Pathological Functions Research Articles

Yoda1 opens the lymphatic path for craniosynostosis therapy.

The rediscovery of meningeal lymphatic vessels (MLVs) has sparked research interest in their function in numerous neurological pathologies. Craniosynostosis (CS) is caused by a premature fusion of cranial sutures during development. In this issue of the JCI, Matrongolo and colleagues show that Twist1-haploinsufficient mice that develop CS exhibit raised intracranial pressure, diminished cerebrospinal fluid (CSF) outflow, and impaired paravascular CSF-brain flow; all features that were associated with MLV defects and exacerbated pathology in mouse models of Alzheimer's disease. Activation of the mechanosensor Piezo1 with Yoda1 restored MLV function and CSF perfusion in CS models and in aged mice, opening an avenue for further development of therapeutics.

Emerging wearable technologies for multisystem monitoring and treatment of Parkinson's disease: a narrative review.

Parkinson's disease (PD) is a chronic movement disorder characterized by a variety of motor and nonmotor comorbidities, including cognitive impairment, gastrointestinal (GI) dysfunction, and autonomic/sleep disturbances. Symptoms typically fluctuate with different settings and environmental factors and thus need to be consistently monitored. Current methods, however, rely on infrequent rating scales performed in clinic. The advent of wearable technologies presents a new avenue to track objective measures of PD comorbidities longitudinally and more frequently. This narrative review discusses and proposes emerging wearable technologies that can monitor manifestations of motor, cognitive, GI, and autonomic/sleep comorbidities throughout the daily lives of PD individuals. This can provide more wholistic insight into real-time physiological versus pathological function with the potential to better assess treatments during clinical trials and allow physicians to optimize treatment regimens. Additionally, this narrative review briefly examines novel applications of wearables as therapy for PD patients.

(219) Prevalence of Sexual Incontinence in Men with Stress Urinary Incontinence After Radical Prostatectomy

Abstract Introduction Sexual incontinence (SI) includes arousal incontinence and climacturia. SI is under-reported after radical prostatectomy (RP), significantly bothering the patient and the partner. Objective This study aimed to evaluate the prevalence of SI based on the SUI severity and identify predictors of SI during the first year after RP. Methods This study included men with RP and a follow-up until 1 year post-surgery. Patients who received ADT or radiation therapy either pre or post-RP were excluded. We performed a descriptive assessment of demographics, comorbidities, pre-RP prostate-specific antigen (PSA), Gleason group of the surgical pathology, nerve-sparing status (NSS), and erectile function (EF) based on the IIEF score. SI was defined as the presence or absence of climacturia or arousal incontinence reported by the patient at 3, 6, 9, and 12 months post-RP. SUI was described based on the number of pads used per day. These were categorized as 0 to 1 pad per day (No SUI or mild SUI), 2 pads per day (moderate SUI), and ≥ 3 pads per day (severe SUI) at 3, 6, and 12 months post-RP. We determined the prevalence of SI for each SUI category at each time period. We analyzed predictors of SI using a logistic regression model at 3, 6, 9, and 12 months post-RP. Factors entered into the model included: patient age, number of comorbidities (≥ 3, yes), NSS both resected (yes) and severe SUI (≥ 3 pads per day, yes). Results Our study included 2768 men with a median age of 60 (55-66). 11% had diabetes. 27% obstructive sleep apnea, and the median number of comorbidities was 1 (1-2). The median preoperative PSA was 5.6 ng/ml. The median Gleason grade group was 2 (2, 3). 71% had bilateral NSS, 22% unilateral, and 7% had both sides resected. The prevalence of SI was 26%, 24%, 23%, and 27% at 3, 6, 9, and 12 months post-RP, respectively. The prevalence of SI was higher among men with severe SUI compared to men with 0 to 1 pad per day at 6, 9, and 12 months post-RP. At 3 months, men with 0 to 1 pad per day reported 25% SI, vs. men with severe SUI described 28% SI. At 6 months, for men with no SUI/mild SUI, 19% described SI, vs. men with severe SUI, 32% had SI. At 9 months, for men with no SUI/mild SUI, 20% described SI vs. men with severe SUI, 33% had SI. And at 12 months, men with 0 to 1 pad per day reported 23% SI, vs. men with severe SUI described 36% SI. On the logistic regression model, severe SUI ≥ 3 pads/day was the only independent predictor of SI at 6, 9, and 12 months postoperative (Table 1). Conclusions Approximately one-quarter of our cohort experienced SI within 12 months after RP. SI was more prevalent among patients with severe SUI, particularly at the 6-month mark and beyond after RP during the first-year post-surgery. Severe SUI significantly predicted SI during the first year following surgery. Disclosure No.

N4-acetylcytidine modifies primary microRNAs for processing in cancer cells

N4 acetylcytidine (ac4C) modification mainly occurs on tRNA, rRNA, and mRNA, playing an important role in the expression of genetic information. However, it is still unclear whether microRNAs have undergone ac4C modification and their potential physiological and pathological functions. In this study, we identified that NAT10/THUMPD1 acetylates primary microRNAs (pri-miRNAs) with ac4C modification. Knockdown of NAT10 suppresses and augments the expression levels of mature miRNAs and pri-miRNAs, respectively. Molecular mechanism studies found that pri-miRNA ac4C promotes the processing of pri-miRNA into precursor miRNA (pre-miRNA) by enhancing the interaction of pri-miRNA and DGCR8, thereby increasing the biogenesis of mature miRNA. Knockdown of NAT10 attenuates the oncogenic characters of lung cancer cells by regulating miRNA production in cancers. Moreover, NAT10 is highly expressed in various clinical cancers and negatively correlated with poor prognosis. Thus, our results reveal that NAT10 plays a crucial role in cancer initiation and progression by modulating pri-miRNA ac4C to affect miRNA production, which would provide an attractive therapeutic strategy for cancers.

Progress on functions of intracellular domain of trimeric ligand-gated ion channels.

Ligand-gated ion channels are a large category of essential ion channels, modulating their state by binding to specific ligands to allow ions to pass through the cell membrane. Purinergic ligand-gated ion channel receptors (P2XRs) and acid-sensitive ion channels (ASICs) are representative members of trimeric ligand-gated ion channel. Recent studies have shown that structural differences in the intracellular domain of P2XRs may determine the desensitization process. The lateral fenestrations of P2XRs potentially serve as a pathway for ion conductance and play a decisive role in ion selectivity. Phosphorylation of numerous amino acid residues in the P2XRs are involved in regulating the activity of ion channels. Additionally, the P2XRs interact with other ligand-gated ion channels including N-methyl-D-aspartate receptors, γ-aminobutyric acid receptors, 5-hydroxytryptamin receptors and nicotinic acetylcholine receptors, mediating physiological processes such as synaptic plasticity. Conformational changes in the intracellular domain of the ASICs expose binding sites of intracellular signal partners, facilitating metabolic signal transduction. Amino acids such as Val16, Ser17, Ile18, Gln19 and Ala20 in the ASICs participate in channel opening and membrane expression. ASICs can also bind to intracellular proteins, such as CIPP and p11, to regulate channel function. Many phosphorylation sites at the C-terminus and N-terminus of ASICs are involved in the regulation of receptors. Furthermore, ASICs are involved in various physiological and pathophysiological processes, which include pain, ischemic stroke, psychiatric disorders, and neurodegenerative disease. In this article, we review the roles of the intracellular domains of these trimeric ligand-gated ion channels in channel gating as well as their physiological and pathological functions, in order to provide new insights into the discovery of related drugs.

The association between hydration state and the metabolism of phospholipids and amino acids among young adults: a metabolomic analysis

BackgroundWater is vital for humans' survival and general health, which is involved in various metabolic activities. ObjectivesThe aim of this study was to investigate the variation in urine metabolome and associated metabolic pathways among people with different hydration states. MethodsA metabolomic analysis was conducted using 24-h urine samples collected during a cross-sectional study on fluid intake behavior from December 9 to 11, 2021, in Hebei, China. Subjects were divided into the optimal hydration (OH, ≤500 mOsm/kg, n = 21), middle hydration (500–800 mOsm/kg, n = 33), and hypohydration groups (HH, >800 mOsm/kg, n = 13) based on the 3-d average 24-h urine osmolality. Collected 24-h urine samples from 67 subjects (43 males and 34 females) were analyzed for urine metabolome using liquid chromatography-MS. ResultsThe untargeted metabolomic analysis yielded 1055 metabolites by peak intensities. Integrating the results of the orthogonal projections to latent structures discriminant analysis and fold change test, 115 differential metabolites between the OH and HH groups, including phospholipids (PLs) and lysophospholipids, were identified. Among the 115 metabolites identified as differential metabolites, 85 were recorded by the Human Metabolome Database and uploaded to the Kyoto Encyclopedia of Genes and Genomes databases for pathway analysis. Twenty-one metabolic pathways were recognized. Phenylalanine metabolism (0.50, P = 0.007), phenylalanine, tyrosine, and tryptophan biosynthesis (0.50, P = 0.051), glycerophospholipid metabolism (0.31, P < 0.001), sphingolipid metabolism (0.27, P = 0.029), and cysteine and methionine metabolism (0.10, P = 0.066) had the leading pathway impacts. ConclusionsWe found variations in the urinary PLs and amino acids among subjects with different hydration states. Pathways associated with these differential metabolites could further impact various physiologic and pathologic functions. A more comprehensive and in-depth investigation of the physiologic and pathologic impact of the hydration state and the underlying mechanisms to elucidate and advocate optimal fluid intake habits is needed.This trial was registered at Chinese Clinical Trial Registry as ChiCTR2100045268.

Transmastoid Surgery for Superior Canal Dehiscence: Prospective Longitudinal Objective and Patient-Reported Audiovestibular Outcomes.

We assess symptom control, reversal and stability of objective third-window indicators, and hearing and balance function after transmastoid superior canal dehiscence plugging. To do this, we combine patient self-assessment questionnaires with auditory and vestibular test data collected at a preoperative and multiple postoperative visits. Prospective cohort study. Tertiary referral center. Patients who underwent transmastoid plugging for superior canal dehiscence from 2012 to 2020. Plugging of the superior semicircular canal using the transmastoid approach. Patients were evaluated preoperatively, 3-month postoperative, and at yearly follow-ups (up to 8 yr postoperative). Self-assessment questionnaires included Autophony Index, Dizziness Handicap Inventory, Tinnitus Handicap Inventory, and Hearing Handicap Inventory. Objective tests included audiometry, cervical vestibular evoked myogenic potential, ocular vestibular evoked myogenic potential, and video head impulse test. There was a statistically significant improvement in Autophony Index and Hearing Handicap Inventory total scores from the preoperative evaluation to 1 year postoperative. Dizziness Handicap Inventory and Tinnitus Handicap Inventory total scores also improved but statistically insignificant. Cervical and ocular vestibular evoked myogenic potential amplitudes and low-frequency air-bone gap showed statically significant reversal of the third-window effect preoperative versus 1 year postoperative. Video head impulse test of the superior semicircular canal revealed cases of pathological function preoperative with postoperative recovery. Results were stable over time. Superior canal dehiscence repair resolves symptoms of autophony and improves hearing disability. Objective third-window indicators reverse and show long-term stability. Auditory and vestibular function is preserved postoperative, even superior semicircular canal function may be normal. Data suggest that surgical outcomes should not be evaluated until 1 year postoperative.

Glutathione peroxidase LtGPX3 contributes to oxidative stress tolerance, virulence, and plant defense suppression in the peach gummosis fungus Lasiodiplodia theobromae

The notorious woody plant-degrading pathogen Lasiodiplodia theobromae is a major causal agent of peach gummosis, one of the prevalent and devastating trunk diseases to peach production; however, its pathogenesis is largely unknown. Our previous study showed that L. theobromae LtGPX3, which encodes a glutathione peroxidase resembling yeast GPX3/HYR1-like, was constantly and dramatically upregulated at the infectious stages. Here, we functionally characterized LtGPX3 using the CRISPR-Cas9-aided split marker approach. The ΔLtgpx3 deletion mutants displayed increased sensitivity to the osmotic stress agent KCl and less sensitivity to the cell wall-damaging agent calcofluor white. Exogenous oxidants highly induced the expression of LtGPX3, and the ΔLtgpx3 mutants displayed increased sensitivity to ROS-generating oxidants. Pathogenicity assays revealed that ΔLtgpx3 mutants showed compromised virulence in peach shoots, which was partially restored when peach shoots were pretreated with an NADPH oxidase inhibitor before inoculation. Moreover, ROS levels were strongly boosted, and transcripts of plant defense-related genes were highly induced in the ΔLtgpx3 mutants-infected peach shoots compared with the wild-type-inoculated. Overall, our results showed the essential roles of LtGPX3 in the oxidative stress response and tolerance and pathological functions in L. theobromae. These findings deepen our understanding of the survival strategies of the woody plant-degrading pathogen L. theobromae and provide new insights into developing new strategies for peach gummosis disease control.

Characteristics of renal pathology and coagulation function in IgA nephropathy and IgA vasculitis associated nephritis

BackgroundThe objective of this study is to investigate the clinical and pathological differences between patients with IgA nephropathy (IgAN) and IgA vasculitis associated nephritis (IgAVN).MethodsA total of 253 patients with IgAN and 71 patients with IgAVN were retrospectively included in the study, and clinical and laboratory data were collected and analysed.ResultsCompared with IgAVN group, months from onset to kidney biopsy were significantly prolonged in IgAN patients because of the lack of obvious symptoms such as rash, abdominal symptoms, and joint pain (13.5 ± 26.6 vs. 10.2 ± 31.6 months, P = 0.007), and the levels of serum creatinine (92.3 ± 94.7 vs. 68.9 ± 69.2 µmol/L, P = 0.015) was higher and eGFR (99.1 ± 35.2 vs. 123.4 ± 41.8 mL/min/1.73m2, P < 0.001) was lower in IgAN group. The pathological results revealed that patients with IgAN have a greater degree of chronic kidney injury compared to patients with IgAVN. In addition, the levels of plasma D-Dimers (1415.92 ± 1774.69 vs. 496.78 ± 711.91 ng/mL, P < 0.001) and fibrinogen degradation products (FDP) (3.92 ± 4.73 vs. 1.63 ± 2.46 µg/mL, P = 0.001) were significantly higher in IgAVN patients than in IgAN patients. The deposition of fibrinogen in the renal tissues was more severe and the cumulative partial remission rate was higher in patients with IgAVN as compared to those with IgAN (P = 0.001).ConclusionsIn comparison, IgAN patients had poorer renal function, whereas IgAVN patients had more severe coagulation abnormalities. These findings provide a basis for the differentiation of the two diseases at an early stage.

Cellular Self-Digestion Unveiled: Autophagy's Impact on Cancer

Autophagy is a strictly controlled process in which cells break down and recycle their own components by transporting them to lysosomes. Multiple studies have shown that autophagy has a diverse range of physiological and pathological functions in cells. Autophagy in cancer has contradictory functions, serving as both a suppressor and a driver of tumor growth. Specifically, it may exhibit several roles in relation to cancer treatment, either leading to cancer resistance or enhancing susceptibility to radiation and chemotherapy. Hence, autophagy has the potential to augment the efficacy of anticancer medications and radiation treatment. CBMJ 2024 January: vol. 13 no. 01 P: 107-118

ECCO Grant Investigating regenerative pathways in salivary glands to mitigate oral manifestations of inflammatory bowel diseases

Abstract Background and Aims Inflammatory bowel diseases (IBD) impact 4-16% of patients with extraintestinal manifestations in the upper gastrointestinal (GI) tract, including stomach and esophageal ulcers, dry mouth, taste alterations, halitosis, ulcers, and periodontitis. The underlying mechanisms remain unclear. This study hypothesizes that intestinal inflammation disrupts upper GI tract homeostasis by impairing salivary gland functions and aims to: Aim 1: Elucidate cellular and molecular mechanisms of intestinal inflammation on upper GI tract mucosa and salivary glands. Aim 2: Evaluate therapeutic potential of liver X receptor (LXR) activation in restoring salivary gland function in colitis-induced oral pathology. Methods I will use a novel mounting method for spatial proteogenomic analysis of upper GI tract mucosa to identify colitis-induced perturbations. Salivary glands will be studied separately, employing bulk and single-cell transcriptomic profiling to identify mechanisms driving colitis-induced atrophy, dysfunction, and candidate regenerative pathways. Additionally, salivary gland organoids will be used to study regeneration mechanisms in vitro, such as LXR activation, and the therapeutic potential of successful candidate pathways will be tested in vivo using pre-clinical models of colitis and salivary gland damage/repair (irradiation). Anticipated Impact This research will provide insights into mechanisms by which intestinal inflammation disrupts upper GI tract homeostasis through salivary gland impairment and assess the role of candidate pathways in salivary gland regeneration. In the short to medium term, findings may contribute to developing novel therapeutic strategies for managing colitis-induced oral pathology, benefiting the IBD community by improving patients' quality of life.

Collagen I-induced VCAN/ERK signaling and PARP1/ZEB1-mediated metastasis facilitate OSBPL2 defect to promote colorectal cancer progression

The global burden of colorectal cancer (CRC) has rapidly increased in recent years. Dysregulated cholesterol homeostasis facilitated by extracellular matrix (ECM) remodeling transforms the tumor microenvironment. Collagen I, a major with ECM component is highly expressed in colorectal tumors with infiltrative growth. Although oxysterol binding protein (OSBP)-related proteins accommodate tumorigenesis, OSBPL2, which is usually involved in deafness, is not associated with CRC progression. Therefore, we aimed to investigate the pathological function of OSBPL2 and identify the molecular link between ECM-Collagen I and OSBPL2 in CRC to facilitate the development of new treatments for CRC. OSBPL2 predicted a favorable prognosis in stage IV CRC and substantially repressed Collagen I-induced focal adhesion, migration, and invasion. The reduction of OSBPL2 activated ERK signaling through the VCAN/AREG/EREG axis during CRC growth, while relying on PARP1 via ZEB1 in CRC metastasis. OSBPL2 defect supported colorectal tumor growth and metastasis, which were suppressed by the ERK and PARP1 inhibitors SCH772984 and AG14361, respectively. Overall, our findings revealed that the Collagen I-induced loss of OSBPL2 aggravates CRC progression through VCAN-mediated ERK signaling and the PARP1/ZEB1 axis. This demonstrates that SCH772984 and AG14361 are reciprocally connective therapies for OSBPL2Low CRC, which could contribute to further development of targeted CRC treatment.

Early modulation of the gut microbiome by female sex hormones alters amyloid pathology and microglial function.

It is well-established that women are disproportionately affected by Alzheimer's disease. The mechanisms underlying this sex-specific disparity are not fully understood, but several factors that are often associated-including interactions of sex hormones, genetic factors, and the gut microbiome-likely contribute to the disease's etiology. Here, we have examined the role of sex hormones and the gut microbiome in mediating Aβ amyloidosis and neuroinflammation in APPPS1-21 mice. We report that postnatal gut microbiome perturbation in female APPPS1-21 mice leads to an elevation in levels of circulating estradiol. Early stage ovariectomy (OVX) leads to a reduction of plasma estradiol that is correlated with a significant alteration of gut microbiome composition and reduction in Aβ pathology. On the other hand, supplementation of OVX-treated animals with estradiol restores Aβ burden and influences gut microbiome composition. The reduction of Aβ pathology with OVX is paralleled by diminished levels of plaque-associated microglia that acquire a neurodegenerative phenotype (MGnD-type) while estradiol supplementation of OVX-treated animals leads to a restoration of activated microglia around plaques. In summary, our investigation elucidates the complex interplay between sex-specific hormonal modulations, gut microbiome dynamics, metabolic perturbations, and microglial functionality in the pathogenesis of Alzheimer's disease.

Induced pluripotent stem cell models as a tool to investigate and test fluid biomarkers in Alzheimer's disease and frontotemporal dementia.

Neurodegenerative diseases are increasing in prevalence and comprise a large socioeconomic burden on patients and their caretakers. The need for effective therapies and avenues for disease prevention and monitoring is of paramount importance. Fluid biomarkers for neurodegenerative diseases have gained a variety of uses, including informing participant selection for clinical trials, lending confidence to clinical diagnosis and disease staging, determining prognosis, and monitoring therapeutic response. Their role is expected to grow as disease-modifying therapies start to be available to a broader range of patients and as prevention strategies become established. Many of the underlying molecular mechanisms of currently used biomarkers are incompletely understood. Animal models and in vitro systems using cell lines have been extensively employed but face important translatability limitations. Induced pluripotent stem cell (iPSC) technology, where a theoretically unlimited range of celltypes can be reprogrammed from peripheral cells sampled from patients or healthy individuals, has gained prominence over the last decade. It is a promising avenue to study physiological and pathological biomarker function and response to experimental therapeutics. Such systems are amenable to high-throughput drug screening or multiomics readouts such as transcriptomics, lipidomics, and proteomics for biomarker discovery, investigation, and validation. The present review describes the current state of biomarkers in the clinical context of neurodegenerative diseases, with a focus on Alzheimer's disease and frontotemporal dementia. We include a discussion of how iPSC models have been used to investigate and test biomarkers such as amyloid-β, phosphorylated tau, neurofilament light chain or complement proteins, and even nominate novel biomarkers. We discuss the limitations of current iPSC methods, mentioning alternatives such as coculture systems and three-dimensional organoids which address some of these concerns. Finally, we propose exciting prospects for stem cell transplantation paradigms using animal models as a preclinical tool to study biomarkers in the in vivo context.

ErbB3 Governs Endothelial Dysfunction in Hypoxia-Induced Pulmonary Hypertension.

Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases. Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell-specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms. ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell-specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia-inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH. Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH.

Glycolysis: an emerging regulator of osteoarthritis.

Osteoarthritis (OA) has been a leading cause of disability in the elderly and there remains a lack of effective therapeutic approaches as the mechanisms of pathogenesis and progression have yet to be elucidated. As OA progresses, cellular metabolic profiles and energy production are altered, and emerging metabolic reprogramming highlights the importance of specific metabolic pathways in disease progression. As a crucial part of glucose metabolism, glycolysis bridges metabolic and inflammatory dysfunctions. Moreover, the glycolytic pathway is involved in different areas of metabolism and inflammation, and is associated with a variety of transcription factors. To date, it has not been fully elucidated whether the changes in the glycolytic pathway and its associated key enzymes are associated with the onset or progression of OA. This review summarizes the important role of glycolysis in mediating cellular metabolic reprogramming in OA and its role in inducing tissue inflammation and injury, with the aim of providing further insights into its pathological functions and proposing new targets for the treatment of OA.

The chemokine receptor CXCR3 promotes CD8+ T cell-dependent lung pathology during influenza pathogenesis.

The dual role of CD8+ T cells in influenza control and lung pathology is increasingly appreciated. To explore whether protective and pathological functions can be linked to specific subsets, we dissected CD8+ T responses in influenza-infected murine lungs. Our single-cell RNA-sequencing (scRNA-seq) analysis revealed notable diversity in CD8+ T subpopulations during peak viral load and infection-resolved state. While enrichment of a Cxcr3hi CD8+ T effector subset was associated with a more robust cytotoxic response, both CD8+ T effector and central memory exhibited equally potent effector potential. The scRNA-seq analysis identified unique regulons regulating the cytotoxic response in CD8+ T cells. The late-stage CD8+ T blockade in influenza-cleared lungs or continuous CXCR3 blockade mitigated lung injury without affecting viral clearance. Furthermore, adoptive transfer of wild-type CD8+ T cells exacerbated influenza lung pathology in Cxcr3-/- mice. Collectively, our data imply that CXCR3 interception could have a therapeutic effect in preventing influenza-linked lung injury.

Pulmonary Hypertension Induces Serotonin Hyperreactivity and Metabolic Reprogramming in Coronary Arteries via NOX1/4-TRPM2 Signaling Pathway.

Clinical evidence revealed abnormal prevalence of coronary artery (CA) disease in patients with pulmonary hypertension (PH). The mechanistic connection between PH and CA disease is unclear. Serotonin (5-hydroxytryptamine), reactive oxygen species, and Ca2+ signaling have been implicated in both PH and CA disease. Our recent study indicates that NOXs (NADPH [nicotinamide adenine dinucleotide phosphate] oxidases) and TRPM2 (transient receptor potential cation channel subfamily M member 2) are key components of their interplay. We hypothesize that activation of the NOX-TRPM2 pathway facilitates the remodeling of CA in PH. Left and right CAs from chronic hypoxia and monocrotaline-induced PH rats were collected to study vascular reactivity, gene expression, metabolism, and mitochondrial function. Inhibitors or specific siRNA were used to examine the pathological functions of NOX1/4-TRPM2 in CA smooth muscle cells. Significant CA remodeling and 5-hydroxytryptamine hyperreactivity in the right CA were observed in PH rats. NOX1/4-mediated reactive oxygen species production coupled with TRPM2-mediated Ca2+ influx contributed to 5-hydroxytryptamine hyperresponsiveness. CA smooth muscle cells from chronic hypoxia-PH rats exhibited increased proliferation, migration, apoptosis, and metabolic reprogramming in an NOX1/4-TRPM2-dependent manner. Furthermore, the NOX1/4-TRPM2 pathway participated in mitochondrial dysfunction, involving mitochondrial DNA damage, reactive oxygen species production, elevated mitochondrial membrane potential, mitochondrial Ca2+ accumulation, and mitochondrial fission. In vivo knockdown of NOX1/4 alleviated PH and suppressed CA remodeling in chronic hypoxia rats. PH triggers an increase in 5-hydroxytryptamine reactivity in the right CA and provokes metabolic reprogramming and mitochondrial disruption in CA smooth muscle cells via NOX1/4-TRPM2 activation. This signaling pathway may play an important role in CA remodeling and CA disease in PH.

Physiological and Pathological Functions of Reactive Nitrogen Species (RNS) and Reactive Sulphur Species (RSS) on Male Reproductive Functions

Physiological and Pathological Functions of Reactive Nitrogen Species (RNS) and Reactive Sulphur Species (RSS) on Male Reproductive Functions

Free-moving-state microscopic imaging of cerebral oxygenation and hemodynamics with a photoacoustic fiberscope

We report the development of a head-mounted photoacoustic fiberscope for cerebral imaging in a freely behaving mouse. The 4.5-gram imaging probe has a 9-µm lateral resolution and 0.2-Hz frame rate over a 1.2-mm wide area. The probe can continuously monitor cerebral oxygenation and hemodynamic responses at single-vessel resolution, showing significantly different cerebrovascular responses to external stimuli under anesthesia and in the freely moving state. For example, when subjected to high-concentration CO2 respiration, enhanced oxygenation to compensate for hypercapnia can be visualized due to cerebral regulation in the freely moving state. Comparative studies exhibit significantly weakened compensation capabilities in obese rodents. This new imaging modality can be used for investigating both normal and pathological cerebrovascular functions and shows great promise for studying cerebral activity, disorders and their treatments.