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European Heart Journal Aug 2023The PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly... (Randomized Controlled Trial)
Randomized Controlled Trial
Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: a pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF.
AIMS
The PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly reduced or preserved ejection fraction who had a recent worsening HF event, but was not adequately powered to examine clinical outcomes. PARAGON-HF included a subset of PARAGLIDE-HF-like patients who were recently hospitalized for HF. Participant-level data from PARAGLIDE-HF and PARAGON-HF were pooled to better estimate the efficacy and safety of sacubitril/valsartan in reducing cardiovascular and renal events in HF with mildly reduced or preserved ejection fraction.
METHODS AND RESULTS
Both PARAGLIDE-HF and PARAGON-HF were multicentre, double-blind, randomized, active-controlled trials of sacubitril/valsartan vs. valsartan in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF >40% in PARAGLIDE-HF and ≥45% in PARAGON-HF). In the pre-specified primary analysis, we pooled participants in PARAGLIDE-HF (all of whom were enrolled during or within 30 days of a worsening HF event) with a 'PARAGLIDE-like' subset of PARAGON-HF (those hospitalized for HF within 30 days). We also pooled the entire PARAGLIDE-HF and PARAGON-HF populations for a broader context. The primary endpoint for this analysis was the composite of total worsening HF events (including first and recurrent HF hospitalizations and urgent visits) and cardiovascular death. The secondary endpoint was the pre-specified renal composite endpoint for both studies (≥50% decline in estimated glomerular filtration rate from baseline, end-stage renal disease, or renal death). Compared with valsartan, sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death in both the primary pooled analysis of participants with recent worsening HF [n = 1088; rate ratio (RR) 0.78; 95% confidence interval (CI) 0.61-0.99; P = 0.042] and in the pooled analysis of all participants (n = 5262; RR 0.86; 95% CI: 0.75-0.98; P = 0.027). In the pooled analysis of all participants, first nominal statistical significance was reached by Day 9 after randomization, and treatment benefits were larger in those with LVEF ≤60% (RR 0.78; 95% CI 0.66-0.91) compared with those with LVEF >60% (RR 1.09; 95% CI 0.86-1.40; Pinteraction = 0.021). Sacubitril/valsartan was also associated with lower rates of the renal composite endpoint in the primary pooled analysis [hazard ratio (HR) 0.67; 95% CI 0.43-1.05; P = 0.080] and the pooled analysis of all participants (HR 0.60; 95% CI 0.44-0.83; P = 0.002).
CONCLUSION
In pooled analyses of PARAGLIDE-HF and PARAGON-HF, sacubitril/valsartan reduced cardiovascular and renal events among patients with HF with mildly reduced or preserved ejection fraction. These data provide support for use of sacubitril/valsartan in patients with HF with mildly reduced or preserved ejection fraction, particularly among those with an LVEF below normal, regardless of care setting.
Topics: Humans; Stroke Volume; Tetrazoles; Ventricular Function, Left; Angiotensin Receptor Antagonists; Valsartan; Heart Failure; Aminobutyrates; Drug Combinations
PubMed: 37210743
DOI: 10.1093/eurheartj/ehad344 -
Journal of Nanobiotechnology Nov 2023Osteoarthritis (OA) is an age-related disease characterised by the accumulation of senescent chondrocytes, which drives its pathogenesis and progression. Senescent cells...
BACKGROUND
Osteoarthritis (OA) is an age-related disease characterised by the accumulation of senescent chondrocytes, which drives its pathogenesis and progression. Senescent cells exhibit distinct features, including mitochondrial dysfunction and the excessive accumulation and release of reactive oxygen species (ROS), which are highly correlated and lead to a vicious cycle of increasing senescent cells. Stem cell therapy has proven effective in addressing cellular senescence, however, it still has issues such as immune rejection and ethical concerns. Microvesicles (MVs) constitute the primary mechanism through which stem cell therapy exerts its effects, offering a cell-free approach that circumvents these risks and has excellent anti-ageing potential. Nonetheless, MVs have a short in vivo half-life, and their secretion composition varies considerably under diverse conditions. This study aims to address these issues by constructing a ROS-responsive hydrogel loaded with pre-stimulant MVs. Through responding to ROS levels this hydrogel intelligently releases MVs, and enhancing mitochondrial function in chondrocytes to improving cellular senescence.
RESULT
We employed Interferon-gamma (IFN-γ) as a stem cell-specific stimulus to generate IFN-γ-microvesicles (iMVs) with enhanced anti-ageing effects. Simultaneously, we developed a ROS-responsive carrier utilising 3-aminophenylboronic acid (APBA)-modified silk fibroin (SF) and polyvinyl alcohol (PVA). This carrier served to protect MVs, prolong longevity, and facilitate intelligent release. In vitro experiments demonstrated that the Hydrogel@iMVs effectively mitigated cell senescence, improved mitochondrial function, and enhanced cellular antioxidant capacity. In vivo experiments further substantiated the anti-ageing capabilities of the Hydrogel@iMVs.
CONCLUSION
The effect of MVs can be significantly enhanced by appropriate pre-stimulation and constructing a suitable carrier. Therefore, we have developed a ROS-responsive hydrogel containing IFN-γ pre-stimulated iMVs to target the characteristics of ageing chondrocytes in OA for therapeutic purposes. Overall, this novel approach effectively improving mitochondrial dysfunction by regulating the balance between mitochondrial fission and fusion, and the accumulation of reactive oxygen species was reduced, finally, alleviates cellular senescence, offering a promising therapeutic strategy for OA.
Topics: Humans; Reactive Oxygen Species; Hydrogels; Cellular Senescence; Osteoarthritis; Mitochondria
PubMed: 37968657
DOI: 10.1186/s12951-023-02211-8 -
Angiogenesis May 2024Vascularized organoid-on-a-chip (VOoC) models achieve substance exchange in deep layers of organoids and provide a more physiologically relevant system in vitro. Common... (Review)
Review
Vascularized organoid-on-a-chip (VOoC) models achieve substance exchange in deep layers of organoids and provide a more physiologically relevant system in vitro. Common designs for VOoC primarily involve two categories: self-assembly of endothelial cells (ECs) to form microvessels and pre-patterned vessel lumens, both of which include the hydrogel region for EC growth and allow for controlled fluid perfusion on the chip. Characterizing the vasculature of VOoC often relies on high-resolution microscopic imaging. However, the high scattering of turbid tissues can limit optical imaging depth. To overcome this limitation, tissue optical clearing (TOC) techniques have emerged, allowing for 3D visualization of VOoC in conjunction with optical imaging techniques. The acquisition of large-scale imaging data, coupled with high-resolution imaging in whole-mount preparations, necessitates the development of highly efficient analysis methods. In this review, we provide an overview of the chip designs and culturing strategies employed for VOoC, as well as the applicable optical imaging and TOC methods. Furthermore, we summarize the vascular analysis techniques employed in VOoC, including deep learning. Finally, we discuss the existing challenges in VOoC and vascular analysis methods and provide an outlook for future development.
Topics: Endothelial Cells; Organoids; Hydrogels; Microvessels; Lab-On-A-Chip Devices
PubMed: 38409567
DOI: 10.1007/s10456-024-09905-z -
Environmental Research Dec 2023The cardiovascular diseases have been among the most common malignancies and the first leading cause of death, even higher than cancer. The cardiovascular diseases can... (Review)
Review
The cardiovascular diseases have been among the most common malignancies and the first leading cause of death, even higher than cancer. The cardiovascular diseases can be developed as a result of cardiac dysfunction and damages to heart tissue. Exposure to toxic agents and chemicals that induce cardiac dysfunction has been of interest in recent years. The chemotherapy drugs are commonly used for cancer therapy and in these patients, cardiovascular diseases have been widely observed that is due to negative impact of chemotherapy drugs on the heart. These drugs increase oxidative damage and inflammation, and mediate apoptosis and cardiac dysfunction. Hence, nanotechnological approaches have been emerged as new strategies in attenuation of chemotherapy-mediated cardiotoxicity. The first advantage of nanoparticles can be explored in targeted and selective delivery of drugs to reduce their accumulation in heart tissue. Nanostructures can deliver bioactive and therapeutic compounds in reducing cardiotoxicity and alleviation toxic impacts of chemotherapy drugs. The functionalization of nanostructures increases their selectivity against tumor cells and reduces accumulation of drugs in heart tissue. The bioplatforms such as chitosan and alginate nanostructures can also deliver chemotherapy drugs and reduce their cardiotoxicity. The function of nanostructures is versatile in reduction of cardiotoxicity by chemotherapy drugs and new kind of platforms is hydrogels that can mediate sustained release of drug to reduce its toxic impacts on heart tissue. The various kinds of nanoplatforms have been developed for alleviation of cardiotoxicity and their future clinical application depends on their biocompatibility. High concentration level of chitosan nanoparticles can stimulate cardiotoxicity. Therefore, if nanotechnology is going to be deployed for drug delivery and reducing cardiotoxicity, the first pre-requirement is to lack toxicity on normal cells and have high biocompatibility.
Topics: Humans; Cardiotoxicity; Cardiovascular Diseases; Chitosan; Neoplasms; Heart Diseases; Pharmaceutical Preparations; Antineoplastic Agents
PubMed: 37633635
DOI: 10.1016/j.envres.2023.116989 -
CNS Neuroscience & Therapeutics Jul 2023The analgesic effect of acupuncture is widely recognized, but the mechanical characteristics of acupuncture for pain relief, compared to non-steroidal anti-inflammatory... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The analgesic effect of acupuncture is widely recognized, but the mechanical characteristics of acupuncture for pain relief, compared to non-steroidal anti-inflammatory (NSAIDs) and placebo medication, remain unknown.
AIMS
To compare the modulation effects of acupuncture treatment with NSAIDs and placebo medication on descending pain modulation system (DPMS) in knee osteoarthritis (KOA) patients.
METHODS
This study recruited 180 KOA patients with knee pain and 41 healthy controls (HCs). Individuals with KOA knee pain were divided randomly into groups of verum acupuncture (VA), sham acupuncture (SA), celecoxib (SC), placebo (PB), and waiting list (WT), with 36 patients in each group. VA and SA groups included ten sessions of puncturing acupoints or puncturing non-acupoints acupuncture treatment for two successive weeks. Celecoxib capsules were continuously given orally to patients in the SC group at a dosage of 200 mg daily for 2 weeks. In the PB group, patients received a placebo capsule once a day for 2 weeks at the same dosage as celecoxib capsules. In the WL group, patients did not receive any treatment. Patients underwent a resting-state BOLD-fMRI scan pre- and post-receiving the therapy, whereas HCs only underwent a baseline scan. Seed (ventrolateral periaqueductal gray, vlPAG, a key node in DPMS) based resting-state functional connectivity (rs-FC) was applied in the data analysis.
RESULTS
All groups demonstrated improved knee pain scores relative to the initial state. There was no statistical difference between the VA and SA groups in all clinical outcomes, and vlPAG rs-FC alterations. KOA knee pain individuals reported higher vlPAG rs-FC in the bilateral thalamus than HCs. KOA knee pain patients in the acupuncture group (verum + sham, AG) exhibited increased vlPAG rs-FC with the right dorsolateral prefrontal cortex (DLPFC) and the right angular, which is associated with knee pain improvement. In contrast with the SC and PB group, the AG exhibited significantly increased vlPAG rs-FC with the right DLPFC and angular. Contrary to the WT group, the AG showed greater vlPAG rs-FC with the right DLPFC and precuneus.
CONCLUSIONS
Acupuncture treatment, celecoxib, and placebo medication have different modulation effects on vlPAG DPMS in KOA knee pain patients. Acupuncture could modulate vlPAG rs-FC with brain regions associated with cognitive control, attention, and reappraisal for knee pain relief in KOA patients, compared with celecoxib and placebo medication.
Topics: Humans; Osteoarthritis, Knee; Periaqueductal Gray; Celecoxib; Capsules; Pain; Acupuncture Therapy; Anti-Inflammatory Agents, Non-Steroidal; Magnetic Resonance Imaging
PubMed: 36890655
DOI: 10.1111/cns.14153 -
Phytotherapy Research : PTR Jun 2024Neurodegenerative disorders (NDs) are among the most common causes of death across the globe. NDs are characterized by progressive damage to CNS neurons, leading to... (Review)
Review
Neurodegenerative disorders (NDs) are among the most common causes of death across the globe. NDs are characterized by progressive damage to CNS neurons, leading to defects in specific brain functions such as memory, cognition, and movement. The most common NDs are Parkinson's, Alzheimer's, Huntington's, and amyotrophic lateral sclerosis (ALS). Despite extensive research, no therapeutics or medications against NDs have been proven to be effective. The current treatment of NDs involving symptom-based targeting of the disease pathogenesis has certain limitations, such as drug resistance, adverse side effects, poor blood-brain barrier permeability, and poor bioavailability of drugs. Some studies have shown that plant-derived natural compounds hold tremendous promise for treating and preventing NDs. Therefore, the primary objective of this review article is to critically analyze the properties and potency of some of the most studied phytomedicines, such as quercetin, curcumin, epigallocatechin gallate (EGCG), apigenin, and cannabinoids, and highlight their advantages and limitations for developing next-generation alternative treatments against NDs. Further extensive research on pre-clinical and clinical studies for developing plant-based drugs against NDs from bench to bedside is warranted.
Topics: Humans; Neurodegenerative Diseases; Catechin; Phytotherapy; Curcumin; Quercetin; Animals; Cannabinoids; Apigenin; Blood-Brain Barrier; Phytochemicals; Plant Extracts
PubMed: 38600725
DOI: 10.1002/ptr.8192 -
European Journal of Ophthalmology Mar 2024One of the major challenges in preventing glaucoma progression is patient compliance with medication regimens. Since conventional ophthalmic dosage forms have numerous... (Review)
Review
One of the major challenges in preventing glaucoma progression is patient compliance with medication regimens. Since conventional ophthalmic dosage forms have numerous limitations, researchers have been intensively working on developing polymers-based delivery systems for glaucoma drugs. Specifically, research and development efforts have increased using polysaccharide polymers such as sodium alginate, cellulose, β-cyclodextrin, hyaluronic acid, chitosan, pectin, gellan gum, galactomannans for sustained release to the eye to overcome treatment challenges, showing promise in improving drug release and delivery, patient experience, and treatment compliance. In the recent past, multiple research groups have successfully designed sustained drug delivery systems, promoting the efficacy as well as the feasibility of glaucoma drugs with single/combinations of polysaccharides to eliminate the drawbacks associated with the glaucoma treatment. Naturally available polysaccharides, when used as drug vehicles can increase the retention time of eye drops on the ocular surface, leading to improved drug absorption and bioavailability. Additionally, some polysaccharides can form gels or matrices that can release drugs slowly over time, providing sustained drug delivery and reducing the need for frequent dosing. Thus, this review aims to provide an overview of the pre-clinical and clinical studies of polysaccharide polymers applied for glaucoma treatment along with their therapeutic outcomes.
Topics: Humans; Polymers; Drug Delivery Systems; Polysaccharides; Glaucoma; Eye; Pharmaceutical Preparations
PubMed: 37231538
DOI: 10.1177/11206721231178057 -
Drugs Dec 2023Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) provides a critical intervention toward ending the HIV epidemic and protecting people with reasons to... (Review)
Review
Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) provides a critical intervention toward ending the HIV epidemic and protecting people with reasons to utilize PrEP. PrEP options continue to expand as new administration modalities offer the potential to tailor PrEP use for individual success. We have provided the evidence for new and emerging antiretroviral agents for PrEP (cabotegravir, lenacapavir, dapivirine, and broadly neutralizing antibodies), divided into pharmacology, animal model, and human data, accompanied by a summary and suggested place in therapy. Cabotegravir is a US Food and Drug Administration (FDA)-approved intramuscular injection given every 2 months with a strong body of evidence demonstrating efficacy for HIV PrEP, lenacapavir administered subcutaneously every 6 months is currently under investigation for HIV PrEP, dapivirine vaginal ring is an available PrEP option for women in certain areas of Africa, and broadly neutralizing monoclonal antibodies have been challenged in demonstrating efficacy in phase 1-2 study for HIV PrEP to date. Clinical literature for individual agents is discussed with data from major studies summarized in tables. This review provides a detailed overview of recently available and premier candidate PrEP drugs.
Topics: Animals; Humans; Female; HIV; HIV Infections; Pharmaceutical Preparations; Anti-HIV Agents; Anti-Retroviral Agents; Pre-Exposure Prophylaxis
PubMed: 38079092
DOI: 10.1007/s40265-023-01963-9 -
Nutrients Sep 2023Aronia melanocarpa berries are rich in antioxidants and possess a high antioxidant capacity. Aronia berries have shown potential in type 2 diabetes mellitus (T2DM)... (Randomized Controlled Trial)
Randomized Controlled Trial
Aronia melanocarpa berries are rich in antioxidants and possess a high antioxidant capacity. Aronia berries have shown potential in type 2 diabetes mellitus (T2DM) treatment, and previous studies indicate improvements in glycemia after supplementation. Unfortunately, the effectiveness of aronia berries is limited by the low bioavailability of aronia, which fermentation could potentially overcome. The objective of this study was to compare the effects of fermented or non-fermented aronia pulp with placebo in subjects with T2DM. This study was a triple-blinded, triple-crossover study with eight-week intervention periods with fermented aronia extract (FAE), non-fermented aronia extract (AE), and placebo. Extracts were incorporated in snack bars with 37% aronia (FAE or AE) or wheat bran (placebo) and 63% raisins and coconut oil. Pre- and post-treatment period, we did fasting blood samples, including hemoglobin A1c, fructosamine, insulin, glucose, glucagon-like peptide-1, glucose-dependent insulinotropic peptide (GIP) and glucagon, oral glucose tolerance tests, and anthropometric measurements. Of 36 randomized participants, 23 completed the trial. Aside from a higher increase in GIP after FAE supplementation compared to after placebo supplementation, aronia extracts had no effect. The increase in GIP levels after FAE supplementation may hold potential benefits, but the overall clinical impact remains unclear.
Topics: Humans; Diabetes Mellitus, Type 2; Photinia; Cross-Over Studies; Antioxidants; Insulin; Plant Extracts
PubMed: 37836472
DOI: 10.3390/nu15194188 -
Human Vaccines & Immunotherapeutics Dec 2024Cancer immunotherapy has emerged as a promising strategy to treat cancer patients. Among the wide range of immunological approaches, cancer vaccines have been... (Review)
Review
Cancer immunotherapy has emerged as a promising strategy to treat cancer patients. Among the wide range of immunological approaches, cancer vaccines have been investigated to activate and expand tumor-reactive T cells. However, most cancer vaccines have not shown significant clinical benefit as monotherapies. This is likely due to the antigen targets of vaccines, "self" proteins to which there is tolerance, as well as to the immunosuppressive tumor microenvironment. To help circumvent immune tolerance and generate effective immune responses, adjuvants for cancer vaccines are necessary. One representative adjuvant family is Toll-Like receptor (TLR) agonists, synthetic molecules that stimulate TLRs. TLRs are the largest family of pattern recognition receptors (PRRs) that serve as the sensors of pathogens or cellular damage. They recognize conserved foreign molecules from pathogens or internal molecules from cellular damage and propel innate immune responses. When used with vaccines, activation of TLRs signals an innate damage response that can facilitate the development of a strong adaptive immune response against the target antigen. The ability of TLR agonists to modulate innate immune responses has positioned them to serve as adjuvants for vaccines targeting infectious diseases and cancers. This review provides a summary of various TLRs, including their expression patterns, their functions in the immune system, as well as their ligands and synthetic molecules developed as TLR agonists. In addition, it presents a comprehensive overview of recent strategies employing different TLR agonists as adjuvants in cancer vaccine development, both in pre-clinical models and ongoing clinical trials.
Topics: Humans; Adjuvants, Vaccine; Toll-Like Receptor Agonists; Cancer Vaccines; Adjuvants, Immunologic; Antigens; Neoplasms; Tumor Microenvironment
PubMed: 38155525
DOI: 10.1080/21645515.2023.2297453