Explore the vast range of titles available.

This study investigates the humoral and cellular immune responses and health-related quality of life measures in individuals with mild to moderate long COVID (LC) compared to age and gender matched recovered COVID-19 controls (MC) over 24 months. LC participants show elevated nucleocapsid IgG levels at 3 months, and higher neutralizing capacity up to 8 months post-infection. Increased spike-specific and nucleocapsid-specific CD4 + T cells, PD-1, and TIM-3 expression on CD4 + and CD8 + T cells were observed at 3 and 8 months, but these differences do not persist at 24 months. Some LC participants had detectable IFN-γ and IFN-β, that was attributed to reinfection and antigen re-exposure. Single-cell RNA sequencing at the 24 month timepoint shows similar immune cell proportions and reconstitution of naïve T and B cell subsets in LC and MC. No significant differences in exhaustion scores or antigen-specific T cell clones are observed. These findings suggest resolution of immune activation in LC and return to comparable immune responses between LC and MC over time. Improvement in self-reported health-related quality of life at 24 months was also evident in the majority of LC (62%). PTX3, CRP levels and platelet count are associated with improvements in health-related quality of life. Post-acute sequelae of COVID (PASC) or long-COVID can affect a proportion of those infected but this is not well understood. Here the authors perform a single cell transcriptomics analysis of immune cells from long-COVID patients at 24 months and find that cell changes observed at 3 and 8 months do not persist to 24 months.

The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly with ER and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers. Around 70% of breast cancers in women need one or both of the female hormones (estrogen and progesterone) to grow. To treat these 'hormone-dependent' cancers, patients receive drugs that either block the production of estrogen or directly target a receptor protein that senses estrogen in the cancer cells. Unfortunately, many breast cancers develop resistance to these drugs. This resistance is often caused by genetic mutations that alter the estrogen receptor; for example, the receptor may develop the ability to interact with other proteins in the cell known as coregulators to promote tumor growth. Developing new drugs that prevent estrogen receptors from interacting with coregulators may provide more options for treating hormone-dependent breast cancers. Here, Raj et al. developed a new small molecule named ERX-11 that is able to inhibit the growth of human breast cancer cells that are sensitive to existing drugs as well as cells that have become drug-resistant. For the experiments, hormone-dependent breast cancer cells from humans were transplanted into mice. This procedure usually causes the mice to develop tumors, but giving the mice ERX-11 by mouth stopped estrogen receptors from interacting with coregulators and blocked the growth of tumors. Furthermore, ERX-11 does not appear to have any toxic effects on the mice, indicating that it may also be safe for humans. The findings of Raj et al. suggest that ERX-11 is a promising new drug candidate for treating some breast cancers. The next steps are to examine the effects of ERX-11 on mice and other animals in more detail before deciding whether this molecule is suitable for clinical trials. In the longer term, molecules similar to ERX-11 could also be developed into drugs to treat other types of cancer that are also caused by abnormal interactions of coregulator proteins.

Cigarette smoke is considered a primary risk factor for chronic obstructive pulmonary disease. Numerous toxicants present in cigarette smoke are known to induce oxidative stress and airway inflammation that further exacerbate disease progression. Generally, the broncho-epithelial cells and alveolar macrophages exposed to cigarette smoke release massive amounts of oxidative stress and inflammation mediators. Chronic exposure of cigarette smoke leads to premature senescence of airway epithelial cells. This impairs cellular function and ultimately leads to the progression of chronic lung diseases. Therefore, an ideal therapeutic candidate should prevent disease progression by controlling oxidative stress, inflammation, and senescence during the initial stage of damage. In our study, we explored if berberine (an alkaloid)-loaded liquid crystalline nanoparticles (berberine-LCNs)-based treatment to human broncho-epithelial cells and macrophage inhibits oxidative stress, inflammation, and senescence induced by cigarette-smoke extract. The developed berberine-LCNs were found to have favourable physiochemical parameters, such as high entrapment efficiency and sustained in vitro release. The cellular-assay observations revealed that berberine-LCNs showed potent antioxidant activity by suppressing the generation of reactive oxygen species in both broncho-epithelial cells (16HBE) and macrophages (RAW264.7), and modulating the genes involved in inflammation and oxidative stress. Similarly, in 16HBE cells, berberine-LCNs inhibited the cigarette smoke-induced senescence as revealed by X-gal staining, gene expression of CDKN1A (p21), and immunofluorescent staining of p21. Further in-depth mechanistic investigations into antioxidative, anti-inflammatory, and antisenescence research will diversify the current findings of berberine as a promising therapeutic approach for inflammatory lung diseases caused by cigarette smoking.

Epidemiological studies have established that a high plasma high density lipoprotein cholesterol (HDL-C) level is associated with reduced cardiovascular risk. However, recent randomised clinical trials of interventions that increase HDL-C levels have failed to establish a causal basis for this relationship. This has led to a shift in HDL research efforts towards developing strategies that improve the cardioprotective functions of HDLs, rather than simply increasing HDL-C levels. These efforts are also leading to the discovery of novel HDL functions that are unrelated to cardiovascular disease. One of the most recently identified functions of HDLs is their potent antidiabetic properties. The antidiabetic functions of HDLs, and recent key advances in this area are the subject of this review. Given that all forms of diabetes are increasing at an alarming rate globally, there is a clear unmet need to identify and develop new approaches that will complement existing therapies and reduce disease progression as well as reverse established disease. Exploration of a potential role for HDLs and their constituent lipids and apolipoproteins in this area is clearly warranted. This review highlights focus areas that have yet to be investigated and potential strategies for exploiting the antidiabetic functions of HDLs.

Non-small-cell lung cancer (NSCLC) is the most common form of lung cancer, which is a leading cause of cancer-related deaths worldwide. Berberine is an isoquinoline alkaloid that is commercially available for use as a supplement for the treatment of diabetes and cardiovascular diseases. However, the therapeutic benefits of berberine are limited by its extremely low bioavailability and toxicity at higher doses. Increasing evidence suggests that the incorporation of drug compounds in liquid crystal nanoparticles provides a new platform for the safe, effective, stable, and controlled delivery of the drug molecules. This study aimed to formulate an optimized formulation of berberine–phytantriol-loaded liquid crystalline nanoparticles (BP-LCNs) and to investigate the in vitro anti-cancer activity in a human lung adenocarcinoma A549 cell line. The BP-LCN formulation possessing optimal characteristics that was used in this study had a favorable particle size and entrapment efficiency rate (75.31%) and a superior drug release profile. The potential mechanism of action of the formulation was determined by measuring the mRNA levels of the tumor-associated genes PTEN, P53, and KRT18 and the protein expression levels with a human oncology protein array. BP-LCNs decreased the proliferation, migration, and colony-forming activity of A549 cells in a dose-dependent manner by upregulating the mRNA expression of PTEN and P53 and downregulating the mRNA expression of KRT18. Similarly, BP-LCNs also decreased the expression of proteins related to cancer cell proliferation and migration. This study highlights the utility of phytantriol-based LCNs in incorporating drug molecules with low GI absorption and bioavailability to increase their pharmacological effectiveness and potency in NSCLC.

Inflammation and oxidative stress are interrelated processes that represent the underlying causes of several chronic inflammatory diseases that include asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), allergies, diabetes, and cardiovascular diseases. Macrophages are key initiators of inflammatory processes in the body. When triggered by a stimulus such as bacterial lipopolysaccharides (LPS), these cells secrete inflammatory cytokines namely TNF-α that orchestrate the cellular inflammatory process. Simultaneously, pro-inflammatory stimuli induce the upregulation of inducible nitric oxide synthase (iNOS) which catalyzes the generation of high levels of nitric oxide (NO). This, together with high concentrations of reactive oxygen species (ROS) produced by macrophages, mediate oxidative stress which, in turn, exacerbates inflammation in a feedback loop, resulting in the pathogenesis of several chronic inflammatory diseases. Berberine is a phytochemical embedded with potent in vitro anti-inflammatory and antioxidant properties, whose therapeutic application is hindered by poor solubility and bioavailability. For this reason, large doses of berberine need to be administered to achieve the desired pharmacological effect, which may result in toxicity. Encapsulation of such a drug in liquid crystalline nanoparticles (LCNs) represents a viable strategy to overcome these limitations. We encapsulated berberine in phytantriol-based LCNs (BP-LCNs) and tested the antioxidant and anti-inflammatory activities of BP-LCNs in vitro on LPS-induced mouse RAW264.7 macrophages. BP-LCNs showed potent anti-inflammatory and antioxidant activities, with significant reduction in the gene expressions of TNF-α and iNOS, followed by concomitant reduction of ROS and NO production at a concentration of 2.5 µM, which is lower than the concentration of free berberine concentration required to achieve similar effects as reported elsewhere. Furthermore, we provide evidence for the suitability for BP-LCNs both as an antioxidant and as an anti-inflammatory agent with potential application in the therapy of chronic inflammatory diseases.

Background Decreased insulin availability and high blood glucose levels, the hallmark features of poorly controlled diabetes, drive disease progression and are associated with decreased skeletal muscle mass. We have shown that mice with β‐cell dysfunction and normal insulin sensitivity have decreased skeletal muscle mass. This project asks how insulin deficiency impacts on the structure and function of the remaining skeletal muscle in these animals. Methods Skeletal muscle function was determined by measuring exercise capacity and specific muscle strength prior to and after insulin supplementation for 28 days in 12‐week‐old mice with conditional β‐cell deletion of the ATP binding cassette transporters ABCA1 and ABCG1 (β‐DKO mice). Abca1 and Abcg1 floxed (fl/fl) mice were used as controls. RNAseq was used to quantify changes in transcripts in soleus and extensor digitorum longus muscles. Skeletal muscle and mitochondrial morphology were assessed by transmission electron microscopy. Myofibrillar Ca2+ sensitivity and maximum isometric single muscle fibre force were assessed using MyoRobot biomechatronics technology. Results RNA transcripts were significantly altered in β‐DKO mice compared with fl/fl controls (32 in extensor digitorum longus and 412 in soleus). Exercise capacity and muscle strength were significantly decreased in β‐DKO mice compared with fl/fl controls (P = 0.012), and a loss of structural integrity was also observed in skeletal muscle from the β‐DKO mice. Supplementation of β‐DKO mice with insulin restored muscle integrity, strength and expression of 13 and 16 of the dysregulated transcripts in and extensor digitorum longus and soleus muscles, respectively. Conclusions Insulin insufficiency due to β‐cell dysfunction perturbs the structure and function of skeletal muscle. These adverse effects are rectified by insulin supplementation.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are among the leading causes of mortality worldwide. Cigarette smoking is among the main aetiologic factors for both ailments. These diseases share common pathogenetic mechanisms including inflammation, oxidative stress, and tissue remodelling. Current therapeutic approaches are limited by low efficacy and adverse effects. Consequentially, LC has a 5-year survival of < 20%, while COPD is incurable, underlining the necessity for innovative treatment strategies. Two promising emerging classes of therapy against these diseases include plant-derived molecules (phytoceuticals) and nucleic acid-based therapies. The clinical application of both is limited by issues including poor solubility, poor permeability, and, in the case of nucleic acids, susceptibility to enzymatic degradation, large size, and electrostatic charge density. Nanoparticle-based advanced drug delivery systems are currently being explored as flexible systems allowing to overcome these limitations. In this review, an updated summary of the most recent studies using nanoparticle-based advanced drug delivery systems to improve the delivery of nucleic acids and phytoceuticals for the treatment of LC and COPD is provided. This review highlights the enormous relevance of these delivery systems as tools that are set to facilitate the clinical application of novel categories of therapeutics with poor pharmacokinetic properties. Graphical abstract This picture was generated with BioRender