Folylpolyglutamate synthetase inactivation in relapsed ALL induces a druggable folate metabolic vulnerability.

AIMS: The antifolate methotrexate (MTX) is an anchor drug used in acute lymphoblastic leukemia (ALL) with poorly understood chemoresistance mechanisms in relapse. Herein we find decreased folate polyglutamylation network activities and inactivating FPGS mutations, both of which could induce MTX resistance and folate metabolic vulnerability in relapsed ALL. METHODS: We utilized integrated systems biology analysis of transcriptomic and genomic data from relapse ALL cohorts to infer hidden ALL relapse drivers and related genetic alternations during clonal evolution. The drug sensitivity assay was used to determine the impact of relapse-specific FPGS mutations on sensitivity to different antifolates and chemotherapeutics in ALL cells. We used liquid chromatography-mass spectrometry (LC-MS) to quantify MTX and folate polyglutamate levels in folylpoly-γ-glutamate synthetase (FPGS) mutant ALL cells. Enzymatic activity and protein degradation assays were also conducted to characterize the catalytic properties and protein stabilities of FPGS mutants. An ALL cell line-derived mouse leukemia xenograft model was used to evaluate the in vivo impact of FPGS inactivation on leukemogenesis and sensitivity to the polyglutamatable antifolate MTX as well as non-polyglutamatble lipophilic antifolate trimetrexate (TMQ). RESULTS: We found a significant decrease in folate polyglutamylation network activities during ALL relapse using RNA-seq data. Supported by functional evidence, we identified multifactorial mechanisms of FPGS inactivation in relapsed ALL, including its decreased network activity and gene expression, focal gene deletion, impaired catalytic activity, and increased protein degradation. These deleterious FPGS alterations induce MTX resistance and inevitably cause marked intracellular folate shrinkage, which could be efficiently targeted by a polyglutamylation-independent lipophilic antifolate TMQ in vitro and in vivo. CONCLUSIONS: MTX resistance in relapsed ALL relies on FPGS inactivation, which inevitably induces a folate metabolic vulnerability, allowing for an efficacious antifolate ALL treatment strategy that is based upon TMQ, thereby surmounting chemoresistance in relapsed ALL.

Combining untargeted and targeted metabolomics to reveal the mechanisms of herb pair Anemarrhena asphodeloides Bunge and Phellodendron chinense C. K. Schneid on benign prostatic hyperplasia.

ETHNOPHARMACOLOGICAL RELEVANCE: Anemarrhena asphodeloides Bunge (Ane) and Phellodendron chinense C. K. Schneid (Phe) is classical herb pair in traditional Chinese medicine, commonly used to ameliorate the symptoms of Benign Prostatic Hyperplasia (BPH). However, the mechanisms underlying this effect are remained indistinct. AIM OF THE STUDY: This study aimed to clarify potential therapeutic mechanisms of herb pair on BPH from a metabolic perspective. MATERIALS AND METHODS: Testosterone propionate-induced BPH rat model was established, prostatic parameters, histopathology and the levels of serum dihydrotestosterone (DHT) and testosterone (T) were used to evaluate the pharmacological effect of the herb pair on BPH. Subsequently, untargeted metabolomics of prostate tissues samples was performed by UHPLC-Q-Exactive-Orbitrap-MS, followed by multivariate statistical analysis. Targeted metabolomics by UHPLC-QQQ-MS was further utilized to verify and supplement the results of lipids and amino acids found by untargeted metabolomics, clarifying the relationship between disease, herbal pair and metabolism pathway. RESULTS: The study found that Ane-Phe could relieve the progression of BPH and regulate metabolic imbalances. The levels of 13 metabolites decreased and 11 increased in prostatic tissues including glycerolphospholipid, arachidonic acid, citric acid and so on, these altered metabolites were primarily associated with TCA cycle, arachidonic acid metabolism, lipid metabolism and amino acid metabolism. Furthermore, targeted metabolomics was fulfilled to further analyze the lipid metabolism disorders, the levels of 5 lipids in serum and 21 in prostatic tissues were changed in the herb pair group compared to the model group, which closely related to glycerophospholipid, sphingolipid and glycerolipid metabolism. Besides, amino acid metabolism may be regulated by activating arginine metabolism pathway. CONCLUSIONS: In this study, the combination of untargeted metabolomics and targeted metabolomics was applied to explore therapeutic mechanisms of Ane-Phe on BPH. In summary, Ane-Phe could improve the levels of endogenous metabolites by regulating multiple metabolic pathways and plays a role in energy supply, anti-inflammation and oxidative stress in BPH treatment.

Integrated network pharmacology and serum metabonomics analysis to explore the potential mechanism of Anemarrhena asphodeloides Bunge-Phellodendron chinense Schneid herb pair in the treatment of benign prostatic hyperplasia.

Anemarrhena asphodeloides Bunge-Phellodendron chinense Schneid (AAPC) is one of the most widely accepted herb pairs in Chinese medicine prescription for treating benign prostatic hyperplasia (BPH). However, the mechanisms underlying the combination of the two herbs for anti-BPH are still not completely clear. To uncover the potential mechanism of the AAPC herb pair in the treatment of BPH, chemical profiling, network pharmacology, serum metabonomics and experimental validation were integrated. UHPLC-Q-Exactive Orbitrap-MS was performed to characterize the chemical profiling of the herb pair extract, and network pharmacology was employed to forecast the potential effective components, core targets and key signaling pathways. Then, western blot and RT-PCR experiments were conducted to verify the PI3K/Akt/NF-κB signaling pathway predicted by network pharmacology. Finally, the serum differential metabolites and metabolic pathways were analyzed by serum non-targeted metabonomics, and these results were jointly analyzed by MetScape. 51 chemical components of the AAPC herb pair extract were identified, including phellodendrine, magnoflorine, berberine, mangiferin, anemarsaponin BIII, etc. In network pharmacology, the predicted core targets of these components include AKT1, TNF, EGFR, PTGS2, PIK3CA, etc. The KEGG pathway enrichment analysis indicated that PI3K-Akt, Rap1 and MAPK signaling pathways may play a key role in the AAPC herb pair for the treatment of BPH, and the results of animal experiments demonstrated that the herb pair could significantly inhibit the activation and expression of p-PI3K/PI3K, p-Akt/Akt, p-NF-κB/NF-κB in protein and mRNA levels. Furthermore, 31 serum differential metabolites and three main metabolic pathways were obtained by serum non-targeted metabonomics. And the crucial metabolic pathway of arachidonic acid (AA) was obtained by integrated analysis of network pharmacology and metabonomics results. In conclusion, the AAPC herb pair can improve BPH through inhibiting the activation and expression of the PI3K/Akt/NF-κB signaling pathway and AA metabolism.

Effects of sintilimab plus chemotherapy as first-line treatment on health-related quality of life in patients with advanced esophageal squamous cell carcinoma: results from the randomized phase 3 ORIENT-15 study.

Background: In ORIENT-15 study, sintilimab plus chemotherapy demonstrated significant improvement on overall survival (OS) versus placebo plus chemotherapy in first-line treatment of advanced esophageal squamous cell carcinoma (ESCC). Here, we report effect of sintilimab plus chemotherapy on health-related quality of life (HRQoL) in patients with advanced ESCC. Methods: From December 14, 2018 to August 28, 2022, HRQoL was evaluated in all randomized patients using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), EORTC Quality of Life Questionnaire Oesophageal Cancer Module 18 items (QLQ-OES18), and visual analogue scale (VAS) of the EuroQol five-dimensional five-level questionnaire (EQ-5D-5L). Mean scores of each scale were described by treatment group through week 60. Least-squares mean (LSM) score change from baseline through week 24 were analyzed using the mixed-model repeated-measures method. Time to the first onset of deterioration (TTD) and OS for each scale were estimated. Clinical Trials Registration: NCT03748134. Findings: As of August 28, 2022, 689 of 690 enrolled patients were assessed for HRQoL analysis (sintilimab group: 340, placebo group: 349). Median follow-up was 32.2 months. Differences in LSM favored sintilimab over placebo for QLQ-C30 social functioning (LSM difference: 3.06, 95% CI: 0.55 to 5.57; P = 0.0170), pain (-2.24, 95% CI: -4.30 to -0.17; P = 0.0337), fatigue (-2.24, 95% CI: -4.46 to -0.02; P = 0.0479), constipation (-3.27, 95% CI -5.49 to -1.05; P = 0.0039), QLQ-OES18 pain (-1.77, 95% CI -3.11 to -0.43; P = 0.0097), trouble swallowing saliva (-2.09, 95% CI: -3.77 to -0.42; P = 0.0146), and choked when swallowing (-3.23, 95% CI: -5.60 to -0.86; P = 0.0076). TTD favored sintilimab over placebo for QLQ-OES18 dysphagia (Hazard ratio [HR]: 0.76, 95% CI: 0.61-0.94, P = 0.0104), and trouble swallowing saliva (HR: 0.48, 95% CI: 0.35-0.67, P < 0.0001). Improved OS were observed in patients with better performance in several functioning and symptom scales of QLQ-C30 and QLQ-QES18. Interpretation: The statistically significant differences of several HRQoL scales and improvements in delayed deterioration observed in our study further support the use of sintilimab plus chemotherapy as first-line treatment for advanced ESCC. Funding: This study was funded by Innovent Biologics and was co-funded by Eli Lilly.

A novel antagonist of the CCL5/CCR5 axis suppresses the tumor growth and metastasis of triple-negative breast cancer by CCR5-YAP1 regulation.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) with a high mortality rate, and few effective therapeutic strategies are available. CCL5/CCR5 is an appealing immunotherapeutic target for TNBC. However, its signaling mechanism is poorly understood and its direct antagonists have not been reported. Here, we developed a high-throughput screening (HTS) assay for discovering its antagonists. Verteporfin was identified as a more selective and potent antagonist than the known CCR5 antagonist maraviroc. Without photodynamic therapy, verteporfin demonstrated significant inhibition on TNBC tumor growth through immune regulation, remarkable suppression of lung metastasis by cell-intrinsic mechanism, and a significant extension of overall survival in vivo. Mechanistically, CCR5 was found to be essential for expression of the key hippo effector YAP1. It promoted YAP1 transcription via HIF-1α and exerted further control over the migration of CD8+ T, NK, and MDSC immune cells through chemokines CXCL16 and CXCL8 which were identified from RNA-seq. Moreover, the CCR5-YAP1 axis played a vital role in promoting metastasis by modulating ß-catenin and core epithelial-mesenchymal transition transcription factors ZEB1 and ZEB2. It is noteworthy that the regulatory relationship between CCR5 and YAP1 was observed across various BC subtypes, TNBC patients, and showed potential relevance in fifteen additional cancer types. Overall, this study introduced an easy-to-use HTS assay that streamlines the discovery of CCL5/CCR5 axis antagonists. Verteporfin was identified as a specific molecular probe of this axis with great potentials as a therapeutic agent for treating sixteen malignant diseases characterized by heightened CCR5 and YAP1 levels.

Effectiveness of Huangqi Guizhi Wuwu decoction combined with rehabilitation training for shoulder hand syndrome after stroke: A systematic review and meta-analysis.

BACKGROUND: Shoulder hand syndrome (SHS) is a common complication of stroke. This meta-analysis aimed to evaluate the effectiveness of Huangqi Guizhi Wuwu decoction (HGWD) combined with rehabilitation training in managing it, as its efficacy remains inconclusive. METHODS: Seven databases, including PubMed, EMBASE, Cochrane Library, SinoMed, Chinese National Knowledge Infrastructure, Wanfang Data, and VIP database were searched in this study. The search deadline was April 30, 2023. Randomized controlled trials that included either standalone rehabilitation training or HGWD combined with rehabilitation training were included, and data were independently extracted by 2 reviewers who assessed the risk of bias. RESULTS: Thirteen studies involving 1270 patients were included in this study. Meta-analysis showed that the combined treatment was significantly more effective than standalone rehabilitation therapy (odds ratio = 4.49; 95%CI: 2.98-6.76; Z = 7.17; P < .00001). Compared with the control group, the intervention group had a lower visual analog scale score (mean difference [MD] = -2.80, 95%CI (-3.15, -2.45), Z = 15.84, P < .00001). In addition, the Fugl-Meyer assessment scale score improved (MD = 9.69, 95%CI (7.60, 11.78), Z = 9.08, P < .00001). The SHS score in the intervention group decreased more compared to the control group (standard mean difference = -2.27, 95%CI (-3.19, -1.34), Z = 4.79, P < .00001). Serum biomarkers related to SHS decreased, including serum substance P (MD = -7.52, 95%CI (-8.55, -6.48), Z = 14, P < .00001) and bradykinin (MD = -1.81, 95%CI (-2.68, -0.95), Z = 4.1, P < .00001). Although there was no statistical difference in joint mobility score (MD = -4.19, 95%CI (-8.16, -0.22), Z = 4.79, P = .28), sensitivity analysis after excluding one study still suggested that the joint mobility score of the combined treatment group was higher than that of the standalone rehabilitation treatment group. CONCLUSION: The results of this study indicate that HGWD combined with rehabilitation training may be more effective in treating SHS after stroke compared to standalone rehabilitation therapy.

Structurally Diverse Sesquiterpenoids from the Genus of Ainsliaea.

The genus of Ainsliaea embraces approximately 70 recognized species, many of which have been used to treat various diseases in folklore medicines. As the main metabolites of Ainsliaea plants, Ainsliaea sesquiterpenoids have drawn considerable attention in related scientific communities due to their intriguing structures and a variety of bioactivities. In this review, we intend to provide a full-aspect coverage of sesquiterpenoids reported from the genus of Ainsliaea, including 145 monomeric sesquiterpenoids and 30 oligomeric ones. Multiple aspects will be summarized, including their classification, distributions, structures, bioactivities, and biomimetic syntheses. In addition, their possible biosynthetic pathway will be discussed in detail.

Study on mechanism of Zishen Pill treating benign prostatic hyperplasia based on serum pharmacochemistry and network pharmacology.

Zishen Pill (ZSP) is a traditional Chinese medicine that is frequently used to treat Benign Prostatic Hyperplasia (BPH), however its specific mechanism of action and active ingredients are yet unknown. We used a combination of serum pharmacochemistry and network pharmacology and a series of biochemical assays to explore the action mechanism of ZSP in the treatment of BPH. The BPH rat model was created using testosterone propionate, and following oral ZSP administration, the components of ZSP in rat serum were detected by UPLC-Q-Exactive Orbitrap/MS method. A "component-target-disease" network and PPI networks were constructed on this foundation. The primary mechanism of ZSP decreasing BPH in rats was studied by KEGG pathway and GO analysis. Finally, the potential pathways and key targets were further verified in vivo by molecular biology and immunological methods. 46 substances were charactered from rat serum, and 164 anti-BPH targets were screened from the database. According to network pharmacology, the primary targets were CASP3, STAT3, JUN, and PTGS2/COX2. Three related pathways (PI3K/Akt signaling pathway, AGE-RAGE signaling pathway and EGFR tyrosine kinase inhibitor resistance) were closely related to the therapeutic effects of ZSP. The findings of molecular biology demonstrated that ZSP may bring Bcl-2, BAX, CASP3, COX2, and 5LOX protein and gene expression in BPH rats appreciably closer to that of normal rats. Additionally, ZSP can lessen the expression of inflammatory cytokines in BPH rats, including VEGF, TNF-α, CCL5, and interleukin. CONCLUSION: The above results suggest that ZSP may reduce BPH through inflammation/immunity and apoptosis/proliferation-related pathways. This study offers a fresh approach to investigate the basic pharmacological effects and mechanism of ZSP in the treatment of BPH.

Correction: Uncovering the effect of Moringa oleifera Lam. leaf addition to Fuzhuan Brick Tea on sensory properties, volatile profiles and anti-obesity activity.

Correction for 'Uncovering the effect of Moringa oleifera Lam. leaf addition to Fuzhuan Brick Tea on sensory properties, volatile profiles and anti-obesity activity' by Xin Li et al., Food Funct., 2023, 14, 2404-2415, https://doi.org/10.1039/D2FO03531F.

Uncovering the effect of Moringa oleifera Lam. leaf addition to Fuzhuan Brick Tea on sensory properties, volatile profiles and anti-obesity activity.

As a nutritious plant with valuable potential, the Moringa oleifera Lam. leaf addition to Fuzhuan Brick Tea (FBT) for co-fermentation is an industrial innovation and a new route to make full use of Moringa oleifera Lam. leaves. However, the sensory properties, volatile profiles and anti-obesity activity of Fuzhuan Brick (Moringa oleifera Lam.) tea (MFBT) are still unknown. The results demonstrated that MFBT has richer and more complex smell and taste, better color and higher overall acceptance scores. In total, 57 volatile flavor compounds, consisting of 3 acids, 16 hydrocarbons, 5 esters, 8 ketones, 13 aldehydes, 6 alcohols and others, were identified using HS-SPME-GC-MS. The characteristic odor components in MFBT were 3-buten-2-one, 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)- and 1-cyclohexene-1-carboxaldehyde, 2,6,6-trimethyl-, which gave it a floral, woody, sweet, herbal and fruity aroma. 2-Octenal, (E) contributed significantly to the aroma of FBT, which could impart fresh, fatty and green aromas. In addition, MFBT could better regulate lipid accumulation, glucose tolerance, insulin tolerance and inflammation response more effectively than FBT. The mechanism is that MFBT could better regulate the dysbiosis of gut microbiota induced by HFFD, mainly increasing the abundance of beneficial bacteria such as SCFA-producing bacteria (Bacteroidetes, Lactobacillaceae, Bacteroidales_S24-7_group and Clostridiaceae_1) and decreasing the abundance of harmful bacteria such as pro-inflammatory/obesity and metabolic syndrome-related bacteria (Proteobacteria, Deferribacteres, Desulfovibrio, Catenibacterium and Helicobacter), which in turn increased feces short-chain fatty acids and lowered circulating lipopolysaccharides. These results suggested that co-fermentation with Moringa oleifera Lam. leaf could significantly improve the quality and enhance the anti-obesity effect of FBT.

Purification, structural characterization and antioxidant activities of two neutral polysaccharides from persimmon peel.

Two neutral polysaccharides (PPP1-1 and PPP1-2) were purified from persimmon peel. PPP1-1 (21.84 kDa) was mainly composed of arabinose (22.92 %), galactose (21.09 %), glucose (35.13 %), and xylose (19.09 %), while PPP1-2 (10.42 kDa) mainly contained arabinose (32.98 %), galactose (20.81 %), glucose (26.86 %), xylose (10.46 %), and mannose (7.63 %). Methylation and NMR spectra analysis demonstrated that the backbone of PPP1-1 appeared to be →6)-α-D-Glcp-(1→, →2,6)-α-D-Glcp-(1→, →5)-α-L-Araf-(1→, and →3,5)-α-L-Araf-(1 â†’ residues with branches consisting of →3)-α-L-Araf-(1→, →4)-α-D-Glcp-(1→, →3)-ß-D-Galp-(1→, →4)-ß-D-Galp-(1→, →4)-ß-D-Xylp-(1→, →6)-ß-D-Galp-(1→, →4)-ß-D-Manp-(1→, and α-L-Araf-(1 â†’ residues. The main chain of PPP1-2 was composed of →6)-α-D-Glcp-(1→, →5)-α-L-Araf-(1→, and →3,5)-α-L-Araf-(1 â†’ residues with branches consisting of →3)-α-L-Araf-(1→, →1,2)-α-D-Glcp-(6→, →4)-α-D-Glcp-(1→, →3)-ß-D-Galp-(1→, →4)-ß-D-Galp-(1→, →6)-ß-D-Galp-(1→, →4)-ß-D-Xylp-(1→, →4,6)-α-D-Glcp-(1→, and →4)-ß-D-Manp-(1 â†’ residues and terminal of α-L-Araf-(1 â†’ residue. PPP1-2 exhibited stronger antioxidant activities and better thermal stability than PPP1-1. Our results provided the foundation for further investigating the structure and biological activities of persimmon peel polysaccharides and highlighted their potential to become potential antioxidants in functional food.

Extraction optimization and characterization of persimmon peel pectin extracted by subcritical water.

Persimmon peel pectin (PPP) was extracted by subcritical water via the response surface methodology. The optimal crude PPP extraction yield of 7.62 ± 0.7 % was found at 138 °C, 2.84 min, and liquid-solid ratio of 1:10.02. After treatment of deproteinization and decolorization with papain and hydrogen peroxide, 83.19 % of protein and 78.56 % of the colour in crude PPP were removed, respectively. PPP owned the Mw of 21.79 kDa and its uronic acids content was 64.03 %. PPP was further affirmed by fourier transform infrared, X-ray diffractometer and 1H NMR analysis. Moreover, the degradation temperature (228.05 â„ƒ) of PPP was verified via differential scanning calorimetry. Then, the IC50 of PPP to ABTS•+ was 9.8 times that of commercial citrus pectin. Moreover, PPP could change microbial communities and selectively enrich Bacteroides, Cetobacterium, Erysipelatoclostridium, Parabacteroides and Phocaeicola sartorii. This study demonstrated that subcritical water was practicable for extraction of persimmon peel pectin.

Antileukemic effects of topoisomerase I inhibitors mediated by de-SUMOylase SENP1.

SUMO-specific proteases (SENPs) play pivotal roles in maintaining the balance of SUMOylation/de-SUMOylation and in SUMO recycling. Deregulation of SENPs leads to cellular dysfunction and corresponding diseases. As a key member of the SENP family, SENP1 is highly correlated with various cancers. However, the potential role of SENP1 in leukemia, especially in acute lymphoblastic leukemia (ALL), is not clear. This study shows that ALL cells knocking down SENP1 display compromised growth rather than significant alterations in chemosensitivity, although ALL relapse samples have a relatively higher expression of SENP1 than the paired diagnosis samples. Camptothecin derivatives 7-ethylcamptothecin (7E-CPT, a monomer compound) and topotecan (TPT, an approved clinical drug) induce specific SENP1 reduction and severe apoptosis of ALL cells, showing strong anticancer effects against ALL. Conversely, SENP1 could attenuate this inhibitory effect by targeting DNA topoisomerase I (TOP1) for de-SUMOylation, indicating that specific reduction in SENP1 induced by 7E-CPT and/or topotecan inhibits the proliferation of ALL cells.

Interaction of Companilactobacillus crustorum MN047-derived bacteriocins with gut microbiota.

Companilactobacillus crustorum MN047-derived bacteriocins (CCDB) have inhibitory effects on the growth of pathogens. In this study, a pectin/zein beads delivery system was used to investigate the effects of CCDB on the dextran sulfate sodium-induced colitis in mice. The focus was given on aspects linked with the gut microbiota, intestinal epithelial barrier, oxidative stress, and inflammation. Results suggested that CCDB alleviated the pathological symptoms of colitis, including increased disease activity index and shortened colon length. CCDB strengthened the gut barrier by increasing goblet cells and promoting the expressions of MUC2 and tight junctions-related proteins. CCDB decreased oxidative mediators and increased antioxidant mediators in serum or colon tissue. Furthermore, CCDB reduced harmful bacteria and enriched beneficial bacteria, which further decreased serum LPS and increased fecal butyric acid. In addition, CCDB inhibited the overexpressions of proinflammatory cytokines, chemokines, and pathogens/LPS-activated TLR4/NF-κB pathway. Therefore, CCDB is a potential dietary supplement to relieve colitis.

UBR5 targets tumor suppressor CDC73 proteolytically to promote aggressive breast cancer.

UBR5, a HECT-domain E3 ubiquitin ligase, is an attractive therapeutic target for aggressive breast cancers. Defining the substrates of UBR5 is crucial for scientific understanding and clinical intervention. Here, we demonstrate that CDC73, a component of the RNA polymerase II-associated factor 1 complex, is a key substrate that impedes UBR5's profound tumorigenic and metastatic activities in triple-negative breast cancer (TNBC) via mechanisms of regulating the expression of ß-catenin and E-cadherin, tumor cell apoptosis and CD8+ T cell infiltration. Expression of CDC73 is also negatively associated with the progression of breast cancer patients. Moreover, we show that UBR5 destabilizes CDC73 by polyubiquitination at Lys243, Lys247, and Lys257 in a non-canonical manner that is dependent on the non-phosphorylation state of CDC73 at Ser465. CDC73 could serve as a molecular switch to modulate UBR5's pro-tumor activities and may provide a potential approach to developing breast cancer therapeutic interventions.

A review on the potential use of natural products in overweight and obesity.

With the increase in unhealthy lifestyles, obesity is increasingly common, which could cause many metabolic diseases. In recent research, natural product extracts have shown tremendous potential antiobesity effects via different mechanisms. In this review, we focused on widely adopted extraction methods, bioactive ingredients types, and antiobesity mechanisms of natural product extracts in the recent reports. The extraction methods include solid-liquid extraction, microwave-assisted extractions, and supercritical fluid extraction. Moreover, the bioactive ingredients identified in natural product extracts are phenolic compounds, oligosaccharides, polysaccharides, and terpenoids. These exert antiobesity effects through multiple mechanisms, including suppressing the appetite, increasing energy expenditure, inhibiting enzyme activity, modulating lipid homeostasis and adipocyte lifecycle, reducing oxidative and inflammation, and improving intestinal bacteria. However, the antiobesity effects of natural products require further evaluation. Furthermore, the improvement of the bioavailability and effective and safe human dose of these bioactive ingredients should be the focus of future work.

A γ-glutamyl hydrolase lacking the signal peptide confers susceptibility to folates/antifolates in acute lymphoblastic leukemia cells.

A key cofactor of several enzymes implicated in DNA synthesis, repair, and methylation, folate has been shown to be required for normal cell growth and replication and is the basis for cancer chemotherapy using antifolates. γ-Glutamyl hydrolase (GGH) catalyzes the removal of γ-polyglutamate tails of folylpoly-/antifolylpoly-γ-glutamates to facilitate their export out of the cell, thereby maintaining metabolic homeostasis of folates or pharmacological efficacy of antifolates. However, the factors that control or modulate GGH function are not well understood. In this study, we show that intact GGH is not indispensable for the chemosensitivity and growth of acute lymphoblastic leukemia (ALL) cells, whereas GGH lacking N-terminal signal peptide (GGH-ΔN ) confers the significant drug resistance of ALL cells to the antifolates MTX and RTX. In addition, ALL cells harboring GGH-ΔN show high susceptibility to the change in folates, and glycosylation is not responsible for these phenotypes elicited by GGH-ΔN . Mechanistically, the loss of signal peptide enhances intracellular retention of GGH and its lysosomal disposition. Our findings clearly define the in vivo role of GGH in ALL cells and indicate a novel modulation of the GGH function, suggesting new avenues for ALL treatment in future.

Protective Effects of Companilactobacillus crustorum MN047 against Dextran Sulfate Sodium-Induced Ulcerative Colitis: A Fecal Microbiota Transplantation Study.

Gut microbiota dysbiosis could aggravate the development of ulcerative colitis (UC). Companilactobacillus crustorum MN047 (CCMN) is a potential gut microbiota-regulating probiotic that could produce multiple novel bacteriocins. In this study, fecal microbiota transplantation (FMT) was used to verify whether CCMN could alleviate dextran sulfate sodium-induced UC by regulating gut microbiota. Results showed that both CCMN and FMT ameliorated the symptoms of UC, including attenuating the increased disease activity index, shortened colon length, gut barrier damage, and inflammation. Briefly, CCMN and FMT upregulated the expressions of MUCs and tight junctions, downregulated the expressions of proinflammatory cytokines and chemokines, increased fecal short-chain fatty acids, and lowered serum lipopolysaccharides, which were associated with the regulation of gut microbiota (e.g., increased Akkermansia, Blautia, and Ruminococcus levels). These results demonstrated that CCMN could ameliorate UC by modulating gut microbiota and inhibiting the TLR4/NF-κB pathway. Therefore, CCMN could be considered as a potential probiotic supplement for ameliorating UC.

Consistent Clustering Pattern of Prokaryotic Genes Based on Base Frequency at the Second Codon Position and its Association with Functional Category Preference.

In 2002, our research group observed a gene clustering pattern based on the base frequency of A versus T at the second codon position in the genome of Vibrio cholera and found that the functional category distribution of genes in the two clusters was different. With the availability of a large number of sequenced genomes, we performed a systematic investigation of A2-T2 distribution and found that 2694 out of 2764 prokaryotic genomes have an optimal clustering number of two, indicating a consistent pattern. Analysis of the functional categories of the coding genes in each cluster in 1483 prokaryotic genomes indicated, that 99.33% of the genomes exhibited a significant difference (p < 0.01) in function distribution between the two clusters. Specifically, functional category P was overrepresented in the small cluster of 98.65% of genomes, whereas categories J, K, and L were overrepresented in the larger cluster of over 98.52% of genomes. Lineage analysis uncovered that these preferences appear consistently across all phyla. Overall, our work revealed an almost universal clustering pattern based on the relative frequency of A2 versus T2 and its role in functional category preference. These findings will promote the understanding of the rationality of theoretical prediction of functional classes of genes from their nucleotide sequences and how protein function is determined by DNA sequence.

A low-temperature hydrothermal synthesis of submicron spherical BaF2.

The sub-micron spherical barium fluoride (BaF2) was successfully synthesized via a low-temperature hydrothermal method using ethylenediamine tetraacetic acid disodium salt (EDTA-2Na) as the chelating agent. The effect of pH, the molar ratio of EDTA to Ba2+, barium hydroxide octahydrate (Ba(OH)2·8H2O) concentration, hydrofluoric acid (HF) concentration, hydrothermal temperature and time, on the formation of spherical BaF2 were investigated. The formation mechanism of spherical BaF2 has been proposed based on the experimental results. The results show that the spherical BaF2, with an average size of 346.9 nm, is formed by the self-assembly of nanocubes. The optimized synthesis conditions are: pH = 14, EDTA-2Na : Ba2+ = 1 : 1, Ba(OH)2 concentration is 0.1 mol L-1, HF concentration is 2.0 mol L-1, hydrothermal temperature is 80 °C and hydrothermal time is 2.0 h. The self-assembly mechanism of the spherical secondary structure was revealed from the perspective of crystal nucleation and growth, and the important role of EDTA in the spherical BaF2 formation is explained.