Impact of extraction method on the lipids of Himalayan marmot oil with ultrahigh-performance liquid chromatography Q-Exactive Orbitrap mass spectrometry analysis.

RATIONALE: Himalayan marmot oil (SPO) has been used for pharmaceutical purposes for centuries, but its composition is still unclear. The bioactivity of SPO highly depends on the techniques used for its processing. This study focused on the comprehensive lipidomics of SPO, especially on the ones derived from dry rendering, wet rendering, cold pressing, and ultrasound-assisted solvent extraction. METHODS: We performed lipid profiling of SPO acquired by different extraction methods using ultrahigh-performance liquid chromatography Q-Exactive Orbitrap mass spectrometry, and 17 classes of lipids (2 BMPs, 12 LysoPCs, 9 LysoPEs, 41 PCs, 24 PEs, 23 Plasmenyl-PCs, 10 Plasmenyl-PEs, 10 MGs, 63 DGs, 187 TGs, 2 MGDGs, 3 Cer[NDS]s, 22 Cer[NS]s, 2 GlcCer[NS]s, 14 SMs, 14 CEs, and 6 AcylCarnitines) were characterized. RESULTS: Fifty-five lipids were differentially altered (VIP > 1.5, p < 0.05) between the extraction techniques, which can be used as potential biomarkers to differentiate SPO extracted by various methods. Additionally, the contents of oleic acid and arachidic acid were abundant in all samples that may suggest their medicinal values and are conducive to in-depth research. CONCLUSIONS: These findings reveal the alterations of lipid profile and free fatty acid composition in SPO obtained with different extraction methods, providing a theoretical foundation for investigating its important components as functional factors in medicines and cosmetics.

Which Drugs are More Effective in Preventing Familial Adenomatous Polyposis Progression Based on Network Meta-Analysis?

BACKGROUND: Familial adenomatous polyposis (FAP) is an inherited disorder. At present, an increasing number of medications are being employed to treat FAP; however, only a few have been assessed for their efficacy and safety. Therefore, this study aimed to conduct a network meta-analysis to compare the therapeutic outcomes and adverse drug reactions of all FAP-associated medications. METHOD: Six relevant databases were searched to identify pertinent randomized controlled trials (RCTs), and information on the dosage and frequency of various drugs was extracted. Additionally, data on changes in polyp counts and dimensions, as well as treatment-related adverse reactions for different medications were collected. The Bayesian method was employed to directly or indirectly compare the impact of different treatment regimens on changes in polyp numbers and diameters, and the safety of the drugs was investigated. RESULTS: CXB at 16 mg/kg/day significantly reduced polyp numbers. Celecoxib at 8 mg/kg/day and sulindac (150 mg twice daily) plus erlotinib (75 mg/day) were effective for tolerant FAP patients. Additionally, EPAFFA 2 g daily and sulindac (150 mg twice daily) plus erlotinib (75 mg/day) emerged as the most effective for reducing polyp size. CONCLUSION: The most effective treatment for reducing the number of colorectal polyps is celecoxib 16 mg/kg/day. On the other hand, a daily dosage of 2 g EPA-FFA demonstrates the best results in terms of decreasing colorectal polyp diameter.

A novel conditional survival nomogram for monitoring real-time prognosis of non-metastatic colorectal cancer.

AIMS: The aim of this study is to enhance the accuracy of monitoring and treatment information for patients diagnosed with colorectal cancer (CRC). METHODS: Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, a cohort of 335,948 eligible CRC patients was included in this investigation. Conditional survival probability and actuarial overall survival were employed as methodologies to investigate the association between clinicopathological characteristics and cancer prognosis. RESULTS: Among CRC patients, the 5-year survival rate was 59%, while the 10-year survival rate was 42%. Over time, conditional survival showed a consistent increase, with rates reaching 45% and 48% for individuals surviving 1 and 2 years, respectively. Notably, patients with unfavorable tumor stages exhibited substantial improvements in conditional survival, thereby narrowing the disparity with actuarial overall survival over time. CONCLUSION: This study underscores the significance of time-dependent conditional survival probability, particularly for patients with a poorer prognosis. The findings suggest that long-term CRC survivors may experience improved cancer prognosis over time.

Throat microbiota drives alterations in pulmonary alveolar microbiota in patients with septic ARDS.

OBJECTIVES: The translocation of intestinal flora has been linked to the colonization of diverse and heavy lower respiratory flora in patients with septic ARDS, and is considered a critical prognostic factor for patients. METHODS: On the first and third days of ICU admission, BALF, throat swab, and anal swab were collected, resulting in a total of 288 samples. These samples were analyzed using 16S rRNA analysis and the traceability analysis of new generation technology. RESULTS: On the first day, among the top five microbiota species in abundance, four species were found to be identical in BALF and throat samples. Similarly, on the third day, three microbiota species were found to be identical in abundance in both BALF and throat samples. On the first day, 85.16% of microorganisms originated from the throat, 5.79% from the intestines, and 9.05% were unknown. On the third day, 83.52% of microorganisms came from the throat, 4.67% from the intestines, and 11.81% were unknown. Additionally, when regrouping the 46 patients, the results revealed a significant predominance of throat microorganisms in BALF on both the first and third day. Furthermore, as the disease progressed, the proportion of intestinal flora in BALF increased in patients with enterogenic ARDS. CONCLUSIONS: In patients with septic ARDS, the main source of lung microbiota is primarily from the throat. Furthermore, the dynamic trend of the microbiota on the first and third day is essentially consistent.It is important to note that the origin of the intestinal flora does not exclude the possibility of its origin from the throat.

Chemical derivatization strategies for enhancing the HPLC analytical performance of natural active triterpenoids.

Triterpenoids widely exist in nature, displaying a variety of pharmacological activities. Determining triterpenoids in different matrices, especially in biological samples holds great significance. High-performance liquid chromatography (HPLC) has become the predominant method for triterpenoids analysis due to its exceptional analytical performance. However, due to the structural similarities among botanical samples, achieving effective separation of each triterpenoid proves challenging, necessitating significant improvements in analytical methods. Additionally, triterpenoids are characterized by a lack of ultraviolet (UV) absorption groups and chromophores, along with low ionization efficiency in mass spectrometry. Consequently, routine HPLC analysis suffers from poor sensitivity. Chemical derivatization emerges as an indispensable technique in HPLC analysis to enhance its performance. Considering the structural characteristics of triterpenoids, various derivatization reagents such as acid chlorides, rhodamines, isocyanates, sulfonic esters, and amines have been employed for the derivatization analysis of triterpenoids. This review comprehensively summarized the research progress made in derivatization strategies for HPLC detection of triterpenoids. Moreover, the limitations and challenges encountered in previous studies are discussed, and future research directions are proposed to develop more effective derivatization methods.

[Progress in research on mRNA therapeutics for the treatment of genetic diseases].

In recent years, mRNA drugs have shown a great potential for the treatment of genetic diseases and attracted the attention of many researchers. This article has reviewed the advance in the research of mRNA drugs for the treatment of genetic diseases over the past 30 years, including their mechanisms of action and structure design, with a focus on their advantages as alternative therapies such as high specificity, low dosage, and sustained expression. Meanwhile, challenges for the effective delivery and storage methods for the mRNA drugs are discussed, with an aim to provide guidance for subsequent researches.

Accurate Kinetic Studies of OH + HO2 Radical-Radical Reaction through Direct Measurement of Precursor and Radical Concentrations with High-Resolution Time-Resolved Dual-Comb Spectroscopy.

The radical-radical reaction between OH and HO2 has been considered for a long time as an important reaction in tropospheric photochemistry and combustion chemistry. However, a significant discrepancy of an order of magnitude for rate coefficients of this reaction is found between two recent experiments. Herein, we investigate the reaction OH + HO2 via direct spectral quantification of both the precursor (H2O2) and free radicals (OH and HO2) upon the 248 nm photolysis of H2O2 using infrared two-color time-resolved dual-comb spectroscopy. With quantitative and kinetic analysis of concentration profiles of both OH and HO2 at varied conditions, the rate coefficient kOH+HO2 is determined to be (1.10 ± 0.12) × 10-10 cm3 molecule-1 s-1 at 296 K. Moreover, we explore the kinetics of this reaction under conditions in the presence of water, but no enhancement in the kOH+HO2 can be observed. This work as an independent experiment plays a crucial role in revisiting this prototypical radical-radical reaction.

Estrogen signaling in the dorsal raphe regulates binge-like drinking in mice.

Estrogens promote binge alcohol drinking and contribute to sex differences in alcohol use disorder. However, the mechanisms are largely unknown. This study aims to test if estrogens act on 5-hydroxytryptamine neurons in the dorsal raphe nucleus (5-HTDRN) to promote binge drinking. We found that female mice drank more alcohol than male mice in chronic drinking in the dark (DID) tests. This sex difference was associated with distinct alterations in mRNA expression of estrogen receptor α (ERα) and 5-HT-related genes in the DRN, suggesting a potential role of estrogen/ERs/5-HT signaling. In supporting this view, 5-HTDRN neurons from naïve male mice had lower baseline firing activity but higher sensitivity to alcohol-induced excitation compared to 5-HTDRN neurons from naïve female mice. Notably, this higher sensitivity was blunted by 17ß-estradiol treatment in males, indicating an estrogen-dependent mechanism. We further showed that both ERα and ERß are expressed in 5-HTDRN neurons, whereas ERα agonist depolarizes and ERß agonist hyperpolarizes 5-HTDRN neurons. Notably, both treatments blocked the stimulatory effects of alcohol on 5-HTDRN neurons in males, even though they have antagonistic effects on the activity dynamics. These results suggest that ERs' inhibitory effects on ethanol-induced burst firing of 5-HTDRN neurons may contribute to higher levels of binge drinking in females. Consistently, chemogenetic activation of ERα- or ERß-expressing neurons in the DRN reduced binge alcohol drinking. These results support a model in which estrogens act on ERα/ß to prevent alcohol-induced activation of 5-HTDRN neurons, which in return leads to higher binge alcohol drinking.

Preclinical Investigations on Anti-fibrotic Potential of Long-Term Oral Therapy of Sodium Astragalosidate in Animal Models of Cardiac and Renal Fibrosis.

In traditional Chinese medicine, Radix Astragali has played a vital role in treating progressive fibrotic diseases. One of its main active components, astragaloside IV, is a promising anti-fibrotic treatment despite its extremely low bioavailability. Our study aimed to optimize sodium astragalosidate (SA) by salt formation to improve solubility and oral absorption for anti-fibrotic therapy in vivo. Isoproterenol-induced myocardial fibrosis rat models and obese BKS-db mice presenting diabetic kidney fibrosis were used in this study. Daily oral administration of SA (20 mg/kg) for 14 days ameliorated cardiac fibrosis by reducing collagen accumulation and fibrosis-related inflammatory signals, including TNF-α, IL-1ß, and IL-6. In db/db mice, SA (5,10, and 20 mg/kg per day for 8 weeks) dose-dependently alleviated lipid metabolism impairment and renal dysfunction when administered orally. Furthermore, Western blot and immunohistochemistry analyses demonstrated that SA treatment inhibited renal fibrosis by suppressing TGF-ß1/Smads signaling. Taken together, our findings provide the oral-route medication availability of SA, which thus might offer a novel lead compound in preclinical trial-enabling studies for developing a long-term therapy to treat and prevent fibrosis.

Enhancing Generic Reaction Yield Prediction through Reaction Condition-Based Contrastive Learning.

Deep learning (DL)-driven efficient synthesis planning may profoundly transform the paradigm for designing novel pharmaceuticals and materials. However, the progress of many DL-assisted synthesis planning (DASP) algorithms has suffered from the lack of reliable automated pathway evaluation tools. As a critical metric for evaluating chemical reactions, accurate prediction of reaction yields helps improve the practicality of DASP algorithms in the real-world scenarios. Currently, accurately predicting yields of interesting reactions still faces numerous challenges, mainly including the absence of high-quality generic reaction yield datasets and robust generic yield predictors. To compensate for the limitations of high-throughput yield datasets, we curated a generic reaction yield dataset containing 12 reaction categories and rich reaction condition information. Subsequently, by utilizing 2 pretraining tasks based on chemical reaction masked language modeling and contrastive learning, we proposed a powerful bidirectional encoder representations from transformers (BERT)-based reaction yield predictor named Egret. It achieved comparable or even superior performance to the best previous models on 4 benchmark datasets and established state-of-the-art performance on the newly curated dataset. We found that reaction-condition-based contrastive learning enhances the model's sensitivity to reaction conditions, and Egret is capable of capturing subtle differences between reactions involving identical reactants and products but different reaction conditions. Furthermore, we proposed a new scoring function that incorporated Egret into the evaluation of multistep synthesis routes. Test results showed that yield-incorporated scoring facilitated the prioritization of literature-supported high-yield reaction pathways for target molecules. In addition, through meta-learning strategy, we further improved the reliability of the model's prediction for reaction types with limited data and lower data quality. Our results suggest that Egret holds the potential to become an essential component of the next-generation DASP tools.

Mechanistic research: Selenium regulates virulence factors, reducing adhesion ability and inflammatory damage of Helicobacter pylori.

BACKGROUND: The pathogenicity of Helicobacter pylori is dependent on factors including the environment and the host. Although selenium is closely related to pathogenicity as an environmental factor, the specific correlation between them remains unclear. AIM: To investigate how selenium acts on virulence factors and reduces their toxicity. METHODS: H. pylori strains were induced by sodium selenite. The expression of cytotoxin-associated protein A (CagA) and vacuolating cytotoxin gene A (VacA) was determined by quantitative PCR and Western blotting. Transcriptomics was used to analyze CagA, CagM, CagE, Cag1, Cag3, and CagT. C57BL/6A mice were infected with the attenuated strains subjected to sodium selenite induction, and H. pylori colonization, inflammatory reactions, and the cell adhesion ability of H. pylori were assessed. RESULTS: CagA and VacA expression was upregulated at first and then downregulated in the H. pylori strains after sodium selenite treatment. Their expression was significantly and steadily downregulated after the 5th cycle (10 d). Transcriptome analysis revealed that sodium selenite altered the levels affect H. pylori virulence factors such as CagA, CagM, CagE, Cag1, Cag3, and CagT. Of these factors, CagM and CagE expression was continuously downregulated and further downregulated after 2 h of induction with sodium selenite. Moreover, CagT expression was upregulated before the 3rd cycle (6 d) and significantly downregulated after the 5th cycle. Cag1 and Cag3 expression was upregulated and downregulated, respectively, but no significant change was observed by the 5th cycle. C57BL/6A mice were infected with the attenuated strains subjected to sodium selenite induction. The extent of H. pylori colonization in the stomach increased; however, sodium selenite also induced a mild inflammatory reaction in the gastric mucosa of H. pylori-infected mice, and the cell adhesion ability of H. pylori was significantly weakened. CONCLUSION: These results demonstrate that H. pylori displayed virulence attenuation after the 10th d of sodium selenite treatment. Sodium selenite is a low toxicity compound with strong stability that can reduce the cell adhesion ability of H. pylori, thus mitigating the inflammatory damage to the gastric mucosa.

Branched fructo-oligosaccharides from Polygonatum Cyrtonema Hua as crosslinking agents for cellulose: A novel injectable and on-demand dissolution hydrogel for diabetic wound.

Oligosaccharide-containing macromolecular bio adhesives are emerging as highly promising eco-friendly materials to enhance the cytocompatibility of viscous hydrogels for wound healing applications. In our prior research, we extensively elucidated the properties of branch-structure fructo-oligosaccharides derived from Polygonatum Cyrtonema Hua (referred to as PCOS). However, the characteristics of hydrogels based on fructo-oligosaccharides remain to be fully explored. In present work, we developed an injectable, PCOS/carboxymethyl cellulose (CMC) hydrogel which is a dual ion-physical cross-linked hydrogel that can be considered as a potential diabetic wound dressing. The tests showed that the optimal ratios for hydrogel preparation were 2 % CBM 940 (Carbomer 940), 5 % CMC and 10 % PCOS. The resultant hydrogel was formulated into composite hydrogels that were then used for the treatment of full-thickness excisional wounds in a db/db diabetic mouse model. Wound closure and histological evaluation confirmed its beneficial effect on wound healing. Further morphological analysis through scanning electron microscopy images revealed a porous hydrogel structure, while Fourier-transform infrared spectroscopy provided structural insights on the crosslinking reaction. Physicochemical properties of the hybrid hydrogels determined by rheological properties, thermogravimetric, water loss rate, et al., indicated that the double crosslinking PCOS/CMC hybrid hydrogel showed enhanced dynamic mechanical properties and water retention capacity compared to the CMC cellulose matrix hydrogels. Thus, this novel PCOS-hybrid hydrogel exhibited good dissolvability and injectable properties, which was proved to facilitate for the diabetic wound healing both in vitro and in vivo test and holds a potential clinical application in the wound healing.

The transcription factor GATA6 accelerates vascular smooth muscle cell senescence-related arterial calcification by counteracting the role of anti-aging factor SIRT6 and impeding DNA damage repair.

Arterial calcification is a hallmark of vascular pathology in the elderly and in individuals with chronic kidney disease (CKD). Vascular smooth muscle cells (VSMCs), after attaining a senescent phenotype, are implicated in the calcifying process. However, the underlying mechanism remains to be elucidated. Here, we reveal an aberrant upregulation of transcriptional factor GATA6 in the calcified aortas of humans, mice with CKD and mice subjected to vitamin D3 injection. Knockdown of GATA6, via recombinant adeno-associated virus carrying GATA6 shRNA, inhibited the development of arterial calcification in mice with CKD. Further gain- and loss-of function experiments in vitro verified the contribution of GATA6 in osteogenic differentiation of VSMCs. Samples of human aorta exhibited a positive relationship between age and GATA6 expression and GATA6 was also elevated in the aortas of old as compared to young mice. Calcified aortas displayed senescent features with VSMCs undergoing premature senescence, blunted by GATA6 downregulation. Notably, abnormal induction of GATA6 in senescent and calcified aortas was rescued in Sirtuin 6 (SIRT6)-transgenic mice, a well-established longevity mouse model. Suppression of GATA6 accounted for the favorable effect of SIRT6 on VSMCs senescence prevention. Mechanistically, SIRT6 inhibited the transcription of GATA6 by deacetylation and increased degradation of transcription factor Nkx2.5. Moreover, GATA6 was induced by DNA damage stress during arterial calcification and subsequently impeded the Ataxia-telangiectasia mutated (ATM)-mediated DNA damage repair process, leading to accelerated VSMCs senescence and osteogenic differentiation. Thus, GATA6 is a novel regulator in VSMCs senescence. Our findings provide novel insight in arterial calcification and a potential new target for intervention.

Pyramiding BPH genes in rice maintains resistance against the brown planthopper under climate change.

BACKGROUND: Nilaparvata lugens (brown planthopper; BPH) is a significant rice pest in Asia, causing substantial yield losses. Pyramiding BPH resistance genes with diverse resistance traits into rice cultivars is an effective strategy for pest management. However, the response of pyramiding combinations to environmental changes remains unclear. To address this knowledge gap, we investigated three pyramiding rice lines (BPH2 + 32, BPH9 + 32, and BPH18 + 32) in the context of varying climate change conditions, ensuring sufficient N. lugens-rice interactions. Thus, we set three environmental conditions [30/25 °C (day/night) with 500 ppm CO2 concentration, 32/27 °C (day/night) with 600 ppm CO2 concentration, and 35/30 °C (day/night) with 1000 ppm CO2 concentration]. RESULTS: All three pyramiding rice lines maintained the insect resistant ability under the three environmental settings. In particular, the BPH18 + 32 rice line exhibited stronger antibiotic and antixenosis effects against N. lugens. In addition, BPH18 + 32 rice line had better shoot resilience under N. lugens infestation, whereas the performance of the other two selected pyramiding rice lines varied. Thus, although BPH2, BPH9, and BPH18 represent three alleles at the same locus, their resistance levels against N. lugens may vary under distinct climate change scenarios, as evidenced by the performance of N. lugens on the three pyramiding rice lines. CONCLUSION: Our findings indicate that all three tested pyramiding rice lines maintained their insect resistance in the face of diverse climate change scenarios. However, these lines exhibited varied repellent responses and resilience capacities in response to climate change. Thus, the combination of pyramiding genes needs to be considered for future breeding programs. © 2023 Society of Chemical Industry.

Drp1 regulated PINK1-dependent mitophagy protected duck follicular granulosa cells from acute heat stress injury.

The mitochondrial quality control system is crucial in maintaining cellular homeostasis during environmental stress. Granulosa cells are the main cells secreting steroid hormones, and mitochondria are the key organelles for steroid hormone synthesis. The impact of the mitochondrial quality control system on granulosa cells' steroid hormone synthesis and survival under heat stress is still unclear. Here, we showed that acute heat stress induces mitochondrial damage and significantly increases the number of mitophagy-like vesicles in the cytoplasm of duck ovary granulosa cells at the ultra-structural level. Meanwhile, we also found heat stress significantly increased mitochondrial fission and mitophagy-related protein expression levels both in vivo and in vitro. Furthermore, by confocal fluorescence analysis, we discovered that LC3 was distributed spot-like manner near the nucleus in the heat treatment group, and the LC3 spots and lysosomes were colocalized with Mito-Tracker in the heat treatment group. We further detected the mitophagy-related protein in the cytoplasm and mitochondria, respectively. Results showed that the PINK1 protein was significantly increased both in cytoplasm and mitochondria, while the LC3-Ⅱ/LC3-Ⅰ ratio increase only occurred in mitochondrial. In addition, the autophagy protein induced by acute heat treatment was effectively inhibited by the mitophagy inhibitor CysA. Finally, we demonstrated that the alteration of cellular mitophagy by siRNA interference with Drp1 and PINK1 inhibited the steroid synthesis of granulosa cells and increased cell apoptosis. Study provides strong evidence that the Drp1 regulated PINK1-dependent mitophagy pathway protects follicular granulosa cells from acute heat stress-induced injury.

Measurements of absolute line strength of the ν1 fundamental transitions of OH radical and rate coefficient of the reaction OH + H2O2 with mid-infrared two-color time-resolved dual-comb spectroscopy.

Absolute line strengths of several transitions in the ν1 fundamental band of the hydroxyl radical (OH) have been measured by simultaneous determination of hydrogen peroxide (H2O2) and OH upon laser photolysis of H2O2. Based on the well-known quantum yield for the generation of OH radicals in the 248-nm photolysis of H2O2, the line strength of the OH radicals can be accurately derived by adopting the line strength of the well-characterized transitions of H2O2 and analyzing the difference absorbance time traces of H2O2 and OH obtained upon laser photolysis. Employing a synchronized two-color dual-comb spectrometer, we measured high-resolution time-resolved absorption spectra of H2O2 near 7.9 µm and the OH radical near 2.9 µm, simultaneously, under varied conditions. In addition to the studies of the line strengths of the selected H2O2 and OH transitions, the kinetics of the reaction between OH and H2O2 were investigated. A pressure-independent rate coefficient kOH+H2O2 was determined to be [1.97 (+0.10/-0.15)] × 10-12 cm3 molecule-1 s-1 at 296 K and compared with other experimental results. By carefully analyzing both high-resolution spectra and temporal absorbance profiles of H2O2 and OH, the uncertainty of the obtained OH line strengths can be achieved down to <10% in this work. Moreover, the proposed two-color time-resolved dual-comb spectroscopy provides a new approach for directly determining the line strengths of transient free radicals and holds promise for investigations on their self-reaction kinetics as well as radical-radical reactions.

Sexual differentiation of neural mechanisms of stress sensitivity during puberty.

Anxiety disorders are a major public health concern and current treatments are inadequate for many individuals. Anxiety is more common in women than men and this difference arises during puberty. Sex differences in physiological stress responses may contribute to this variability. During puberty, gonadal hormones shape brain structure and function, but the extent to which these changes affect stress sensitivity is unknown. We examined how pubertal androgens shape behavioral and neural responses to social stress in California mice (Peromyscus californicus), a model species for studying sex differences in stress responses. In adults, social defeat reduces social approach and increases social vigilance in females but not males. We show this sex difference is absent in juveniles, and that prepubertal castration sensitizes adult males to social defeat. Adult gonadectomy does not alter behavioral responses to defeat, indicating that gonadal hormones act during puberty to program behavioral responses to stress in adulthood. Calcium imaging in the medioventral bed nucleus of the stria terminalis (BNST) showed that social threats increased neural activity and that prepubertal castration generalized these responses to less threatening social contexts. These results support recent hypotheses that the BNST responds to immediate threats. Prepubertal treatment with the nonaromatizable androgen dihydrotestosterone acts in males and females to reduce the effects of defeat on social approach and vigilance in adults. These data indicate that activation of androgen receptors during puberty is critical for programming behavioral responses to stress in adulthood.

Insights into the Mechanism of Supramolecular Self-Assembly in the Astragalus membranaceus-Angelica sinensis Codecoction.

Astragalus membranaceus (Fisch.) Bge. (AM) and Angelica sinensis (Oliv.) Diels (AS) constitute a classic herb pair in prescriptions to treat myocardial fibrosis. To date, research on the AM-AS herb pair has mainly focused on the chemical compositions associated with therapeutic efficacy. However, supermolecules actually exist in herb codecoctions, and their self-assembly mechanism remains unclear. In this study, supermolecules originating from AM-AS codoping reactions (AA-NPs) were first reported. The chemical compositions of AA-NPs showed a dynamic self-assembly process. AA-NPs with different decoction times had similar surface groups and amorphous states; however, the size distributions of these nanoparticles might be different. Taking the interaction between Z-ligustilide and astragaloside IV as an example to understand the self-assembly mechanism of AA-NPs, it was found that the complex could be formed with a molar ratio of 2:1. Later, AA-NPs were proven to be effective in the treatment of myocardial fibrosis both in vivo and in vitro, the in-depth mechanisms of which were related to the recovery of cardiac function, reduced collagen deposition, and inhibition of the endothelial-to-mesenchymal transition that occurred in the process of myocardial fibrosis. Thus, AA-NPs may be the chemical material basis of the molecular mechanism of the AM-AS decoction in treating isoproterenol-induced myocardial fibrosis. Taken together, this work provides a supramolecular strategy for revealing the interaction between effective chemical components in herb-pair decoctions.

Generic Interpretable Reaction Condition Predictions with Open Reaction Condition Datasets and Unsupervised Learning of Reaction Center.

Effective synthesis planning powered by deep learning (DL) can significantly accelerate the discovery of new drugs and materials. However, most DL-assisted synthesis planning methods offer either none or very limited capability to recommend suitable reaction conditions (RCs) for their reaction predictions. Currently, the prediction of RCs with a DL framework is hindered by several factors, including: (a) lack of a standardized dataset for benchmarking, (b) lack of a general prediction model with powerful representation, and (c) lack of interpretability. To address these issues, we first created 2 standardized RC datasets covering a broad range of reaction classes and then proposed a powerful and interpretable Transformer-based RC predictor named Parrot. Through careful design of the model architecture, pretraining method, and training strategy, Parrot improved the overall top-3 prediction accuracy on catalysis, solvents, and other reagents by as much as 13.44%, compared to the best previous model on a newly curated dataset. Additionally, the mean absolute error of the predicted temperatures was reduced by about 4 °C. Furthermore, Parrot manifests strong generalization capacity with superior cross-chemical-space prediction accuracy. Attention analysis indicates that Parrot effectively captures crucial chemical information and exhibits a high level of interpretability in the prediction of RCs. The proposed model Parrot exemplifies how modern neural network architecture when appropriately pretrained can be versatile in making reliable, generalizable, and interpretable recommendation for RCs even when the underlying training dataset may still be limited in diversity.