Corylifol A suppresses osteoclastogenesis and alleviates ovariectomy-induced bone loss via attenuating ROS production and impairing mitochondrial function.

Osteoporosis is a systemic disease characterized by an imbalance in bone homeostasis, where osteoblasts fail to fully compensate for the bone resorption induced by osteoclasts. Corylifol A, a flavonoid extracted from Fructus psoraleae, has been identified as a potential treatment for this condition. Predictions from network pharmacology and molecular docking studies suggest that Corylifol A exhibits strong binding affinity with NFATc1, Nrf2, PI3K, and AKT1. Empirical evidence from in vivo experiments indicates that Corylifol A significantly mitigates systemic bone loss induced by ovariectomy by suppressing both the generation and activation of osteoclasts. In vitro studies further showed that Corylifol A inhibited the activation of PI3K-AKT and MAPK pathways and calcium channels induced by RANKL in a time gradient manner, and specifically inhibited the phosphorylation of PI3K, AKT, GSK3 ß, ERK, CaMKII, CaMKIV, and Calmodulin. It also diminishes ROS production through Nrf2 activation, leading to a decrease in the expression of key regulators such as NFATcl, C-Fos, Acp5, Mmp9, and CTSK that are involved in osteoclastogenesis. Notably, our RNA-seq analysis suggests that Corylifol A primarily impacts mitochondrial energy metabolism by suppressing oxidative phosphorylation. Collectively, these findings demonstrate that Corylifol A is a novel inhibitor of osteoclastogenesis, offering potential therapeutic applications for diseases associated with excessive bone resorption.

Appraising the causal relationship between thyroid function and rheumatoid arthritis: a two-sample bidirectional Mendelian randomization study.

Background: Hypothyroidism and hyperthyroidism are observationally associated with rheumatoid arthritis (RA), but causality is unclear. To evaluate the causal relationship between thyroid function and RA, we conducted a two-Sample bidirectional Mendelian Randomization (MR) study. Methods: Single nucleotide polymorphisms associated with six phenotypes were selected from the FinnGen biobank database, The ThyroidOmics Consortium database, and the IEU Open GWAS database. For the forward MR analysis, we selected hypothyroidism (N=213,390), Graves' disease (GD) (N=199,034), other types of hyperthyroidism (N=190,799), free thyroxine (FT4, N=49,269), and thyroid-stimulating hormone (TSH, N=54,288) as the five related thyroid function phenotypes for exposure, with RA (N=58,284) as the outcome. Reverse MR analysis selected RA as the exposure and five phenotypes of thyroid function as the outcome. The Inverse variance weighting (IVW) method was used as the primary analysis method, supplemented by weighted median (WM) and MR-Egger methods. Cochran's Q test, MR-PRESSO, MR-Egger regression methods, and leave-one-out analysis were employed to assess sensitivity and pleiotropy. Results: Forward MR evidence indicates that genetic susceptibility to hypothyroidism is associated with an increased risk of RA (ORIvw=1.758, P=7.61×10-5). Reverse MR evidence suggests that genetic susceptibility to RA is associated with an increased risk of hypothyroidism (ORIvw=1.274, P=3.88×10-20), GD (ORIvw=1.269, P=8.15×10-05), and other types of hyperthyroidism (ORIvw=1.141, P=1.80×10-03). There is no evidence to support a forward or reverse causal relationship between genetic susceptibility to RA and FT4, TSH. Conclusion: Our results provide genetic evidence supporting bidirectional causal relationships between thyroid function and RA. These findings inform preventive strategies and interventions targeting RA and thyroid dysfunction.

Evaluation of Prebiotic Activity of Stellariae Radix Polysaccharides and Its Effects on Gut Microbiota.

This study aims to evaluate the prebiotic potential of polysaccharides derived from Stellariae Radix (SRPs) and explore their influence on the gut microbiota composition in mice. Lactobacillus acidophilus and Bifidobacterium longum were cultivated in an MRS medium, while their growth kinetics, clumping behavior, sugar utilization, pH variation, growth density, and probiotic index were meticulously monitored. Additionally, the impact of crude Stellariae Radix polysaccharides (CSRP) on the richness and diversity of gut microbiota in mice was assessed via 16S rDNA sequencing. The results demonstrated the remarkable ability of CSRPs to stimulate the proliferation of Lactobacillus acidophilus and Bifidobacterium longum. Moreover, the oral administration of CSRPs to mice led to a noticeable increase in beneficial bacterial populations and a concurrent decrease in detrimental bacterial populations within the intestinal flora. These findings provided an initial validation of CSRPs as a promising agent in maintaining the equilibrium of gut microbiota in mice, thereby offering a substantial theoretical foundation for developing Stellariae Radix as a prebiotic ingredient in various applications, including food, healthcare products, and animal feed. Furthermore, this study presented novel insights for the exploration and utilization of Stellariae Radix resources.

Appraising causal risk and protective factors for rheumatoid arthritis.

Aims: Mendelian randomization (MR) is considered to overcome the bias of observational studies, but there is no current meta-analysis of MR studies on rheumatoid arthritis (RA). The purpose of this study was to summarize the relationship between potential pathogenic factors and RA risk based on existing MR studies. Methods: PubMed, Web of Science, and Embase were searched for MR studies on influencing factors in relation to RA up to October 2022. Meta-analyses of MR studies assessing correlations between various potential pathogenic factors and RA were conducted. Random-effect and fixed-effect models were used to synthesize the odds ratios of various pathogenic factors and RA. The quality of the study was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization (STROBE-MR) guidelines. Results: A total of 517 potentially relevant articles were screened, 35 studies were included in the systematic review, and 19 studies were eligible to be included in the meta-analysis. Pooled estimates of 19 included studies (causality between 15 different risk factors and RA) revealed that obesity, smoking, coffee intake, lower education attainment, and Graves' disease (GD) were related to the increased risk of RA. In contrast, the causality contribution from serum mineral levels (calcium, iron, copper, zinc, magnesium, selenium), alcohol intake, and chronic periodontitis to RA is not significant. Conclusion: Obesity, smoking, education attainment, and GD have real causal effects on the occurrence and development of RA. These results may provide insights into the genetic susceptibility and potential biological pathways of RA.

SLC38A5 aggravates DC-mediated psoriasiform skin inflammation via potentiating lysosomal acidification.

Amino acid (aa) metabolism is closely correlated with the pathogenesis of psoriasis; however, details on aa transportation during this process are barely known. Here, we find that SLC38A5, a sodium-dependent neutral aa transporter that counter-transports protons, is markedly upregulated in the psoriatic skin of both human patients and mouse models. SLC38A5 deficiency significantly ameliorates the pathogenesis of psoriasis, indicating a pathogenic role of SLC38A5. Surprisingly, SLC38A5 is almost exclusively expressed in dendritic cells (DCs) when analyzing the psoriatic lesion and mainly locates on the lysosome. Mechanistically, SLC38A5 potentiates lysosomal acidification, which dictates the cleavage and activation of TLR7 with ensuing production of pro-inflammatory cytokines such as interleukin-23 (IL-23) and IL-1ß from DCs and eventually aggravates psoriatic inflammation. In summary, this work uncovers an auxiliary mechanism in driving lysosomal acidification, provides inspiring insights for DC biology and psoriasis etiology, and reveals SLC38A5 as a promising therapeutic target for treating psoriasis.

Use of network pharmacology and molecular docking to explore the mechanism of action of curcuma in the treatment of osteosarcoma.

Curcuma has been used as an adjuvant treatment for osteosarcoma (OS) due to its anticancer compounds. However, the underlying mechanism remains unclear. Therefore, this study aimed to explore the mechanism of action of curcuma in the treatment of OS using network pharmacology and molecular docking. In this study, anticancer compounds were obtained from relevant literature, and curcuma-related targets and OS treatment targets were obtained from public databases. Protein‒protein interaction networks were constructed to screen out the hub genes using the STRING database and Cytoscape software. Cluster analysis of the protein modules was then performed using the Cytoscape MCODE plugin. Furthermore, Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed for common targets among curcuma targets and OS-related targets using the DAVID database. Finally, molecular docking was performed, and the results were verified by Auto dock Tool and PyMOL software. Our research identified 11 potential active compounds, 141 potential therapeutic targets and 14 hub genes for curcuma. AKT1, TNF, STAT3, EGFR, and HSP90AA1 were the key targets closely related to the PI3K/Akt signaling pathways, HIF-1 signaling pathways, ErbB signaling pathways, and FOXO signaling pathways, which are involved in angiogenesis, cancer cell proliferation, metastasis, invasion, and chemotherapy resistance in the microenvironment of OS. Molecular docking suggested that the core compound had a strong affinity for key targets, with a binding energy of less than - 5 kJ/mol. The study showed that curcuma-mediated treatment of OS was a complex process involving multiple compounds, targets, and pathways. This study will enhance the understanding of how curcuma affects the proliferation and invasion of OS cells and reveal the potential molecular mechanism underlying the effect of curcuma on OS lung metastasis and chemotherapy resistance.

The Impact of Growth Years on the Medicinal Material Characteristics and Metabolites of Stellaria dichotoma L. var. lanceolata Bge. Reveals the Optimal Harvest Age.

The original plant of Chinese medicine Stellariae Radix (Yin Chai Hu) is Stellaria dichotoma L. var. lanceolata Bge (abbreviated as SDL). SDL is a perennial herbaceous plant and a characteristic crop in Ningxia. Growth years are vital factors that affect the quality of perennial medicinal materials. This study aims to investigate the impact of growth years on SDL and screen for the optimal harvest age by comparing the medicinal material characteristics of SDL with different growth years. Additionally, metabolomics analysis using UHPLC-Q-TOF MS was employed to investigate the impact of growth years on the accumulation of metabolites in SDL. The results show that the characteristics of medicinal materials and the drying rate of SDL gradually increase with the increase in growth years. The fastest development period of SDL occurred during the first 3 years, after which the development slowed down. Medicinal materials characteristics of 3-year-old SDL exhibited mature qualities with a high drying rate, methanol extract content, and the highest content of total sterols and total flavonoids. A total of 1586 metabolites were identified, which were classified into 13 major classes with more than 50 sub-classes. Multivariate statistical analysis indicated significant differences in the diversity of metabolites of SDL in different growth years, with greater differences observed in metabolites as the growth years increased. Moreover, different highly expressed metabolites in SDL at different growth years were observed: 1-2 years old was beneficial to the accumulation of more lipids, while 3-5 years old was conducive to accumulating more alkaloids, benzenoids, etc. Furthermore, 12 metabolites accumulating with growth years and 20 metabolites decreasing with growth years were screened, and 17 significantly different metabolites were noted in 3-year-old SDL. In conclusion, growth years not only influenced medicinal material characteristics, drying rate, content of methanol extract, and total sterol and flavonoid contents, but also had a considerable effect on SDL metabolites and metabolic pathways. SDL planted for 3 years presented the optimum harvest time. The screened significantly different metabolites with biological activity, such as rutin, cucurbitacin e, isorhamnetin-3-o-glucoside, etc., can be utilized as potential quality markers of SDL. This research provides references for studying the growth and development of SDL medicinal materials, the accumulation of metabolites, and the selection of optimal harvest time.

[Advances in surgical strategies for ossification of posterior longitudinal ligament involving the C 2 segment].

Objective: To evaluate the application of surgical strategies for the treatment of cervical ossification of the posterior longitudinal ligament (OPLL) involving the C 2 segment. Methods: The literature about the surgery for cervical OPLL involving C 2 segment was reviewed, and the indications, advantages, and disadvantages of surgery were summarized. Results: For cervical OPLL involving the C 2 segments, laminectomy is suitable for patients with OPLL involving multiple segments, often combined with screw fixation, and has the advantages of adequate decompression and restoration of cervical curvature, with the disadvantages of loss of cervical fixed segmental mobility. Canal-expansive laminoplasty is suitable for patients with positive K-line and has the advantages of simple operation and preservation of cervical segmental mobility, and the disadvantages include progression of ossification, axial symptoms, and fracture of the portal axis. Dome-like laminoplasty is suitable for patients without kyphosis/cervical instability and with negative R-line, and can reduce the occurrence of axial symptoms, with the disadvantage of limited decompression. The Shelter technique is suitable for patients with single/double segments and canal encroachment >50% and allows for direct decompression, but is technically demanding and involves risk of dural tear and nerve injury. Double-dome laminoplasty is suitable for patients without kyphosis/cervical instability. Its advantages are the reduction of damage to the cervical semispinal muscles and attachment points and maintenance of cervical curvature, but there is progress in postoperative ossification. Conclusion: OPLL involving the C 2 segment is a complex subtype of cervical OPLL, which is mainly treated through posterior surgery. However, the degree of spinal cord floatation is limited, and with the progress of ossification, the long-term effectiveness is poor. More research is needed to address the etiology of OPLL and to establish a systematic treatment strategy for cervical OPLL involving the C 2 segment.

The metabolic score of insulin resistance is positively correlated with bone mineral density in postmenopausal patients with type 2 diabetes mellitus.

The prevalence of type 2 diabetes mellitus (T2DM) complicated with osteoporosis (OP) is increasing yearly. Early prevention, detection and treatment of OP are important in postmenopausal patients with T2DM. This study aimed to explore the correlation between insulin resistance and bone mineral density (BMD), and OP in postmenopausal patients with T2DM. In this study, postmenopausal patients with T2DM who visited our hospital from January 2021 to March 2022 were divided into the OP group (n = 91) and non-OP group (n = 119) according to whether they were complicated with OP or not. The general data of patients, BMD, blood routine, glucose metabolism, lipid metabolism, liver and kidney function indexes were collected, and the homeostatic model assessment for IR (HOMA-IR), the triglyceride-glucose (TyG) index and the metabolic score for IR (METS-IR) were calculated. A weighted multivariate linear regression model assessed the correlation between insulin resistance (IR) related indexes and lumbar spine, femoral neck, and hip BMD. A weighted logistic regression model assessed the odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between the IR-related indexes and OP risk. The nonlinear relationship was also evaluated by smooth curve fitting (SCF) and a weighted generalized additive model (GAM). Moreover, the Receiver-operating characteristics (ROC) curve was used to analyze the predictive efficiency of METS-IR in postmenopausal patients with T2DM with OP. HOMA-IR, TyG, and METS-IR in the OP group were lower than those in the non-OP group (all P < 0.05). Weighted multiple linear regression after adjusting covariates showed that METS-IR was positively correlated with the lumbar spine, femoral neck, and hip BMD (ßMETS-IR = 0.006,0.005,0.005, all P < 0.001). The results of weighted Logistic regression and GAM showed that when METS-IR < 44.5, each unit of increased METS-IR value was associated with a decreased OP risk of 12% (P = 0.002). When METS-IR ≥ 44.5, there was no significant correlation between METS-IR and the risk of OP (OR = 1.00, P = 0.934). Similar trends were not observed in HOMA-IR and TyG. The ROC suggested helpful discriminative power of the METS-IR index for T2DM. We confirmed that METS-IR, as a novel alternative marker of IR, had a positive association with BMD in postmenopausal patients with T2DM, and METS-IR was a protective factor for OP in a specific range.

Isoimperatorin attenuates bone loss by inhibiting the binding of RANKL to RANK.

Osteoporosis, an immune disease characterized by bone mass loss and microstructure destruction, is often seen in postmenopausal women. Isoimperatorin (ISO), a bioactive, natural furanocoumarin isolated from many traditional Chinese herbal medicines, has therapeutic effects against various diseases; however, its effect on bone homeostasis remains unclear. In this study, we investigated the effect of ISO on the differentiation and activation of osteoclast and its molecular mechanism in vitro, and evaluated the effect of ISO on bone metabolism by ovariectomized (OVX) rat model. In vitro experiments showed that ISO affected RANKL-induced MAPK, NFAT, NFATc1 trafficking and expression, osteoclast F-actin banding, osteoclast-characteristic gene expression, ROS inhibitory activity, and calcium oscillations, NF-κB signaling pathway. In vivo experiments showed that oral administration of ISO effectively reduced bone loss caused by ovariectomy and retained bone mass.Collectively, ISO inhibits RANK/RANKL binding, thereby reducing the activity of NFATc1, calcium, and ROS and inhibiting osteoclast generation. In addition, ISO protects bone mass by slowing osteoclast production and downregulating NFATc1 gene and protein expression in the bone tissue microenvironment and inhibits OVX-induced bone loss in vivo.

Metabolomic Analysis Reveals the Metabolic Diversity of Wild and Cultivated Stellaria Radix (Stellaria dichotoma L. var. lanceolata Bge.).

Stellaria Radix, called Yinchaihu in Chinese, is a traditional Chinese medicine, which is obtained from the dried roots of Stellaria dichotoma L. var. lanceolata Bge. Cultivated yinchaihu (YCH) has become a main source of production to alleviate the shortage of wild plant resources, but it is not clear whether the metabolites of YCH change with the mode of production. In this study, the contents of methanol extracts, total sterols and total flavonoids in wild and cultivated YCH are compared. The metabolites were analyzed by ultra-high performance liquid chromatography-tandem time-of-flight mass spectrometry. The content of methanol extracts of the wild and cultivated YCH all exceeded the standard content of the Chinese Pharmacopoeia. However, the contents of total sterols and total flavonoids in the wild YCH were significantly higher than those in the cultivated YCH. In total, 1586 metabolites were identified by mass spectrometry, and 97 were significantly different between the wild and cultivated sources, including ß-sitosterol, quercetin derivatives as well as many newly discovered potential active components, such as trigonelline, arctiin and loganic acid. The results confirm that there is a rich diversity of metabolites in the wild and cultivated YCH, and provide a useful theoretical guidance for the evaluation of quality in the production of YCH.

Isoliensinine suppresses bone loss by targeted inhibition of RANKL-RANK binding.

BACKGROUND: Osteoporosis, a systemic metabolic bone disease, is often caused by the disruption of dynamic equilibrium between osteoclasts and osteoblasts. Overactive bone resorption, in which osteoclasts play a major role, is one of the most common and major causes of osteoporosis. Less costly and more effective drug treatments for this disease are needed. Based on the combination of molecular docking techniques and in vitro cell assays, this study aimed to explore the mechanism by which Isoliensinine (ILS) protects the bone loss by inhibiting osteoclast differentiation. METHODS: A virtual docking model based on molecular docking technology was used to investigate the interactions between ILS and the Receptor Activator of Nuclear Kappa-B (RANK)/Receptor Activator of Nuclear Kappa-B Ligand (RANKL).In this study, we determined the effective dose of action of ILS to inhibit osteoclast differentiation in vitro and, using bone resorption experiments, RT-CPR and Western Blot investigated the effects of ILS on bone resorption function and normal expression of osteoclast-associated genes and proteins, and validated potential mechanistic pathways. In vivo experiments revealed that ILS could inhibit bone loss through Micro-CT results. Finally, the molecular interaction between ILS and RANK/RANKL was investigated using biomolecular interaction experiments to verify the correctness and accuracy of the computational results. RESULTS: ILS binds to RANK and RANKL proteins, respectively, through virtual molecular docking. The Surface Plasmon Resonance (SPR) experiment results revealed that phosphorylated JNK, ERK, P38, and P65 expression was significantly downregulated when ILS were targeted to inhibit RANKL/RANK binding. At the same time, the expression of IKB-a was significantly increased under the stimulation of ILS, which rescued the degradation of IKB-a. ILS can significantly inhibit the levels of Reactive Oxygen Species (ROS) and Ca2 + concentration in vitro. Finally, the results of Micro-CT showed that ILS can significantly inhibit bone loss in vivo, indicating that ILS has a potential role in the treatment of osteoporosis. CONCLUSION: ILS inhibits osteoclast differentiation and bone loss by preventing the normal binding of RANKL/RANK, affecting downstream signaling pathways, including MAPK.NF-KB, ROS, Ca2+, genes, and proteins.

GPX4 aggravates experimental autoimmune encephalomyelitis by inhibiting the functions of CD4+ T cells.

Multiple sclerosis (MS) is a common autoimmunity disease of the central nervous system (CNS) that mostly happens in young adults. The chronic clinical features of MS include inflammatory demyelination, infiltration of immune cells, and secretion of inflammatory cytokines, which have been proved to be associated with CD4+ T cells. Ferroptosis is a newly discovered programmed cell death mediated by the massive lipid peroxidation and more sensitive to CD4+ T cells. However, the effect of ferroptosis of CD4+ T cells on the occurrence and progression of MS retains unclear. Here, the experimental autoimmune encephalomyelitis (EAE) model was used to investigate the role of GPX4, a leading inhibitor of ferroptosis, which plays in the function of CD4+ T cells. Our results showed that GPX4 was highly expressed in CD4+ T cells of MS patients based on existing databases. Strikingly, conditional knockout of GPX4 in CD4cre mice (cKO mice) significantly alleviated the average symptom scores and immunopathology of EAE. The infiltration of immune cells, including CD4+ T and CD8+ T cells, and the generation of GM-CSF, TNF-α, and IL-17A, were remarkably reduced in the CNS from cKO mice compared with WT mice. These findings further revealed the vital role of GPX4 in the expansion and function of CD4+ T cells. Moreover, GPX4-deficient CD4+ T cells were susceptible to ferroptosis in EAE model. Overall, this study provided novel insights into therapeutic strategies targeting GPX4 in CD4+ T cells for inhibiting CNS inflammation and treating MS.

Safety and durability of AGT103-T autologous T cell therapy for HIV infection in a Phase 1 trial.

The cell and gene therapy product AGT103-T was designed to restore the Gag-specific CD4+ T cell response in persons with chronic HIV disease who are receiving antiretroviral therapy. This autologous, genetically engineered cell product is under investigation in a Phase 1 clinical trial (NCT03215004). Trial participants were conditioned with cyclophosphamide approximately 1 week before receiving a one-time low (< 109 genetically modified CD4+ T cells) or high (≥109 genetically modified CD4+ T cells) dose of AGT103-T, delivering between 2 and 21 million genetically modified cells per kilogram (kg) body weight. There were no serious adverse events (SAEs) and all adverse events (AEs) were mild. Genetically modified AGT103-T cells were detected in most of the participant blood samples collected 6 months after infusion, which was the last scheduled monitoring visit. Peripheral blood mononuclear cells (PBMC) collected after cell product infusion were tested to determine the abundance of Gag-specific T cells as a measure of objective responses to therapy. Gag-specific CD4+ T cells were detected in all treated individuals and were substantially increased by 9 to 300-fold compared to baseline, by 14 days after cell product infusion. Gag-specific CD8+ T cells were increased by 1.7 to 10-fold relative to baseline, by 28 days after cell product infusion. Levels of Gag-specific CD4+ T cells remained high (~2 to 70-fold higher relative to baseline) throughout 3-6 months after infusion. AGT103-T at low or high doses was safe and effective for improving host T cell immunity to HIV. Further studies, including antiretroviral treatment interruption, are warranted to evaluate the product's efficacy in HIV disease. Clinical trial registration: www.clinicaltrials.gov, identifier: NCT03215004.

Comparative metabolomics provides novel insights into correlation between dominant habitat factors and constituents of Stellaria Radix (Stellaria dichotoma L. var. lanceolata Bge.).

Stellaria dichotoma L. var. lanceolata Bge. (SDL) is the original plant of the traditional Chinese medicine Yinchaihu (Stellaria Radix). It is mainly distributed in the arid desert areas of northwest China, which is the genuine medicinal material and characteristic cultivated crop in Ningxia. This study aims to analyze the effects of different origins on SDL metabolites and quality, as well as to screen the dominant habitat factors affecting SDL in different origins. In this study, metabolites of SDL from nine different production areas were analyzed by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF MS) based metabolomics. And field investigations were conducted to record thirteen habitat-related indicators. Results showed that 1586 metabolites were identified in different origins, which were classified as thirteen categories including lipids, organic acids and organic heterocyclic compounds derivatives. Multivariate statistical analysis showed that the metabonomic spectra of SDL from different origins had various characteristics. What's more, co-expression network correlation analysis revealed that three metabolites modules (MEturquoise, MEbrown and MEblue) were more closely with the habitat factors and 104 hub metabolites were further screened out as the habitat-induced metabolite indicators. Besides, soil texture, soil pH value and soil total salt content were found as the dominant habitat factors which affect SDL metabolites. In conclusion, the study showed different habitat factors had various effects on SDL's quality and established relationship between them, which provide reference for revealing SDL's genuineness formation mechanism and guiding industrial crops practical production by habitat factors selection.

Reducing farnesyl diphosphate synthase levels activates Vγ9Vδ2 T cells and improves tumor suppression in murine xenograft cancer models.

Human Vγ9Vδ2 T cells are attractive candidates for cancer immunotherapy due to their potent capacity for tumor recognition and cytolysis of many tumor cell types. However, efforts to deploy clinical strategies for Vγ9Vδ2 T cell cancer therapy are hampered by insufficient potency. We are pursuing an alternate strategy of modifying tumors to increase the capacity for Vγ9Vδ2 T cell activation, as a means for strengthening the anti-tumor response by resident or ex vivo manufactured Vγ9Vδ2 T cells. Vγ9Vδ2 T cells are activated in vitro by non-peptidic antigens including isopentenyl pyrophosphate (IPP), a substrate of farnesyl diphosphate synthase (FDPS) in the pathway for biosynthesis of isoprenoids. In an effort to improve in vivo potency of Vγ9Vδ2 T cells, we reduced FDPS expression in tumor cells using a lentivirus vector encoding a short-hairpin RNA that targets FDPS mRNA (LV-shFDPS). Prostate (PC3) or hepatocellular carcinoma (Huh-7) cells transduced with LV-shFDPS induced Vγ9Vδ2 T cell stimulation in vitro, resulting in increased cytokine expression and tumor cell cytotoxicity. Immune deficient mice implanted with LV-shFDPS transduced tumor cells showed dramatic responses to intraperitoneal injection of Vγ9Vδ2 T cells with strong suppression of tumor growth. In vivo potency was increased by transducing tumor cells with a vector expressing both shFDPS and human IL-2. Tumor suppression by Vγ9Vδ2 T cells was dose-dependent with greater effects observed in mice injected with 100% LV-shFDPS transduced cells compared to mice injected with a mixture of 50% LV-shFDPS transduced cells and 50% control (no vector) tumor cells. Delivery of LV-shFDPS by intratumoral injection was insufficient to knockdown FDPS in the majority of tumor cells, resulting in insignificant tumor suppression by Vγ9Vδ2 T cells. Thus, Vγ9Vδ2 T cells efficiently targeted and suppressed tumors expressing shFDPS in mouse xenotransplant models. This proof-of-concept study demonstrates the potential for suppression of genetically modified tumors by human Vγ9Vδ2 T cells and indicates that co-expression of cytokines may boost the anti-tumor effect.

An innovative three-layer strategy in response to a quartan malaria outbreak among forest goers in Hainan Island, China: a retrospective study.

BACKGROUND: An outbreak of Plasmodium malariae infection among forest goers in Sanya City of Hainan Island, China was reported in 2015. In response to this outbreak, an innovative three-layer strategy (TLS) targeted forest goers was adapted based on the 1-3-7 approach. MAIN TEXT: Key elements of TLS are: (i) The village with five malaria cases and adjacent villages were set as the first layer. All residents including forest goers were taken as the high-risk population (HRP). Active case detection (ACD) by blood smear microscopy and PCR was selected as the primary measure, and passive case detection (PCD) as complementary measure. One case was identified under TLS implementation. (ii) The township with cases (Gaofeng Town) and the nearby towns were chosen as the second layer. Only forest goers were screened by ACD, while PCD as a routine screening method. 7831 blood smears collected by ACD and PCD and tested with negative results. (iii) The city with cases (Sanya City) and others 12 counties/county-level cities were selected as the third layer. Malaria cases were monitored passively. A total of 77,555 blood slides were screened by PCD with zero positive sample. For each layer, the malaria vector mosquitoes were monitored using light traps, cattle-baited/human-bait traps. Anopheles minimus (dominant species), An. sinensis and An. dirus were captured. Vector control measures mainly include insecticide residual spraying and long-lasting insecticide nets. The capacity of clinicians, public health practitioners and laboratory technicians has been improved through training. During 2016‒2018, TLS and chemoprophylaxis were implemented in the same areas. In the first layer, all residents were monitored by ACD, and malaria chemoprophylaxis were distributed, 89.5% of forest goers were using chemoprophylaxis against malaria. The blood smears (3126 by ACD plus 1516 by PCD) were with zero positive results. Chemoprophylaxis and ACD were offered to forest goers once a year, and PCD in residents as a complementary measure in the second and third layer, 77.8% and 95.1% of forest goers received chemoprophylaxis. In each layer, vector surveillance and control of malaria and trainings for medical staff were still in place. CONCLUSIONS: TLS was effective in blocking the outbreak by P. malariae among forest goers in Hainan in malaria elimination stage. However, whether it could prevent the malaria resurgence in the post-elimination phase needs to be further assessed.

Evaluation of abdominal compression-decompression combined with chest compression CPR performed by a new device: Is the prognosis improved after this combination CPR technique?

INTRODUCTION: This study was designed to compare the outcomes of standard cardiopulmonary resuscitation (STD-CPR) and combined chest compression and abdominal compression-decompression cardiopulmonary resuscitation (CO-CPR) with a new device following out-of-hospital cardiac arrest (OHCA). Moreover, we investigated whether patient prognosis improved with this combination treatment. METHODS: This trial was a single-centre, prospective, randomized trial, and a blinded assessment of the outcomes was performed. A total of 297 consecutive patients with OHCA were initially screened, and 278 were randomized to the STD-CPR group (n = 135) or the CO-CPR group (n = 143). We compared the proportions of patients who achieved a return of spontaneous circulation (ROSC), survived to hospital admission and survived to hospital discharge. In addition, we also performed the Kaplan-Meier analysis with a log-rank test at the end of the follow-up period to compare the survival curves of the two groups. RESULTS: The differences were not statistically significant in the proportion of patients who achieved ROSC [31/135 (23.0%) versus 35/143 (24.5%)] and survived to hospital admission [28/135 (20.7%) versus 33/143 (23.1%)] between the CO-CPR group and STD-CPR group. However, there was a significant difference in the proportion of patients who survived to hospital discharge [16/135 (11.9%) versus 7/143 (4.9%)] between the two groups. Nine patients (6.7%) in the CO-CPR group and 2 patients (1.4%) in the STD group showed good neurological outcomes according to the cerebral performance category (CPC) scale score, and the difference was statistically significant (P = 0.003). The Kaplan-Meier curves showed that the patients in the CO-CPR group achieved better survival benefits than those in the STD-CPR group at the end of the follow-up period (log-rank P = 0.007). CONCLUSION: CO-CPR was more beneficial than STD-CPR in terms of survival benefits in patients who have suffered out-of-hospital cardiac arrest. Trial registration Chinese Clinical Trial Registry, registered number: ChiCTR2100049581 . Registered 30 July 2021- Retrospectively registered. http://www.medresman.org.cn/uc/index.aspx .

Surveillance and response systems driving malaria elimination in the mountain areas of Hainan Province.

Hainan Province is in a tropical area of China and previously experienced serious P. falciparum and P. vivax malaria epidemics. After nearly 70 consecutive years of malaria prevention and control, malaria in Hainan has gradually been eliminated. To achieve the elimination of malaria, Hainan enacted six stages: investigative research and pilot prevention and control, large-scale antimalaria measures, adjustment of strategies for prevention and control, joint prevention and control measures, global funding of routine malaria control, and malaria elimination. Different strategies for malaria control were adopted at different stages. Malaria was most prevalent in the mountainous areas of central and southern Hainan, which contain a high-risk population (the forest goers) and two highly effective malaria vectors (An. dirus and An. minimus). Forest goers have been a high-risk population for malaria in Hainan since their identification in the 1990s. This paper summarizes malaria monitoring in forest goers and the response of forest goers to malaria control and elimination, distilling specific malaria control and elimination measures via case studies in Hainan Province. Two case studies in the malaria control stage demonstrated different measures for outbreaks and sporadic cases in forest goers. In view of the malaria outbreak in Sanya during the elimination stage, three-layered strategies (TLSs) were implemented to control outbreaks and improve control measures. Moreover, this paper also illustrates specific management measures to prevent malaria retransmission from sporadic imported malaria cases during the elimination phase. Hainan finally eliminated malaria in 2020. However, the risk of malaria retransmission is still high due to the prevalence of effective malaria vectors in Hainan, and forest goers are still a high-risk population for malaria retransmission.

Zinc-metal-organic frameworks with tunable UV diffuse-reflectance as sunscreens.

BACKGROUND: UV exposure continues to induce many health issues, though commercial sunscreens are available. Novel UV filters with high safety and efficacy are urgently needed. Metal-organic frameworks (MOFs) could be a suitable platform for UV filter development, due to their tunable optical, electrical, and photoelectric properties by precise controlled synthesis. RESULTS: Herein, four zinc-based MOFs with various bandgap energies were chose to investigate their optical behaviors and evaluate their possibility as sunscreens. Zeolitic imidazolate framework-8 (ZIF-8) was found to possess the highest and widest UV reflectance, thereby protecting against sunburn and DNA damage on mouse skin and even achieving a comparable or higher anti-UV efficacy relative to the commercially available UV filters, TiO2 or ZnO, on pig skin, a model that correlates well with human skin. Also, ZIF-8 exerted appealing characteristics for topical skin use with low radical production, low skin penetration, low toxicity, high transparency, and high stability. CONCLUSION: These results confirmed ZIF-8 could potentially be a safe and effective sunscreen surrogate for human, and MOFs could be a novel source to develop more effective and safe UV filters.