Combination antiretroviral therapy (cART) can suppress human immunodeficiency virus (HIV-1) replication, but some patients develop worsening of co-infections, termed immune reconstitution inflammatory syndrome. Regulatory T cells (Tregs) are a population of CD4+ T cells that modulate immune responses. We hypothesized that immune reconstitution inflammatory syndrome (IRIS) is associated with Tregs dysfunction.
We prospectively enrolled antiretroviral naive HIV patients with co-infection with Mycobacterium tuberculosis (MTB; N = 26) or controls with no prior opportunistic infection (N = 10). We prospectively measured HIV viral load, CD4+ T cell count, regulatory T cell (CD4high, CD127low-neg, Foxp3+) proportion, and Interferon-γ (IFN-γ) response to MTB peptides before and after initiation of combination antiretroviral therapy.
Eleven of the MTB patients developed IRIS; 15 did not. IRIS patients had a lower proportion of Tregs at baseline compared to no-IRIS patients (HIV/no-OI and HIV/MTB no-IRIS), but the difference did not reach statistical significance (IRIS: 9.6 [5.3–11.2]; no-IRIS: 13.9 [7.6–22.5] p = 0.066). After 2 weeks of cART the proportion of Tregs was significantly lower in HIV/MTB IRIS patients (HIV/MTB IRIS: 9.8 [6.6–13.6], HIV/MTB no-IRIS: 15.8 [11.1–18.8]. The antigen-specific IFN-γ production was greater in the patients who developed IRIS compared with those who did not develop IRIS.
IRIS patients had a lower proportion of Tregs and more marked IFN-γ production, suggesting that Tregs may be responsible for suppressing the antigen-specific inflammatory response.
Multiple sclerosis (MS) is a neurological disorder that is directly linked to inflammation in the central nervous system (CNS). The activation of toll-like receptors (TLRs) exacerbates neuroinflammation by increasing the production of reactive oxygen species (ROS) and proinflammatory cytokines. Edaravone (EDV) has been proposed as a potential therapy for CNS diseases because of its free radical scavenging and anti-inflammatory properties. This study investigated the effects of EDV on the inflammatory response in TLR4-stimulated peripheral blood mononuclear cells (PBMNCs) from MS patients and a healthy control group.
The impact of EDV on ROS production in lipopolysaccharide (LPS)-stimulated PBMNCs was assessed using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) reduction and luminol-dependent chemiluminescence assays. The interleukin (IL)-6 concentration in the PBMNC supernatants was measured using enzyme-linked immunosorbent assay (ELISA).
The results showed that ROS production in PBMNCs stimulated using LPS (a TLR4 activator) was significantly inhibited (p < 0.05) by EDV in the MS patients and control group. Additionally, EDV significantly reduced IL-6 secretion in TLR4-stimulated PBMNCs in these groups (p < 0.05). No significant differences were observed between the groups.
Our findings suggest that EDV may serve as an adjunctive therapy for MS by reducing ROS and IL-6 production in TLR4-stimulated PBMNCs in MS patients, highlighting its potential in modulating neuroinflammation and oxidative stress.
Saliva is a crucial bodily fluid that protects the oral cavity from infections. The composition of saliva also changes dynamically depending on conditions such as illness, stress, and diet. Thus, the organic substances in saliva, particularly enzymes, proteins, and hormones, reflect overall health status and are increasingly valued as non-invasive diagnostic tools. Aptamers, which are short single-stranded DNA or RNA molecules with high affinity and specificity, have gained attention as novel biomarker detection tools. This study explores the feasibility of employing aptamers as an innovative diagnostic technique for detecting salivary biomarkers. Specifically, we discuss the development and application of aptamers tailored to detect key salivary biomarkers, such as salivary alpha-amylase, secretory immunoglobulin A (sIgA), human beta-defensin, C-reactive protein, and lactate dehydrogenase. Our group used base-appended bases to achieve high affinity and stability against targets. For instance, cortisol and sIgA in saliva are useful for assessing chronic stress and fatigue, thereby enabling objective evaluations of diseases. Enhanced techniques for measuring salivary biomarkers promise non-invasive and cost-effective diagnostic methods that can significantly contribute to early infection detection, chronic disease monitoring, and psychological stress assessment. This review underscores the extensive applicability of salivary biomarkers and provides critical insights that could improve future public health and medical care quality.
Although peripherally restricted cannabinoid 1 receptor (CB1R) inhibitors reportedly have the potential to improve the metabolic profile of obese subjects without the central nervous system (CNS) liabilities of centrally acting compounds, weight loss in rodent studies has generally been modest. However, the hepatotropic CB1R inverse agonist TM38837 was more efficacious than the centrally acting drug rimonabant in diet-induced obese (DIO) mice, which has been attributed to enhanced exposure in hepatocytes. Accordingly, TM388837 was investigated in DIO rats to assess weight-reducing efficacy and other potential metabolic benefits relative to CNS exposure.
TM38837 was administered to DIO rats for 5 weeks to determine the effects on body weight, metabolic and inflammatory plasma markers, and hepatic steatosis. Subsequently, CNS exposure was assessed in lean rats using an immunohistochemical analysis of cFOS induction. Finally, food intake-independent effects on hepatic steatosis and glucose homeostasis were evaluated using obese Zucker rats with pair-fed controls. All studies used rimonabant as comparator.
Weight loss comparable to that of rimonabant at an equivalent dose was observed for TM38837 in DIO rats, attributed to a loss of fat mass and driven by a sustained reduction in food intake. However, effects on plasma markers and steatosis were not significant (except leptin) for either compound in this study. Unlike for rimonabant, cFOS induction was not significant in any brain areas of lean rats following treatment with the selected efficacious dose of TM38837. Highly significant reductions in liver fat (cf pair-fed controls) and plasma area under the curve above baseline for insulin (AUCB2Insulin), cf vehicle, were subsequently observed following 8- and 4-week dosing with TM38837, respectively, in obese Zucker rats.
Liver-targeted CB1R inverse agonists, such as TM38837, have potential for the treatment of obesity and associated morbidities with generous safety margins from CNS side-effects.
Cardiac amyloidosis (CA) results from the deposition of amyloid fibrils in the myocardium and is mainly caused by two parent proteins: transthyretin (ATTR) and light chain immunoglobulin (AL). ATTR is further differentiated into wild-type (ATTRwt) and hereditary (ATTRv) forms, based on the presence or absence, respectively, of mutations in the TTR gene. Historically, CA has been overlooked in clinical practice, with many cases misdiagnosed or diagnosed at advanced stages due to overlapping features with other cardiomyopathies, such as hypertrophic cardiomyopathy. However, recent advancements in both diagnostic techniques and awareness have led to an increasing recognition of CA, particularly in patients with heart failure with preserved ejection fraction and other forms of restrictive cardiomyopathy. Moreover, the advent of multimodality imaging has significantly enhanced the diagnosis of CA. Imaging modalities such as echocardiography, cardiac magnetic resonance (CMR), and nuclear scintigraphy (using bone-seeking tracers such as 99mTc-pyrophosphate) play pivotal roles in identifying myocardial involvement early in the disease course. CMR imaging allows precise tissue characterization, identifying myocardial edema, fibrosis, and amyloid deposition; meanwhile, nuclear scintigraphy with 99mTc-pyrophosphate has emerged as a non-invasive, highly sensitive imaging technique for detecting ATTR infiltration in the heart; the diagnosis of AL requires histological confirmation. Following the advent of disease-modifying therapies, the need for early disease detection has become more critical to enhance survival rates and improve quality of life.
As organisms age, the gut microbiome experiences pronounced shifts in both its composition and function, resulting in a state of dysbiosis. In order to mitigate the detrimental consequences of aging and promote healthier aging trajectories, it has been suggested that the modulation of the gut microbiome through the implementation of fecal microbiota transplantation may constitute a promising strategy to enhance healthspan and delay age-related decline. This narrative review examines the role of the gut microbiome in aging, with a specific focus on the therapeutic potential of fecal microbiota transplantation in promoting healthy aging. In older adults, the presence of gut microbiome dysbiosis has been linked to a heightened susceptibility to various age-related disorders, as well as to oxidative stress, diminished bioavailability of essential nutrients, persistent systemic inflammation, and insulin resistance. Preclinical studies have evidenced that the administration of fecal microbiota transplantation from young donors to aged recipients can effectively restore the donor’s gut microbiome, thereby enhancing the overall health of the host. In clinical studies, the efficacy of fecal microbiota transplantation in restoring a healthy gut microbiome has been demonstrated in the treatment of numerous conditions, including not only chronic gastrointestinal disorders but also a range of extra-intestinal disorders and symptoms. However, several factors limit its widespread clinical use, including mechanisms of action, treatment costs, application timing and route, efficacy, tolerability, and safety. Therefore, fecal microbiota transplantation shows promise as a microbial approach for addressing aging-related effects, but its full viability and effectiveness are still under investigation, requiring further development and optimization to reach a more refined stage of therapeutic application.