The impact of sarcopenia on the efficacy of PD-1 inhibitors in non-small cell lung cancer and potential strategies to overcome resistance.

Recent studies have revealed that sarcopenia can adversely affect the efficacy of PD-1 inhibitors in the treatment of non-small cell lung cancer (NSCLC). PD-1 inhibitors are immune checkpoint inhibitors widely used in the treatment of various cancers. However, NSCLC patients may have poorer outcomes when receiving PD-1 inhibitor treatment, and sarcopenia may affect the efficacy of PD-1 inhibitors through immune and metabolic mechanisms. In this article, we summarize the reported negative impact of sarcopenia on the effectiveness of PD-1 inhibitors in the treatment of NSCLC in recent years. Based on existing research results, we analyze the possible mechanisms by which sarcopenia affects the efficacy of PD-1 inhibitors and discuss possible strategies to address this issue. This could help to understand the impact of sarcopenia on the treatment of PD-1 inhibitors and provide more accurate expectations of treatment outcomes for clinicians and patients. Additionally, we present tailored intervention strategies for sarcopenic patients undergoing PD-1 inhibitor therapy, aiming to optimize treatment efficacy and enhance patient quality of life. Nevertheless, further research is warranted to elucidate the mechanisms through which sarcopenia impacts PD-1 inhibitors and to identify more efficacious intervention approaches for improving the effectiveness of PD-1 inhibitor treatment in sarcopenic patients.

Migraine versus tension-type headache in automatic emotional processing: A visual mismatch negativity study.

OBJECTIVE: It is important to discriminate different headaches in clinical practice, and neurocognitive biomarkers may serve as objective tools. Several reports have suggested potential cognitive impairment for primary headaches, whereas cognitions within specific domains remain elusive, e.g., emotional processing. In this study, we aimed to characterize processing of facial expressions in migraine and tension-type headache (TTH) by analyzing expression-related visual mismatch negativity (EMMN) and explored whether their processing patterns were distinct. METHODS: Altogether, 73 headache patients (20 migraine with aura (MA), 28 migraine without aura (MwoA), 25 TTH) and 27 age-matched healthy controls were recruited. After a battery of mood/neuropsychological evaluations, an expression-related oddball paradigm containing multiple models of neutral, happy and sad faces was used to investigate automatic emotional processing. RESULTS: We observed cognitive impairment in all headache patients, especially in attention/execution subdomains, but no discrepancy existed among different headaches. Although analyses of P1/N170 did not reach significant levels, amplitude of early and late EMMN was markedly diminished in MA and MwoA compared with controls and TTH, regardless of happy or sad expression. Moreover, sad EMMN was larger (more negative) than happy EMMN only in controls, while not in all headache groups. CONCLUSIONS: Our findings implied that migraine, rather than TTH, might lead to more severe impairment of automatic emotional processing, which was manifested as no observable EMMN elicitation and disappearance of negative bias effect. The EMMN component could assist in discrimination of migraine from TTH and diagnosis of undefined headaches, and its availability needed further validations.

Type 2 diabetes mellitus related sarcopenia: a type of muscle loss distinct from sarcopenia and disuse muscle atrophy.

Muscle loss is a significant health concern, particularly with the increasing trend of population aging, and sarcopenia has emerged as a common pathological process of muscle loss in the elderly. Currently, there has been significant progress in the research on sarcopenia, including in-depth analysis of the mechanisms underlying sarcopenia caused by aging and the development of corresponding diagnostic criteria, forming a relatively complete system. However, as research on sarcopenia progresses, the concept of secondary sarcopenia has also been proposed. Due to the incomplete understanding of muscle loss caused by chronic diseases, there are various limitations in epidemiological, basic, and clinical research. As a result, a comprehensive concept and diagnostic system have not yet been established, which greatly hinders the prevention and treatment of the disease. This review focuses on Type 2 Diabetes Mellitus (T2DM)-related sarcopenia, comparing its similarities and differences with sarcopenia and disuse muscle atrophy. The review show significant differences between the three muscle-related issues in terms of pathological changes, epidemiology and clinical manifestations, etiology, and preventive and therapeutic strategies. Unlike sarcopenia, T2DM-related sarcopenia is characterized by a reduction in type I fibers, and it differs from disuse muscle atrophy as well. The mechanism involving insulin resistance, inflammatory status, and oxidative stress remains unclear. Therefore, future research should further explore the etiology, disease progression, and prognosis of T2DM-related sarcopenia, and develop targeted diagnostic criteria and effective preventive and therapeutic strategies to better address the muscle-related issues faced by T2DM patients and improve their quality of life and overall health.

Association between skeletal muscle and left ventricular mass in patients with hyperthyroidism.

Objective: This study aims to investigate the relationship between skeletal muscle and left ventricular mass (LVM) in patients with hyperthyroidism, providing theoretical and data-based foundations for further research on the interaction between secondary muscle atrophy and cardiac remodeling. Methods: A retrospective data collection was conducted, including 136 patients with hyperthyroidism (Study group) and 50 healthy participants (control group). The Study group was further divided into Group A (high LVM) and Group B (low LVM) based on LVM size. Multiple linear regression analysis was performed to examine the correlation between skeletal muscle and LVM, with model evaluation. Based on the results, further nonlinear regression analysis was conducted to explore the detailed relationship between skeletal muscle and LVM. Results: Compared to the control group, the Study group exhibited significantly lower LVM, skeletal muscle mass index (SMI), and skeletal muscle mass (SMM) (P<0.05). Within the subgroups, Group A had significantly higher SMI, SMM, and hand grip strength compared to Group B (P<0.05). The results of the multiple linear regression showed a certain correlation between SMI (ß=0.60, P=0.042, 95% CI=0.02~1.17) and hand grip strength (ß=0.34, P=0.045, 95% CI=0.01~0.67) with LVM. However, the residuals of the multiple regression did not follow a normal distribution (K-S=2.50, P<0.01). Further results from a generalized linear model and structural equation modeling regression also demonstrated a correlation between SMI (ß=0.60, P=0.040, 95% CI=0.03~1.17) (ß=0.60, P=0.042, 95% CI=0.02~1.17) and hand grip strength (ß=0.34, P=0.043, 95% CI=0.01~0.67) (ß=0.34, P=0.045, 95% CI=0.01~0.67) with LVM. Conclusion: Patients with hyperthyroidism may exhibit simultaneous decreases in LVM, SMM, and SMI. The LVM in patients is correlated with SMM and hand grip strength, highlighting the need for further exploration of the causal relationship and underlying mechanisms. These findings provide a basis for the prevention and treatment of secondary sarcopenia and cardiac pathology in patients with hyperthyroidism.

Visible Light-Mediated Monofluoromethylation/Acylation of Olefins by Dual Organo-Catalysis.

Monofluoromethyl (CH2F) motifs exhibit unique bioactivities and are considered privileged units in drug discovery. The radical monofluoromethylative difunctionalization of alkenes stands out as an appealing approach to access CH2F-containing compounds. However, this strategy remains largely underdeveloped, particularly under metal-free conditions. In this study, we report on visible light-mediated three-component monofluoromethylation/acylation of styrene derivatives employing NHC and organic photocatalyst dual catalysis. A diverse array of α-aryl-ß-monofluoromethyl ketones was successfully synthesized with excellent functional group tolerance and selectivity. The mild and metal-free CH2F radical generation strategy from NaSO2CFH2 holds potential for further applications in fluoroalkyl radical chemistry.

Catalyst-Free Trans-Selective Oxyiodination and Oxychlorination of Alkynes Employing N-X (Halogen) Reagents.

ß-halogenated enol esters and ethers are versatile building blocks in organic synthesis, which has attracted increasing attention. In this study, we report the facile trans-oxyiodination and oxychlorination of alkynes, leading to the direct construction of versatile halogenated enol esters and ethers. This transformation features an easy operation, optimal atomic economy, a strong functional group tolerance, broad substrate scope, and excellent trans-selectivity. Employing highly electrophilic bifunctional N-X (halogen) reagents was the key to achieving broad reaction generality. To our knowledge, this transformation represents the first oxyhalogenation system employing N-X (halogen) reagents as both oxylation and halogenation sources.

The neuroprotective effects of peracetylated chitosan oligosaccharides against ß-amyloid-induced cognitive deficits in rats.

Chitosan oligosaccharides (COSs) have been reported to possess a broad range of activities such as antitumor, antioxidant and neuroprotective activities. In this study, the protective effects and mechanisms of peracetylated chitosan oligosaccharides (PACOs) against Aß-induced cognitive deficits were investigated in Sprague-Dawley (SD) rats. PACOs treatment significantly improved the learning and memory function of Alzheimer's disease (AD) rats and attenuated the neuron cell damage caused by Aß. PACOs also markedly reduced the levels of lactate dehydrogenase (LDH) and Malondialdehyde (MDA) and decreased the phosphorylation of Tau protein to inhibit oxidative injury and inflammatory responses in AD rats. Further studies indicated that PACOs may promote the repair of Aß induced nerve damage and inhibit neuronal apoptosis mainly through regulating PI3K/Akt/GSK3ß signaling pathway. Consistently, the transcriptome analysis verified that the differentially expressed genes (DEGs) were mainly involved in neuron development and the PI3K-Akt signaling pathway. Taken together, peracetylated chitosan oligosaccharides (PACOs) have the potential to be developed into novel anti-AD agents targeting the cellular PI3K/Akt/GSK3ß signaling pathway. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00172-3.

Brain-targeted lycopene-loaded microemulsion modulates neuroinflammation, oxidative stress, apoptosis and synaptic plasticity in ß-amyloid-induced Alzheimer's disease mice.

OBJECTIVES: ß-Amyloid protein (Aß) plays pivotal roles in pathogenesis of Alzheimer's disease (AD) and triggers various pathophysiological events. Lycopene is a promising neuroprotector with multiple bioactivities, while its bioavailability is limited. Lycopene-loaded microemulsion (LME) possessing superior bioavailability and brain-targeting efficiency was developed in our previous study. In this investigation, we aimed to comprehensively evaluate its neuroprotective effects and underlying mechanisms using intracerebroventricular (ICV) Aß1-42 injection mice. METHODS: Mice were assigned to the Sham, Aß, Aß + LME and Aß + lycopene dissolved in olive oil (LOO) groups. ICV Aß1-42 administration was performed, followed by oral gavage of brain-targeted LME or conventional LOO formulation for 3 weeks. Brain samples were harvested for immunohistochemistry, biochemical assays and western blotting analyses. RESULTS: Our findings verified Aß-induced neurotoxicity on neuroinflammation, oxidative stress, apoptosis, Aß metabolisms and synaptic plasticity. LME supplementation dramatically attenuated astrocytosis and microgliosis, decreased malondialdehyde production and rescued antioxidant capacities, normalized apoptotic parameters and alleviated neuronal loss, inhibited amyloidogenic processing and activated non-amyloidogenic pathway, together with upregulating synaptic protein expressions and restoring synaptic plasticity. Nevertheless, most of these phenomena were not observed for mice treated with LOO, implying that LME showed significantly higher therapeutic efficacy against Aß injury. DISCUSSION: In summary, brain-targeted LME could exert neuroprotective function via suppressing a series of cascades triggered by Aß aggregates, thus ameliorating Aß neurotoxicity and associated abnormalities. Given this, LME may serve as an attractive candidate for AD prevention and treatment, and superiority of brain-targeting delivery is highlighted.

Neuroprotective effects of neural stem cells pretreated with neuregulin1ß on PC12 cells exposed to oxygen-glucose deprivation/reoxygenation.

Studies on ischemia/reperfusion (I/R) injury suggest that exogenous neural stem cells (NSCs) are ideal candidates for stem cell therapy reperfusion injury. However, NSCs are difficult to obtain owing to ethical limitations. In addition, the survival, differentiation, and proliferation rates of transplanted exogenous NSCs are low, which limit their clinical application. Our previous study showed that neuregulin1ß (NRG1ß) alleviated cerebral I/R injury in rats. In this study, we aimed to induce human umbilical cord mesenchymal stem cells into NSCs and investigate the improvement effect and mechanism of NSCs pretreated with 10 nM NRG1ß on PC12 cells injured by oxygen-glucose deprivation/reoxygenation (OGD/R). Our results found that 5 and 10 nM NRG1ß promoted the generation and proliferation of NSCs. Co-culture of NSCs and PC12 cells under condition of OGD/R showed that pretreatment of NSCs with NRG1ß improved the level of reactive oxygen species, malondialdehyde, glutathione, superoxide dismutase, nicotinamide adenine dinucleotide phosphate, and nuclear factor erythroid 2-related factor 2 (Nrf2) and mitochondrial damage in injured PC12 cells; these indexes are related to ferroptosis. Research has reported that p53 and solute carrier family 7 member 11 (SLC7A11) play vital roles in ferroptosis caused by cerebral I/R injury. Our data show that the expression of p53 was increased and the level of glutathione peroxidase 4 (GPX4) was decreased after RNA interference-mediated knockdown of SLC7A11 in PC12 cells, but this change was alleviated after co-culturing NSCs with damaged PC12 cells. These findings suggest that NSCs pretreated with NRG1ß exhibited neuroprotective effects on PC12 cells subjected to OGD/R through influencing the level of ferroptosis regulated by p53/SLC7A11/GPX4 pathway.

MicroRNA-29b Suppresses Inflammation and Protects Blood-Brain Barrier Integrity in Ischemic Stroke.

Objectives: Following cerebral ischemia, microRNA- (miR-) 29b in circulating blood is downregulated. This study investigates the underlying mechanism and implications of miR-29b in leukocyte induction. Methods: miR-29b from stroke patients and rats with middle cerebral artery occlusion (MCAO) were assessed using real-time polymerase chain reaction (PCR). miR-29b agomir was used to increase miR-29b expression in leukocytes via intravenous injection. C1q and tumor necrosis factor (C1QTNF) 6, interleukin- (IL-) 1ß, zonula occludens- (ZO-) 1, occludin, and ischemic outcomes were assessed in MCAO rats. Additionally, hCMEC/D3 cells were subjected to oxygen-glucose deprivation (OGD) and cocultured with HL-60 cells. Results: miR-29b levels in neutrophils were found to be significantly lower in stroke patients compared with healthy controls, which may indicate its high diagnostic sensitivity and specificity for stroke. Moreover, miR-29b levels in leukocytes showed a negative correlation with National Institute of Health Stroke Scale (NIHSS) scores and C1QTNF6 levels. In MCAO rats, miR-29b overexpression reduced brain infarct volume and brain edema, decreasing IL-1ß levels in leukocytes and in the brain 24 hours poststroke. miR-29b attenuated IL-1ß expression via C1QTNF6 inhibition, leading to decreased blood-brain barrier (BBB) disruption and leukocyte infiltration. Moreover, miR-29b overexpression in HL-60 cells downregulated OGD-induced hCMEC/D3 cell apoptosis and increased ZO-1 and occludin levels in vitro. Conclusion: Leukocytic miR-29b attenuates inflammatory response by augmenting BBB integrity through C1QTNF6, suggesting a novel miR-29b-based therapeutic therapy for ischemic stroke.