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Osteoarthritis (OA) is the most common form of arthritis and joint disorder worldwide. Metabolic reprogramming of osteoarthritic chondrocytes from oxidative phosphorylation to glycolysis results in the accumulation of lactate from glycolytic metabolite pyruvate by lactate dehydrogenase A (LDHA), leading to cartilage degeneration. In the present study, we investigated the protective effects of the intra-articular administration of oxamate (LDHA inhibitor) against OA development and glycolysis-related protein expression in experimental OA rats. The animals were randomly allocated into four groups: Sham, anterior cruciate ligament transection (ACLT), ACLT + oxamate (0.25 and 2.5 mg/kg). Oxamate-treated groups received an intra-articular injection of oxamate once a week for 5 weeks. Intra-articular oxamate significantly reduced the weight-bearing defects and knee width in ACLT rats. Histopathological analyses showed that oxamate caused significantly less cartilage degeneration in the ACLT rats. Oxamate exerts hypertrophic effects in articular cartilage chondrocytes by inhibiting glucose transporter 1, glucose transporter 3, hexokinase II, pyruvate kinase M2, pyruvate dehydrogenase kinases 1 and 2, pyruvate dehydrogenase kinase 2, and LHDA. Further analysis revealed that oxamate significantly reduced chondrocyte apoptosis in articular cartilage. Oxamate attenuates nociception, inflammation, cartilage degradation, and chondrocyte apoptosis and possibly attenuates glycolysis-related protein expression in ACLT-induced OA rats. The present findings will facilitate future research on LDHA inhibitors in prevention strategies for OA progression.

Lung cancer shows substantial genetic and phenotypic heterogeneity across individuals, driving a need for personalised medicine. Here, we report lung cancer organoids and normal bronchial organoids established from patient tissues comprising five histological subtypes of lung cancer and non-neoplastic bronchial mucosa as in vitro models representing individual patient. The lung cancer organoids recapitulate the tissue architecture of the primary lung tumours and maintain the genomic alterations of the original tumours during long-term expansion in vitro. The normal bronchial organoids maintain cellular components of normal bronchial mucosa. Lung cancer organoids respond to drugs based on their genomic alterations: a BRCA2-mutant organoid to olaparib, an EGFR-mutant organoid to erlotinib, and an EGFR-mutant/MET-amplified organoid to crizotinib. Considering the short length of time from organoid establishment to drug testing, our newly developed model may prove useful for predicting patient-specific drug responses through in vitro patient-specific drug trials. The clinical efficacy of standard therapy in lung cancer is limited by high level of heterogeneity. Here, the authors report patient-derived lung cancer organoids from different histological subtypes and show them to faithfully recapitulate the histology, genomics, and drug responses of the primary lung tumours.

Platelet-rich plasma (PRP) is prepared by centrifuging fresh blood in an anticoagulant state, and harvesting the platelet-rich portion or condensing platelets. Studies have consistently demonstrated that PRP concentrates are an abundant source of growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), and epithelial growth factor (EGF). The complex mechanisms underlying spinal cord injury (SCI) diminish intrinsic repair and neuronal regeneration. Several studies have suggested that growth factor-promoted axonal regeneration can occur for an extended period after injury. More importantly, the delivery of exogenous growth factors contained in PRP, such as EGF, IGF-1, and TGF-β, has neurotrophic effects on central nervous system (CNS) injuries and neurodegenerative diseases. However, only a few studies have investigated the effects of PRP on CNS injuries or neurodegenerative diseases. According to our review of relevant literature, no study has investigated the effect of intrathecal (i.t.) PRP injection into the injured spinal cord and activation of intrinsic mechanisms. In the present study, we directly injected i.t. PRP into rat spinal cords and examined the effects of PRP on normal and injured spinal cords. In rats with normal spinal cords, PRP induced microglia and astrocyte activation and PDGF-B and ICAM-1 expression. In rats with SCIs, i.t. PRP enhanced the locomotor recovery and spared white matter, promoted angiogenesis and neuronal regeneration, and modulated blood vessel size. Furthermore, a sustained treatment (a bolus of PRP followed by a 1/3 dose of initial PRP concentration) exerted more favorable therapeutic effects than a single dose of PRP. Our findings suggest by i.t. PRP stimulate angiogenesis, enhancing neuronal regeneration after SCI in rats. Although PRP induces minor inflammation in normal and injured spinal cords, it has many advantages. It is an autologous, biocompatible, nontoxic material that does not result in a major immune response. In addition, based on its safety and ease of preparation, we hypothesize that PRP is a promising therapeutic agent for SCI.

Aaptamine, a natural marine compound isolated from the sea sponge, has various biological activities, including delta-opioid agonist properties. However, the effects of aaptamine in neuropathic pain remain unclear. In the present study, we used a chronic constriction injury (CCI)-induced peripheral neuropathic rat model to explore the analgesic effects of intrathecal aaptamine administration. We also investigated cellular angiogenesis and lactate dehydrogenase A (LDHA) expression in the ipsilateral lumbar spinal cord after aaptamine administration in CCI rats by immunohistofluorescence. The results showed that aaptamine alleviates CCI-induced nociceptive sensitization, allodynia, and hyperalgesia. Moreover, aaptamine significantly downregulated CCI-induced vascular endothelial growth factor (VEGF), cluster of differentiation 31 (CD31), and LDHA expression in the spinal cord. Double immunofluorescent staining showed that the spinal VEGF and LDHA majorly expressed on astrocytes and neurons, respectively, in CCI rats and inhibited by aaptamine. Collectively, our results indicate aaptamine’s potential as an analgesic agent for neuropathic pain. Furthermore, inhibition of astrocyte-derived angiogenesis and neuronal LDHA expression might be beneficial in neuropathy.

A suitable small animal model may help in the screening and evaluation of new drugs, especially those from natural products, which can be administered at lower dosages, fulfilling an urgent worldwide need. In this study, we explore whether zebrafish could be a model organism for carrageenan-induced abdominal edema. The research results showed that intraperitoneal (i.p.) administration of 1.5% λ-carrageenan in a volume of 20 µL significantly increased abdominal edema in adult zebrafish. Levels of the proinflammatory proteins tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) were increased in carrageenan-injected adult zebrafish during the development of abdominal edema. An associated enhancement was also observed in the leukocyte marker, myeloperoxidase (MPO). To support these results, we further observed that i.p. methylprednisolone (MP; 1 µg), a positive control, significantly inhibited carrageenan-induced inflammation 24 h after carrageenan administration. Furthermore, i.p. pretreatment with either an anti-TNF-α antibody (1∶5 dilution in a volume of 20 µL) or the iNOS-selective inhibitor aminoguanidine (AG; 1 µg) inhibited carrageenan-induced abdominal edema in adult zebrafish. This new animal model is uncomplicated, easy to develop, and involves a straightforward inducement of inflammatory edema for the evaluation of small volumes of drugs or test compounds.

This study aimed to compare the analgesic effects of anesthesiologist-administrated erector spinae plane block (ESPB) and surgeon-administrated intercostal nerve block (ICNB) following video-assisted thoracoscopic surgery (VATS). Randomized, controlled, double-blinded study. Operating room, postoperative recovery room and ward in two centers. One hundred patients, ASA I-III and scheduled for elective VATS. The anesthesiologist-administrated ESPB under ultrasound guidance or surgeon-administrated ICNB under video-assisted thoracoscopy was randomly provided during VATS. Regular oral non-opioid analgesic combined with intravenous rescue morphine were prescribed for multimodal analgesia after surgery. The primary outcomes were the pain score and morphine consumption during 48 h after surgery. Postoperative pain intensity were assessed using the 10-cm visual analogue scale at 1 h, 24 h, and 48 h after surgery. Morphine consumption at these time points was compared between the two study groups. Furthermore, oral weak opioid rescue analgesic was also provided at 24 h after surgery. Postoperative quality of recovery at 24 h was also assessed using the QoR-15 questionnaire, along with duration of chest tube drainage and hospital stay were compared as secondary outcomes. Patients in the two study groups had comparable baseline characteristics, and surgical types were also similar. Postoperative VAS changes at 1 h, 24 h, and 48 h after surgery were also comparable between the two study groups. Both groups had low median scores (<4.0) at all time points (all p > 0.05). Patients in the ESPB group required statistically non-significant higher 48-h morphine consumption [3 (0–6) vs. 0 (0–6) mg in the ESPB group and ICNB group respectively; p = 0.135] and lower numbers of oral rescue analgesic (0.4 ± 1.2 vs. 1.0 ± 1.8 in the ESPB group and ICNB group respectively; p = 0.059). Additionally, patients in the two study groups had similar QoR15 scores and lengths of hospital stay. Both anesthesiologist-administered ultrasound-guided ESPB and surgeon-administered VATS ICNB were effective analgesic techniques for patients undergoing VATS for tumor resection. [Display omitted] •Patients having video-assisted thoracoscopic surgeries (VATS) report moderate to severe pain.•Accessible regional analgesia is important in VATS for pain management.•Surgeon administered ICNB is an alternative option compared to anesthesiologist administered ESPB.•Both ESPB and ICNB can result in good pain control with similar opioid consumption after VATS.

The genetic basis of most traits is highly polygenic and dominated by non-coding alleles. It is widely assumed that such alleles exert small regulatory effects on the expression of cis -linked genes. However, despite the availability of gene expression and epigenomic datasets, few variant-to-gene links have emerged. It is unclear whether these sparse results are due to limitations in available data and methods, or to deficiencies in the underlying assumed model. To better distinguish between these possibilities, we identified 220 gene–trait pairs in which protein-coding variants influence a complex trait or its Mendelian cognate. Despite the presence of expression quantitative trait loci near most GWAS associations, by applying a gene-based approach we found limited evidence that the baseline expression of trait-related genes explains GWAS associations, whether using colocalization methods (8% of genes implicated), transcription-wide association (2% of genes implicated), or a combination of regulatory annotations and distance (4% of genes implicated). These results contradict the hypothesis that most complex trait-associated variants coincide with homeostatic expression QTLs, suggesting that better models are needed. The field must confront this deficit and pursue this ‘missing regulation.’

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in NOTCH3, is the most common cause of hereditary cerebral small vessel disease. Whether it will involve systemic vasculopathy such as retinal vessel remains unknown. Optical coherence tomography angiography (OCT-A) is a noninvasive technique for visualising retinal blood flow. We analysed vessel density and retinal thickness in patients with CADASIL and investigated their correlations with disease severity. This prospective study enrolled 35 patients with CADASIL (59 eyes) and 35 healthy controls (54 eyes). OCT-A was used to measure the vessel density of the macular region and the thickness of retinal layers. Patients with CADASIL were divided into stroke (n = 20) and nonstroke (n = 15) subgroups and underwent cognition and gait speed evaluation. Neuroimaging markers of cortical thickness, white matter hyperintensity, lacunae, and cerebral microbleeds were examined through brain magnetic resonance imaging. The OCT-A parameters, including vessel density, were comparable between the patients with CADASIL and the controls. In patients with CADASIL, vessel density in the superficial retinal plexus in the macula as was inner retinal thickness was significantly lower in the stroke than the nonstroke subgroup. Macular vessel density and inner retinal thickness were positively correlated with gait speed, while negatively correlated with number of lacunae. OCT-A is potentially a useful tool for evaluating disease severity, ischaemic burden, and neurodegeneration in patients with advanced CADASIL.

Prodigiosin, a secondary metabolite isolated from marine Vibrio sp., has antimicrobial and anticancer properties. This study investigated the cell death mechanism of prodigiosin in glioblastoma. Glioblastoma multiforme (GBM) is an aggressive primary cancer of the central nervous system. Despite treatment, or standard therapy, the median survival of glioblastoma patients is about 14.6 month. The results of the present study clearly showed that prodigiosin significantly reduced the cell viability and neurosphere formation ability of U87MG and GBM8401 human glioblastoma cell lines. Moreover, prodigiosin with fluorescence signals was detected in the endoplasmic reticulum and found to induce excessive levels of autophagy. These findings were confirmed by observation of LC3 puncta formation and acridine orange staining. Furthermore, prodigiosin caused cell death by activating the JNK pathway and decreasing the AKT/mTOR pathway in glioblastoma cells. Moreover, we found that the autophagy inhibitor 3-methyladenine reversed prodigiosin induced autophagic cell death. These findings of this study suggest that prodigiosin induces autophagic cell death and apoptosis in glioblastoma cells.

Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, and in vitro cellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions.