout evolution, AMPs are a category of potential alternatives for antibiotic-resistant "superbugs". The Chromogranin A (CgA)-derived peptide Catestatin (CST: hCgA352-372; bCgA344-364) was initially identified in 1997 as an acute nicotinic-cholinergic antagonist. Subsequently, CST was established as a pleiotropic hormone. In 2005, it was reported that N-terminal 15 amino acids of bovine CST (bCST1-15 aka cateslytin) exert antibacterial, antifungal, and antiyeast effects without showing any hemolytic effects. In 2017, D-bCST1-15 (where L-amino acids were changed to D-amino acids) was shown to exert very effective antimicrobial effects against various bacterial strains. Beyond antimicrobial effects, D-bCST1-15 potentiated (additive/synergistic) antibacterial effects of cefotaxime, amoxicillin, and methicillin. Furthermore, D-bCST1-15 neither triggered bacterial resistance nor elicited cytokine release. The present review will highlight the antimicrobial effects of CST, bCST1-15 (aka cateslytin), D-bCST1-15, and human variants of CST (Gly364Ser-CST and Pro370Leu-CST); evolutionary conservation of CST in mammals; and their potential as a therapy for antibiotic-resistant "superbugs".
          Cover page: Catestatin: Antimicrobial Functions and Potential Therapeutics.Creative Commons 'BY' version 4.0 license
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2023)
          BACKGROUND: Microcystins (MCs), potent hepatotoxins pose a significant health risk to humans, particularly children, who are more vulnerable due to higher water intake and increased exposure during recreational activities. METHODS: Here, we investigated the role of host microbiome-linked acetate in modulating inflammation caused by early-life exposure to the cyanotoxin Microcystin-LR (MC-LR) in a juvenile mice model. RESULTS: Our study revealed that early-life MC-LR exposure disrupted the gut microbiome, leading to a depletion of key acetate-producing bacteria and decreased luminal acetate concentration. Consequently, the dysbiosis hindered the establishment of a gut homeostatic microenvironment and disrupted gut barrier function. The NOD-like receptor family pyrin domain - containing 3 (NLRP3) inflammasome, a key player in MC-induced hepatoxicity emerged as a central player in this process, with acetate supplementation effectively preventing NLRP3 inflammasome activation, attenuating hepatic inflammation, and decreasing pro-inflammatory cytokine production. To elucidate the mechanism underlying the association between early-life MC-LR exposure and the progression of metabolic dysfunction associated steatotic liver disease (MASLD), we investigated the role of acetate binding to its receptor -G-protein coupled receptor 43 (GPR43) on NLRP3 inflammasome activation. Our results demonstrated that acetate-GPR43 signaling was crucial for decreasing NLRP3 protein levels and inhibiting NLRP3 inflammasome assembly. Further, acetate-induced decrease in NLRP3 protein levels was likely mediated through proteasomal degradation rather than autophagy. Overall, our findings underscore the significance of a healthy gut microbiome and its metabolites, particularly acetate, in the progression of hepatotoxicity induced by early life toxin exposure, crucial for MASLD progression. CONCLUSIONS: This study highlights potential therapeutic targets in gut dysbiosis and NLRP3 inflammasome activation for mitigating toxin-associated inflammatory liver diseases.
            Cover page: Host microbiome associated low intestinal acetate correlates with progressive NLRP3-dependent hepatic-immunotoxicity in early life microcystin-LR exposure.Creative Commons 'BY' version 4.0 license
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2024)
            Unraveling the multisymptomatic Gulf War Illness (GWI) pathology and finding an effective cure have eluded researchers for decades. The chronic symptom persistence and limitations for studying the etiologies in mouse models that differ significantly from those in humans pose challenges for drug discovery and finding effective therapeutic regimens. The GWI exposome differs significantly in the study cohorts, and the above makes it difficult to recreate a model closely resembling the GWI symptom pathology. We have used a double engraftment strategy for reconstituting a human immune system coupled with human microbiome transfer to create a humanized-mouse model for GWI. Using whole-genome shotgun sequencing and blood immune cytokine enzyme linked immunosorbent assay (ELISA), we show that our double humanized mice treated with Gulf War (GW) chemicals show significantly altered gut microbiomes, similar to those reported in a Veteran cohort of GWI. The results also showed similar cytokine profiles, such as increased levels of IL-1β, IL-6, and TNF R-1, in the double humanized model, as found previously in a human cohort. Further, a novel GWI Veteran fecal microbiota transfer was used to create a second alternative model that closely resembled the microbiome and immune-system-associated pathology of a GWI Veteran. A GWI Veteran microbiota transplant in humanized mice showed a human microbiome reconstitution and a systemic inflammatory pathology, as reflected by increases in interleukins 1β, 6, 8 (IL-1β, IL-6, IL-8), tumor necrosis factor receptor 1 (TNF R-1), and endotoxemia. In conclusion, though preliminary, we report a novel in vivo model with a human microbiome reconstitution and an engrafted human immune phenotype that may help to better understand gut-immune interactions in GWI.
              Cover page: A Double-Humanized Mouse Model for Studying Host Gut Microbiome-Immune Interactions in Gulf War Illness.Creative Commons 'BY' version 4.0 license
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2023)
              Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling.
                Cover page: Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance.Creative Commons 'BY' version 4.0 license
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2022)
                Epidemiological studies have reported a strong association between liver injury and incidences of hepatocellular carcinoma in sections of humans globally. Several preclinical studies have shown a strong link between cyanotoxin exposure and the development of nonalcoholic steatohepatitis, a precursor of hepatocellular carcinoma. Among the emerging threats from cyanotoxins, new evidence shows cylindrospermopsin release in freshwater lakes. A known hepatotoxin in higher concentrations, we examined the possible role of cylindrospermopsin in causing host gut dysbiosis and its association with liver pathology in a mouse model of toxico-pharmacokinetics and hepatic pathology. The results showed that oral exposure to cylindrospermopsin caused decreased diversity of gut bacteria phyla accompanied by an increased abundance of Clostridioides difficile and decreased abundance of probiotic flora such as Roseburia, Akkermanssia, and Bacteroides thetaiotamicron, a signature most often associated with intestinal and hepatic pathology and underlying gastrointestinal disease. The altered gut dysbiosis was also associated with increased Claudin2 protein in the intestinal lumen, a marker of gut leaching and endotoxemia. The study of liver pathology showed marked liver inflammation, the release of damage-associated molecular patterns, and activation of toll-like receptors, a hallmark of consistent and progressive liver damage. Hepatic pathology was also linked to increased Kupffer cell activation and stellate cell activation, markers of progressive liver damage often linked to the development of liver fibrosis and carcinoma. In conclusion, the present study provides additional evidence of cylindrospermopsin-linked progressive liver pathology that may be very well-linked to gut dysbiosis, though definitive evidence involving this link needs to be studied further.
                  Cover page: Subchronic Oral Cylindrospermopsin Exposure Alters the Host Gut Microbiome and Is Associated with Progressive Hepatic Inflammation, Stellate Cell Activation, and Mild Fibrosis in a Preclinical StudyCreative Commons 'BY' version 4.0 license
                  • Article
                  • Peer Reviewed
                  UC Irvine Previously Published Works (2024)
                  Heat stress exposure in intermittent heat waves and subsequent exposure during war theaters pose a clinical challenge that can lead to multi-organ dysfunction and long-term complications in the elderly. Using an aged mouse model and high-throughput sequencing, this study investigated the molecular dynamics of the liver-brain connection during heat stress exposure. Distinctive gene expression patterns induced by periodic heat stress emerged in both brain and liver tissues. An altered transcriptome profile showed heat stress-induced altered acute phase response pathways, causing neural, hepatic, and systemic inflammation and impaired synaptic plasticity. Results also demonstrated that proinflammatory molecules such as S100B, IL-17, IL-33, and neurological disease signaling pathways were upregulated, while protective pathways like aryl hydrocarbon receptor signaling were downregulated. In parallel, Rantes, IRF7, NOD1/2, TREM1, and hepatic injury signaling pathways were upregulated. Furthermore, current research identified Orosomucoid 2 (ORM2) in the liver as one of the mediators of the liver-brain axis due to heat exposure. In conclusion, the transcriptome profiling in elderly heat-stressed mice revealed a coordinated network of liver-brain axis pathways with increased hepatic ORM2 secretion, possibly due to gut inflammation and dysbiosis. The above secretion of ORM2 may impact the brain through a leaky blood-brain barrier, thus emphasizing intricate multi-organ crosstalk.
                    Cover page: Periodic heat waves-induced neuronal etiology in the elderly is mediated by gut-liver-brain axis: a transcriptome profiling approach.Creative Commons 'BY' version 4.0 license
                    • Article
                    • Peer Reviewed
                    UC Irvine Previously Published Works (2020)

                    Background

                    Recent clinical and basic research implicated a strong correlation between NAFLD/NASH phenotypes with ectopic manifestations including neuroinflammation and neurodegeneration, but the mediators and critical pathways involved are not well understood. Lipocalin 2 (Lcn2) is one of the important mediators exclusively produced in the liver and circulation during NASH pathology.

                    Methods

                    Using murine model of NASH, we studied the role of Lcn2 as a potent mediator of neuroinflammation and neurodegeneration in NASH pathology via the liver-brain axis.

                    Results

                    Results showed that high circulatory Lcn2 activated 24p3R (Lipocalin2 receptor) in the brain and induced the release of high mobility group box 1 (HMGB1) preferably from brain cells. Released HMGB1 acted as a preferential ligand to toll-like receptor 4 (TLR4) and induced oxidative stress by activation of NOX-2 signaling involving activated p65 protein of the NF-κB complex. Further, the HMGB1-derived downstream signaling cascade activated NLRP3 inflammasome and release of proinflammatory cytokines IL-6 and IL-1β from brain cells. In addition, to advance our present understanding, in vitro studies were performed in primary brain endothelial cells where results showed high circulatory Lcn2 influenced HMGB1 secretion. Mechanistically, we also showed that elevated Lcn2 level in underlying NASH might be a likely cause for induction of blood-brain barrier dysfunction since the adipokine decreased the expression of tight junction protein Claudin 5 and caused subsequent elevation of pro-inflammatory cytokines IL-6 and IL-1β.

                    Conclusion

                    In conclusion, the NASH-induced brain pathology might be because of increased Lcn2-induced release of HMGB1 and accompanying neuroinflammation.
                      Cover page: Lipocalin 2 induces neuroinflammation and blood-brain barrier dysfunction through liver-brain axis in murine model of nonalcoholic steatohepatitisCreative Commons 'BY' version 4.0 license
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