Exploiting tertiary lymphoid structures gene signature to evaluate tumor microenvironment infiltration and immunotherapy response in colorectal cancer.

Background: Tertiary lymphoid structures (TLS) is a particular component of tumor microenvironment (TME). However, its biological mechanisms in colorectal cancer (CRC) have not yet been understood. We desired to reveal the TLS gene signature in CRC and evaluate its role in prognosis and immunotherapy response. Methods: The data was sourced from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Based on TLS-related genes (TRGs), the TLS related subclusters were identified through unsupervised clustering. The TME between subclusters were evaluated by CIBERSORT and xCell. Subsequently, developing a risk model and conducting external validation. Integrating risk score and clinical characteristics to create a comprehensive nomogram. Further analyses were conducted to screen TLS-related hub genes and explore the relationship between hub genes, TME, and biological processes, using random forest analysis, enrichment and variation analysis, and competing endogenous RNA (ceRNA) network analysis. Multiple immunofluorescence (mIF) and immunohistochemistry (IHC) were employed to characterize the existence of TLS and the expression of hub gene. Results: Two subclusters that enriched or depleted in TLS were identified. The two subclusters had distinct prognoses, clinical characteristics, and tumor immune infiltration. We established a TLS-related prognostic risk model including 14 genes and validated its predictive power in two external datasets. The model's AUC values for 1-, 3-, and 5-year overall survival (OS) were 0.704, 0.737, and 0.746. The low-risk group had a superior survival rate, more abundant infiltration of immune cells, lower tumor immune dysfunction and exclusion (TIDE) score, and exhibited better immunotherapy efficacy. In addition, we selected the top important features within the model: VSIG4, SELL and PRRX1. Enrichment analysis showed that the hub genes significantly affected signaling pathways related to TLS and tumor progression. The ceRNA network: PRRX1-miRNA (hsa-miR-20a-5p, hsa-miR-485-5p) -lncRNA has been discovered. Finally, IHC and mIF results confirmed that the expression level of PRRX1 was markedly elevated in the TLS- CRC group. Conclusion: We conducted a study to thoroughly describe TLS gene signature in CRC. The TLS-related risk model was applicable for prognostic prediction and assessment of immunotherapy efficacy. The TLS-hub gene PRRX1, which had the potential to function as an immunomodulatory factor of TLS, could be a therapeutic target for CRC.

Identification and quality evaluation of Lushan Yunwu tea from different geographical origins based on metabolomics.

The relationship between the chemical composition and quality of Lushan Yunwu tea (LYT) from different geographical origins is not clear. Sensory evaluation, metabolomics analyses combined with chemometrics were conducted on LYT from 8 different geographical origins, and altitude was identified as the main factor responsible for the differences among LYT. A total of 32 non-volatile and 27 volatile compounds were identified as marker metabolites to distinguish the origins of high altitudes from those of low altitudes. LYT samples from higher altitude areas contained more free amino acids, sugars, and organic acids, and less catechins, which may contribute to the reduction of bitterness and astringency and the enhancement of umami. The contents of geranylacetone, ethyl hexanoate, ethyl caprylate, 3-carene, d-cadinene, linalool, nerol, and nerolidol in high altitude areas were higher than those in low altitude areas, indicating that LYT from high altitude had strong floral and fruity aroma. The altitudes were positively correlated with pH value, total flavonoids, soluble protein, total free amino acids, and the antioxidant capacities of the LYT. This study provided a theoretical basis for the study of the effect of altitude on tea quality.

Long-term administration of royal jelly regulates age-related disorders and improves gut function in naturally aging mice.

A natural aging mouse model can exhibit physiological characteristics that closely resemble those of human aging. Through long-term observation, it reflects the occurrence and development of the aging process more accurately. Although numerous beneficial effects of royal jelly (RJ) have been extensively demonstrated in multiple experimental models, the effects of RJ on naturally aging mice have not yet been investigated. In this study, middle-aged male C57BL/6J mice were given RJ for 9 consecutive months to investigate its impact on the intestinal barrier function, gut microbiota, short-chain fatty acids (SCFAs) content and possible mechanisms. The results confirmed that RJ modulated serum lipids by reducing the levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C). Additionally, it protected the liver by increasing antioxidant enzyme levels while decreasing inflammatory cytokines TNF-α (by 51.97%), IL-6 (by 29.73%), and IL-1ß (by 43.89%). Furthermore, RJ inhibited the expression of cell cycle-dependent kinase inhibitors including p16, p21, and p53. Importantly, RJ ameliorated gut dysfunctions by inhibiting reduction of tight junction proteins and reducing inflammatory cytokines content in the colon. We also observed an alteration in gut microbiota characterized by an elevated ratio of Firmicutes to Bacteroides (F/B) along with increased abundance of beneficial bacteria, i.e., Lachnospiraceae NK4A136 and Akkermansia. Correlation analysis revealed positive associations between most bacterial genera and SCFAs production. Functional profiling of gut microbiota composition indicated that RJ intervention regulated amino acid metabolism, glycan biosynthesis, and cofactor/vitamin metabolism. Overall, our findings provide an effective dietary intervention strategy for modulating age-associated frailty through the modulation of the gut microbiota.

Identification and Characterization of Polyamine Metabolism in Citrus in Response to 'Candidatus Liberibacter asiaticus' Infection.

Citrus Huanglongbing, one of the most devastating citrus diseases, is caused by 'Candidatus Liberibacter asiaticus' (CLas). Polyamines are aliphatic nitrogen-containing compounds that play important roles in disease resistance and are synthesized primarily by two pathways: an arginine decarboxylation pathway and an ornithine decarboxylation pathway. However, it is unclear whether polyamines play a role in the tolerance of citrus to infection by CLas and, if so, whether one or both of the core polyamine metabolic pathways are important. We used high-performance liquid chromatography and ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry to detect the contents of nine polyamine metabolism-related compounds in six citrus cultivars with varying levels of tolerance to CLas. We also systematically detected the changes in polyamine metabolism-related compounds and H2O2 contents and compared the gene expression levels and the activities of enzymes involved in the polyamine metabolic pathway among healthy, asymptomatic, and symptomatic leaves of Newhall navel oranges infected with CLas. The tolerant and moderately tolerant varieties showed higher polyamine metabolism-related compound levels than those of susceptible varieties. Compared with the healthy group, the symptomatic group showed significantly increased contents of arginine, ornithine, γ-aminobutyric acid, and putrescine by approximately 180, 19, 1.5, and 0.2 times, respectively, and upregulated expression of biosynthetic genes. Arginase and ornithine decarboxylase enzyme activities were the highest in the symptomatic group, whereas arginine decarboxylase and agmatine deiminase enzyme activities were the highest in the asymptomatic group. The two polyamine biosynthetic pathways showed different trends with the increase of the CLas titer, indicating that polyamines were mainly synthesized through the arginine decarboxylase pathway in the asymptomatic leaves and were synthesized via the ornithine decarboxylase pathway in symptomatic leaves. These findings provide new insight into the changes in polyamine metabolism in citrus infected with CLas.

Reliability and stability of ultrasound-guided attenuation parameter in evaluating hepatic steatosis.

PURPOSE: This study aimed to explore the reliability and stability of ultrasound-guided attenuation parameter (UGAP) values obtained by two measuring methods and different measuring times. METHODS: Patients who underwent liver UGAP examinations in our hospital from September 2022 to December 2022 were retrospectively analyzed. The clinical data and UGAP measurements results were collected. Two different measuring methods: static single-frame multi-point measuring and dynamic multi-frame single-point measuring, were performed for each patient, and 10 UGAP values of each measuring method were recorded. The medians of the UGAP values of the 1st-3rd, 1st-5th, 1st-7th and 1st-10th by each measuring method were taken as the final UGAP values of measuring 3, 5, 7 and 10 times. The UGAP values obtained by the two different measuring methods and different measuring times (3, 5, 7 or 10 times) were compared. RESULTS: 206 patients were included in this study. There was no statistical difference between UGAP values measured by static single-frame multi-point measuring and dynamic multi-frame single-point measuring (P = 0.689, P = 0.270, P = 0.298, P = 0.091), regardless of measuring times (3, 5, 7, 10 times). No significant difference between the UGAP values obtained by 3, 5, 7 and 10 measurements was found (P = 0.554, P = 0.916). CONCLUSION: The UGAP values obtained by the two different measuring methods and different measuring times (3, 5, 7 and 10 times) are stable and reliable. Additionally, 3 times of UGAP measurements might be enough for each patient in clinical practice.

p-Toluenesulfonic acid enhanced neutral deep eutectic solvent pretreatment of soybean straw for efficient lignin removal and enzymatic hydrolysis.

Deep eutectic solvent (DES) is a newly-emerged green solvent for efficient pretreatment of lignocellulosic feedstock. To improve the component fractionation performance of neutral DES, p-toluenesulfonic acid (p-TsOH) was employed as catalyst to form a novel ternary DES with benzyltriethylammonium chloride (TEBAC) and glycerol (Gly) for pretreatment of soybean straw. Under the optimum reaction conditions (TEBAC:Gly = 1:12, 1.6 wt% p-TsOH and reacted at 90 °C for 160 min), the lignin and hemicellulose removal from soybean straw were amounted to 92.0 % and 88.2 %, respectively. The pretreated substrate showed satisfactory enzymatic hydrolysis performance, as the glucose and reducing sugar concentrations reached 37.3 g/L and 42.3 g/L, respectively, after 72 h saccharification under the action of cellulase with a relatively low enzyme loading of 10 FPU/g cellulose.This method provides an efficient and mild route for utilization of agricultural waste and production of platform monosaccharides.

Depletion of JunB increases adipocyte thermogenic capacity and ameliorates diet-induced insulin resistance.

The coexistence of brown adipocytes with low and high thermogenic activity is a fundamental feature of brown adipose tissue heterogeneity and plasticity. However, the mechanisms that govern thermogenic adipocyte heterogeneity and its significance in obesity and metabolic disease remain poorly understood. Here we show that in male mice, a population of transcription factor jun-B (JunB)-enriched (JunB+) adipocytes within the brown adipose tissue exhibits lower thermogenic capacity compared to high-thermogenic adipocytes. The JunB+ adipocyte population expands in obesity. Depletion of JunB in adipocytes increases the fraction of adipocytes exhibiting high thermogenic capacity, leading to enhanced basal and cold-induced energy expenditure and protection against diet-induced obesity and insulin resistance. Mechanistically, JunB antagonizes the stimulatory effects of PPARγ coactivator-1α on high-thermogenic adipocyte formation by directly binding to the promoter of oestrogen-related receptor alpha, a PPARγ coactivator-1α downstream effector. Taken together, our study uncovers that JunB shapes thermogenic adipocyte heterogeneity, serving a critical role in maintaining systemic metabolic health.

Metabolomics and network pharmacology reveal the mechanism of Castanopsis honey against Streptococcus pyogenes.

Streptococcus pyogenes (GAS) is one of the most virulent and infectious bacteria, severely threatening health and lives of people worldwide. Honey has been proven to have effective capability against GAS, but the underlying metabolites and mechanisms are still unclear. In this study, the Castanopsis honey (CH) showed significant antibacterial ability compared to other seven kinds of honey and artificial honey. Furthermore, the antibacterial metabolites and their targets in CH were screened by combined method of metabolomics, network pharmacology, and molecular docking. The results suggested that the activities of two antioxidant enzymes, glutathione peroxidase and tyrosyl tRNA synthetase identified as the primary targets, were significantly inhibited by CH, which significantly increased the level of oxidative stress in GAS. The results revealed a possibly novel mechanism regulating the oxidative stress and inhibits the growth in bacteria, providing strong experimental evidence to support the further development of CH as a novel antibacterial agent.

Analysis of the Correlation and Prognostic Significance of Tertiary Lymphoid Structures in Breast Cancer: A Radiomics-Clinical Integration Approach.

BACKGROUND: Tertiary lymphoid structures (TLSs) are potential prognostic indicators. Radiomics may help reduce unnecessary invasive operations. PURPOSE: To analyze the association between TLSs and prognosis, and to establish a nomogram model to evaluate the expression of TLSs in breast cancer (BC) patients. STUDY TYPE: Retrospective. POPULATION: Two hundred forty-two patients with localized primary BC (confirmed by surgery) were divided into BC + TLS group (N = 122) and BC - TLS group (N = 120). FIELD STRENGTH/SEQUENCE: 3.0T; Caipirinha-Dixon-TWIST-volume interpolated breath-hold sequence for dynamic contrast-enhanced (DCE) MRI and inversion-recovery turbo spin echo sequence for T2-weighted imaging (T2WI). ASSESSMENT: Three models for differentiating BC + TLS and BC - TLS were developed: 1) a clinical model, 2) a radiomics signature model, and 3) a combined clinical and radiomics (nomogram) model. The overall survival (OS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) were compared to evaluate the prognostic value of TLSs. STATISTICAL TESTS: LASSO algorithm and ANOVA were used to select highly correlated features. Clinical relevant variables were identified by multivariable logistic regression. Model performance was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC), and through decision curve analysis (DCA). The Kaplan-Meier method was used to calculate the survival rate. RESULTS: The radiomics signature model (training: AUC 0.766; test: AUC 0.749) and the nomogram model (training: AUC 0.820; test: AUC 0.749) showed better validation performance than the clinical model. DCA showed that the nomogram model had a higher net benefit than the other models. The median follow-up time was 52 months. While there was no significant difference in 3-year OS (P = 0.22) between BC + TLS and BC - TLS patients, there were significant differences in 3-year DFS and 3-year DMFS between the two groups. DATA CONCLUSION: The nomogram model performs well in distinguishing the presence or absence of TLS. BC + TLS patients had higher long-term disease control rates and better prognoses than those without TLS. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Translation, cultural adaptation, and validation of the Chinese standardized outcomes in nephrology-hemodialysis fatigue (C-SONG-HD fatigue) scale: a study of Chinese patients undergoing hemodialysis.

OBJECTIVE: This study aimed to translate and culturally adapt the standardized outcomes in nephrology-hemodialysis fatigue (SONG-HD fatigue) scale and to assess the psychometric properties of the Chinese version of the SONG-HD fatigue (C-SONG-HD fatigue) scale. METHODS: Forward and back translations were used to translate the SONG-HD fatigue scale into Chinese. We used the C-SONG-HD fatigue scale to survey Chinese patients undergoing hemodialysis (HD) in China. We examined the distribution of responses and floor and ceiling effects. Cronbach's alpha and McDonald's omega coefficient, intraclass coefficients, and Spearman correlations were used to assess internal consistency reliability, test-retest reliability, and convergent validity, respectively. Responsiveness was also evaluated. RESULTS: In total, 489 participants across southeast China, northwest China, and central China completed the study. The C-SONG-HD fatigue scale had good internal consistency (Cronbach's alpha coefficient 0.861, omega coefficient 0.916), test-retest reliability (intraclass correlation coefficient 0.695), and convergent validity (Spearman correlation 0.691). The analysis of all first-time HD patients did not show notable responsiveness, and only patients with temporary vascular access had good responsiveness with an effect size (ES) of 0.54, a standardized response mean (SRM) of 0.85, and a standard error of measurement (SEM) of 0.77. CONCLUSION: The Chinese version of the SONG-HD fatigue scale showed satisfactory reliability and validity in patients undergoing hemodialysis (HD) in China. It could be used as a tool to measure the fatigue of Chinese HD patients.

Metabolic profiling of Oryza sativa seedlings under chilling stress using nanoliter electrospray ionization mass spectrometry.

Low temperatures significantly impact on rice (Oryza sativa) yield and quality. Traditional metabolomic techniques, often involving time-consuming chromatography-mass spectrometry procedures, are currently in use. This study investigated metabolomic responses of rice seedlings under low-temperature stress using nanoliter electrospray ionization mass spectrometry (nanoESI-MS) in combination with multivariate analysis. Results revealed distinct metabolic profiles in 'Qiutianxiaoting' (japonica) and '93-11' (indica) rice seedlings. Among the 36 identified compounds in rice, seven key metabolites, comprising l-glutamic acid, asparagine, tryptophan, citric acid, α-linolenic acid, malic acid, and inositol, were identified as responsive to cold stress. Notably, malic acid content reached 1332.40 µg/g dry weight in Qiutianxiaoting and 1444.13 µg/g in 93-11. Both the qualitative and quantitative results of nanoESI-MS were further confirmed through gas chromatography-mass spectrometry validation. The findings highlight the potential of nanoESI-MS for rapidly characterizing crucial metabolites across diverse plant species under exposure to stress.

A CD6-targeted antibody-drug conjugate as a potential therapy for T cell-mediated disorders.

The selective targeting of pathogenic T cells is a holy grail in the development of new therapeutics for T cell-mediated disorders, including many autoimmune diseases and graft versus host disease. We describe the development of a CD6-targeted antibody-drug conjugate (CD6-ADC) by conjugating an inactive form of monomethyl auristatin E (MMAE), a potent mitotic toxin, onto a mAb against CD6, an established T cell surface marker. Even though CD6 is present on all T cells, only the activated (pathogenic) T cells vigorously divide and thus are susceptible to the antimitotic MMAE-mediated killing via the CD6-ADC. We found CD6-ADC selectively killed activated proliferating human T cells and antigen-specific mouse T cells in vitro. Furthermore, in vivo, whereas the CD6-ADC had no significant detrimental effect on normal T cells in naive CD6-humanized mice, the same dose of CD6-ADC, but not the controls, efficiently treated 2 preclinical models of autoimmune uveitis and a model of graft versus host disease. These results provide evidence suggesting that CD6-ADC could be further developed as a potential therapeutic agent for the selective elimination of pathogenic T cells and treatment of many T cell-mediated disorders.

Phase I study of a non-S2P SARS-CoV-2 mRNA vaccine LVRNA009 in Chinese adults.

BACKGROUND: COVID-19 caused by SARS-CoV-2 is a great threat to public health. We present the safety and immunogenicity data from a phase I trial in China of an mRNA vaccine (LVRNA009). METHODS: In the single-centre, double-blind, placebo-controlled and dose-escalation study, 72 healthy unvaccinated adults aged 18-59 years were randomized (3:1) to receive LVRNA009 with one of three vaccine dosage (25, 50 and 100 µg) or placebo, to evaluate for the safety, tolerability and immunogenicity of LVRNA009. RESULTS: All these participants received two injections 28 days apart. No adverse events higher than grade 2 were reported during the study. A total of 30 participants (42 %) reported solicited adverse reactions during the first 14 days after vaccinations. Of the events reported, fever (n = 11, 15 %) was the most common systemic adverse reaction, and pain at the injection site (n = 17, 24 %) was the most frequent solicited local adverse reaction. Anti-S-protein IgG and neutralising antibodies were observed to have been induced 14 days after the first dose, significantly increased 7 days after the second dose, and remained at a high level 28 days after the second dose. Specific T-cell responses peaked 7 days and persisted 28 days after second vaccination. CONCLUSION: LVRNA009 has demonstrated promising results in safety and tolerability at all three dose levels among Chinese adults. LVRNA009 at three dose levels could rapidly induce strong humoral and cellular immune responses, including binding and neutralising antibody production and IFN- γ secretion, which showed good immunogenicity. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT05364047; Chictr.org.cn ChiCTR2100049349.

RIOK3 potentially regulates osteogenesis-related pathways in ankylosing spondylitis and the differentiation of bone marrow mesenchymal stem cells.

RNA-binding proteins (RBPs), which are key effectors of gene expression, play critical roles in inflammation and immune regulation. However, the potential biological function of RBPs in ankylosing spondylitis (AS) remains unclear. We identified differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) of five patients with AS and three healthy persons by RNA-seq, obtained differentially expressed RBPs by overlapping DEGs and RBPs summary table. RIOK3 was selected as a target RBP and knocked down in mouse bone marrow mesenchymal stem cells (mBMSCs), and transcriptomic studies of siRIOK3 mBMSCs were performed again using RNA-seq. Results showed that RIOK3 knockdown inhibited the expression of genes related to osteogenic differentiation, ribosome function, and ß-interferon pathways in mBMSCs. In vitro experiments have shown that RIOK3 knockdown reduced the osteogenic differentiation ability of mBMSCs. Collectively, RIOK3 may affect the differentiation of mBMSCs and participate in the pathogenesis of AS, especially pathological bone formation.

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Tumor-associated tertiary lymphoid structures (TLSs) are ectopic lymphoid formations within tumor tissue, with mainly B and T cell populations forming the organic aggregates. The presence of TLSs in tumors has been strongly associated with patient responsiveness to immunotherapy regimens and improving tumor prognosis. Researchers have been motivated to actively explore TLSs due to their bright clinical application prospects. Various studies have attempted to decipher TLSs regarding their formation mechanism, structural composition, induction generation, predictive markers, and clinical utilization. Meanwhile, the scientific approaches to qualitative and quantitative descriptions are crucial for TLS studies. In terms of detection, hematoxylin and eosin (H&E), multiplex immunohistochemistry (mIHC), multiplex immunofluorescence (mIF), and 12-chemokine gene signature have been the top approved methods. However, no standard methods exist for the quantitative analysis of TLSs, such as absolute TLS count, analysis of TLS constituent cells, structural features, TLS spatial location, density, and maturity. This study reviews the latest research progress on TLS detection and quantification, proposes new directions for TLS assessment, and addresses issues for the quantitative application of TLSs in the clinic.

Emodin derivative E35 and its combination with autophagy inhibitor against acute myeloid leukemia cells in vitro and in vivo.

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy with poor prognosis and high recurrence rate. The discovery of more effective therapeutic strategies for AML plays a crucial role. The present work showed that E35, a novel derivative of emodin, significantly inhibited cell proliferation and induced autophagy and apoptosis in AML cells. Treatment with E35 markedly induced Beclin-1, LC3-II, cleaved Caspase-9 and PARP, and suppressed mitogen-activated protein kinase (MAPK) pathway. E35 exposure evoked autophagic activity prior to apoptosis induction, and autophagy inhibition by 3-methyladenine (3-MA) dramatically increased E35-induced apoptosis in both AML cell lines and patient-derived AML cells. Nevertheless, study on AML xenograft model showed that the combination E35 with 3-MA exhibited much more inhibitory effects on leukemia cell growth in vivo. No obvious adverse reactions occurred in the xenograft animals administered E35 alone or its cotreatment with 3-MA. These findings suggest that E35 could exert anti-leukemia effects, and that the combination of E35 and autophagy inhibitor might prove a more highly efficient strategy for AML treatment.

Fraxin inhibits melanogenesis by suppressing the ERK/MAPK pathway and antagonizes oxidative stress by activating the NRF2 pathway.

Hyperpigmentation disorders, such as melasma and freckles, are highly prevalent and draw increasing attention. Patients thus tend to seek effective and safe cosmetic whitening agents. Fraxin, a bioactive substance extracted from Cortex Fraxini, possesses anti-inflammation and antioxidant properties. In this study, we further explored the anti-melanogenic activities of fraxin were explored in vitro and in vivo. We found that pretreatment with fraxin decreased the melanin content of MNT1 cells and zebrafishes. In MNT1 cells, melanogenesis-related proteins, such as MITF, TYR, TYRP1, and DCT were down-regulated and tyrosinase activity was reduced under fraxin treatment. Further exploration of the mechanism revealed that fraxin could inhibit the phosphorylation of ERK, which is closely related to melanogenesis. Besides, fraxin also protected MNT1 cells from H2O2-induced apoptosis via scavenging reactive oxygen species (ROS) in cells. Further experimentation revealed that fraxin could activate NRF2 and upregulate antioxidase CAT and HO-1. In conclusion, fraxin could be an effective agent with anti-melanogenesis and antioxidant properties for hyperpigmentation disorders.

CD6-targeted antibody-drug conjugate as a new therapeutic agent for T cell lymphoma.

T cell lymphomas (TCL) are heterogeneous, aggressive, and have few available targeted therapeutics. In this study, we determined that CD6, an established T cell marker, was expressed at high levels on almost all examined TCL patient specimens, suggesting that CD6 could be a new therapeutic target for this life-threatening blood cancer. We prepared a CD6-targeted antibody-drug conjugate (CD6-ADC) by conjugating monomethyl auristatin E (MMAE), an FDA-approved mitotic toxin, to a high-affinity anti-human CD6 monoclonal antibody (mAb). In contrast to both the unconjugated anti-CD6 mAb, and the non-binding control ADC, CD6-ADC potently and selectively killed TCL cells in vitro in both time- and concentration-dependent manners. It also prevented the development of tumors in vivo in a preclinical model of TCL. More importantly, systemic or local administration of the CD6-ADC or its humanized version, but not the controls, significantly shrank established tumors in the preclinical mouse model of TCL. These results suggest that CD6 is a novel therapeutic target in TCLs and provide a strong rationale for the further development of CD6-ADC as a promising therapy for patients with these potentially fatal lymphoid neoplasms.

Synthesis and neuroprotective effects of new genipin derivatives against glutamate-induced oxidative damage.

Glutamate-induced oxidative stress is well-known to play a crucial role in the development of neurodegenerative diseases, such as stroke. Genipin, a natural iridoid compound, has demonstrated potential neuroprotective properties but is unstable in physiological conditions. The present study aimed to develop new derivatives of genipin that exhibit improved stability and activity for the treatment of stroke. Nineteen new derivatives were thus designed and synthesized. Their neuroprotective effect against glutamate-induced injury was evaluated in HT22 cells. Among the newly synthesized derivatives, 3e demonstrated significantly greater neuroprotection and improved stability compared to genipin. Specifically, 0.01 µM of 3e was found to effectively attenuate glutamate-induced oxidative damage by inhibiting ROS over-accumulation, reducing MDA content, and restoring the endogenous antioxidative system. Further investigation revealed that 3e inhibited oxidative stress by downregulating the phosphorylation levels of p38 MAPK and activating Nrf2 and HO-1 proteins. These results suggested that 3e has the potential to serve as a promising candidate for the treatment of stroke by protecting against glutamate-induced oxidative stress.

Flavonoid profile of Anoectochilus roxburghii (Wall.) Lindl. Under short-term heat stress revealed by integrated metabolome, transcriptome, and biochemical analyses.

Global warming severely threatens plant growth, and could lead to yield reduction. Although findings suggest that flavonoids play important roles in biological process in plants, their response to heat stress in Anoectochilus roxburghii (Wall.) Lindl. remains unclear. Here, we aimed to examine the flavonoid profile of A. roxburghii under heat stress and assess the effect of exogenous application of quercetin on heat stress tolerance. Metabolome analysis showed that quercetin, tricetin, isorhamnetin, scutellarein, and 4',7-Isoflavandiol were the main upregulated flavonoids in A. roxburghii, based on variable importance in the projection >1 and with fold change >2. Determination of the concentrations of the flavonoids using a standard curve revealed that quercetin, kaempferol, and isorhamnetin contents increased by 8.24-, 7.55-, and 5.01-fold, respectively, during heat stress, whereas rutin concentration decreased from 83.04 to 80.89 mg/kg (dry weight). Additionally, transcriptome analysis indicated increased expression of several genes in flavonoid biosynthesis pathways, including phenylalanine ammonia-lyase and chalcone synthase. Moreover, exogenous application of quercetin improved the antioxidant capacity and physiological parameters, including photosynthetic rate and chlorophyll content, of A. roxburghii under heat stress. Overall, the flavonoid profile of A. roxburghii under short-term heat stress was characterized based on integrated metabolomic, transcriptomic, and biochemical analyses, providing new insights for improving the biological value of A. roxburghii.