Stable Interstrand Cross-Links Generated from the Repair of 1,N6-Ethenoadenine in DNA by α-Ketoglutarate/Fe(II)-Dependent Dioxygenase ALKBH2.

DNA cross-links severely challenge replication and transcription in cells, promoting senescence and cell death. In this paper, we report a novel type of DNA interstrand cross-link (ICL) produced as a side product during the attempted repair of 1,N6-ethenoadenine (εA) by human α-ketoglutarate/Fe(II)-dependent enzyme ALKBH2. This stable/nonreversible ICL was characterized by denaturing polyacrylamide gel electrophoresis analysis and quantified by high-resolution LC-MS in well-matched and mismatched DNA duplexes, yielding 5.7% as the highest level for cross-link formation. The binary lesion is proposed to be generated through covalent bond formation between the epoxide intermediate of εA repair and the exocyclic N6-amino group of adenine or the N4-amino group of cytosine residues in the complementary strand under physiological conditions. The cross-links occur in diverse sequence contexts, and molecular dynamics simulations rationalize the context specificity of cross-link formation. In addition, the cross-link generated from attempted εA repair was detected in cells by highly sensitive LC-MS techniques, giving biological relevance to the cross-link adducts. Overall, a combination of biochemical, computational, and mass spectrometric methods was used to discover and characterize this new type of stable cross-link both in vitro and in human cells, thereby uniquely demonstrating the existence of a potentially harmful ICL during DNA repair by human ALKBH2.

The protein kinase A signaling pathway mediates the effect of electroacupuncture on excessive contraction of the bladder detrusor in a rat model of neurogenic bladder.

BACKGROUND: Neurogenic bladder (NB) is a form of neurological bladder dysfunction characterized by excessive contraction of the bladder detrusor. Protein kinase A (PKA) signaling is involved in the contraction of the detrusor muscle. AIMS: To investigate whether PKA signaling mediates the effect of electroacupuncture (EA) on the excessive contraction of the bladder detrusor in NB. METHODS: Sixty rats were randomly divided into control, sham, NB, NB + EA, and NB + EA + H89 (a PKA receptor antagonist) groups. The modified Hassan Shaker spinal cord transection method was used to generate a NB model. After EA intervention for one week, urodynamic tests were used to evaluate bladder function, hematoxylin and eosin staining was conducted to assess morphological changes, enzyme-linked immunosorbent assay (ELISA) was performed to measure the concentration of PKA, and Western blotting was conducted to measure the protein levels of phosphorylated myosin light chain kinase (p-MLCK)/p-MLC. RESULTS: The results showed that NB resulted in morphological disruption, impairment of urodynamics, and decreases in the concentration of PKA and the protein levels of p-MLCK/p-MLC. EA reversed the changes induced by NB dysfunction. However, the improvement in urodynamics and the increases in the concentration of PKA and the protein levels of p-MLCK/p-MLC were inhibited by H89. CONCLUSION: Our findings indicate that the PKA signaling pathway mediates the beneficial effect of EA on excessive contraction of the bladder detrusor in a rat model of NB.

Species discrimination of multiple botanical origins of Fritillaria species based on infrared spectroscopy, thin layer chromatography-image analysis and untargeted metabolomics.

BACKGROUND: Fritillaria Bulbus (FB), a precious medicinal herb renowned for its heat-clearing, lung-moistening, cough-relieving and phlegm-eliminating effects. In pursuit of profits, unscrupulous merchants have engaged in the substitution or adulteration of valuable varieties with cheaper alternatives. It is, therefore, urgent to develop effective technical approaches to identify FBs from adulterants. METHODS: This paper employed infrared spectroscopy (IR), thin layer chromatography-image analysis (TLC-IA), and untargeted metabolomics techniques to discriminate ten species of FBs. RESULTS: Five species of FBs were successfully differentiated using mid-infrared spectroscopy. Furthermore, the power of TLC-IA technology allowed the differentiation of five species of FBs and two origins of FCBs (Fritillariae Cirrhosae Bulbus). Remarkably, through the application of untargeted metabolomics technique, the precise discrimination of five species of FBs, as well as three origins of FCBs were accomplished. Moreover, a comprehensive identification of 101 markers that reliably distinguished diverse FBs was achieved through the employment of untargeted metabolomics technique. CONCLUSION: The investigation presented powerful means of detection for assuring the quality control of Fritillaria herbs.

MATLAB language assisted data acquisition and processing in liquid chromatography Orbitrap mass spectrometry: Application to the identification and differentiation of Radix Bupleuri from its adulterants.

Comprehensive and rapid analysis of secondary metabolites like saponins remains challenging. This study aimed to establish a semi-automated workflow for filtration, identification, and characterization of saikosaponins in six Bupleurum species. Radix Bupleuri, a high-sales herbal medicine, is often adulterated, restricting its quality control and applications. Two authentic Radix Bupleuri species and four major adulterants were analyzed through UHPLC-LTQ-Orbitrap-MS for targeted saikosaponin analysis. To reveal trace saikosaponins and obtain quality fragment data, a MATLAB-based process automatically enumerating "sugar chain + aglycone + side chain" combinations and deduplicating generated a predicted saikosaponin database covering all possible saikosaponins as a precursor ion list for comprehensive targeted acquisition. To focus on informative ions and reduce MS analysis workload, we utilized MATLAB to automatically filtrate the false positive ions by MS1 and MS2 spectrometry. The newly established MATLAB-assisted data acquisition approach exhibited 50 % improvement in characterization of targeted saikosaponins. Furthermore, positive and negative ionization workflows were designed for accurate saikosaponins characterization based on fragmentation rules. In total, 707 saikosaponins were characterized, including over 500 potential new compounds and previously unreported C29 aglycones. We identified 25 saikosaponins present in both authentic species but absent in adulterants as potential markers. This unprecedented comprehensive multi-origin species differentiation demonstrates the promise of MATLAB-assisted acquisition and processing to advance saponin identification and standardize the Radix Bupleuri market.

Methods on improvements of the poor oral bioavailability of ginsenosides: Pre-processing, structural modification, drug combination, and micro- or nano- delivery system.

Panax ginseng Meyer is a traditional Chinese medicine that is widely used as tonic in Asia. The main pharmacologically active components of ginseng are the dammarane-type ginsenosides, which have been shown to have anti-cancer, anti-inflammatory, immunoregulatory, neuroprotective, and metabolic regulatory activities. Moreover, some of ginsenosides (eg, Rh2 and Rg3) have been developed into nutraceuticals. However, the utilization of ginsenosides in clinic is restrictive due to poor permeability in cells and low bioavailability in human body. Obviously, the dammarane skeleton and glycosyls of ginsenosides are responsible for these limitations. Therefore, improving the oral bioavailability of ginsenosides has become a pressing issue. Here, based on the structures of ginsenosides, we summarized the understanding of the factors affecting the oral bioavailability of ginsenosides, introduced the methods to enhance the oral bioavailability and proposed the future perspectives on improving the oral bioavailability of ginsenosides.

Ginsenoside Rh2 and its octyl ester derivative inhibited invasion and metastasis of hepatocellular carcinoma via the c-Jun/COX2/PGE2 pathway.

BACKGROUND: Liver cancer is a topical global health issue. The treatment of liver cancer meets significant challenges in the high recurrence rate and invasive incidence. Therefore, the treatment strategies that target epithelial-mesenchymal transition (EMT) induced by cyclooxygenase 2 (COX2)/ prostaglandin E2 (PGE2) pathway have become epidemic. Ginsenoside Rh2 has been proved to inhibit the EMT. However, the underlying mechanisms remain unclear. Moreover, the octyl ester derivative of Rh2 (Rh2-O) exhibited superior anti-proliferative and immunomodulatory effects than Rh2 in our previous researches, which indicated that Rh2-O might also exert inhibitory effects on invasion and metastasis. PURPOSE: The aim of current study is to explore the inhibitory effects of Rh2 and Rh2-O on invasion and metastasis of hepatocellular carcinoma, and to investigate whether these effects are dependent on the c-Jun/COX2/PGE2 pathway. STUDY DESIGN: The Huh-7 liver cancer cells and the H22 tumor-bearing mice were treated with Rh2 and Rh2-O. METHOD: In this paper, the inhibitory effects of Rh2 and Rh2-O on invasion and metastasis were tested by wound healing, trans-well assay and tumor-bearing mice, and the involvement of c-Jun/COX2/PGE2 pathway were verified by exogenous PGE2, activation of COX2 and overexpression of c-Jun. RESULTS: The results showed that Rh2 and Rh2-O could efficiently inhibit the invasion and metastasis in a dose-dependent manner (p < 0.05). And the Rh2-O showed stronger effects than Rh2. Moreover, the exogenous PGE2, activation of COX2 by exogenous LPS and the overexpression of c-Jun by transfection all reversed the inhibitory effects of Rh2 and Rh2-O on metastasis or EMT (p < 0.05). CONCLUSION: Rh2 and Rh2-O could inhibit the invasion and metastasis of hepatocellular carcinoma via restraining the EMT, which was mediated by c-Jun/COX2/PGE2 pathway.

Systematical characterization of gypenosides in Gynostemma pentaphyllum and the chemical composition variation of different origins.

Gynostemma pentaphyllum (Thunb.) Makino is an herbaceous plant of Cucurbitaceae family, which has been widely used as an herbal tea and traditional Chinese medicine. Since its saponins are similar to ginsenosides and have a wide range of activities, it has attracted wide interest. However, there are still a large number of unknown saponins that have not been isolated, especially some trace gypenosides. In the present study, a HILIC × RP offline two-dimensional liquid separation combined with a multimode data acquisition was developed for the systematical characterization of gypenosides. On top of the negative mode information, considering that saponins are prone to in-source fragmentations in positive ion mode, a precursor ion list data acquisition method was used for the targeted acquisition of multistage positive data. Reference herbal drug was taken as a golden sample to probe the chemical composition of G. pentaphyllum. The mixed sample of commercially available samples were also analyzed in parallel. Furthermore, the chemical compositions of commercially available samples from different sources were compared. In total, 1108 saponins were characterized, among which 588 were accurately characterized, with 574 identified in the reference herbal drug and 700 in the mixed commercially available samples. The commercially available samples showed great composition variation. These findings clarified the material basis and provided clues for quality control of G. pentaphyllum.

[Mechanism of blood-activating and mass-dissipating Chinese patent medicine against hyperplasia of mammary glands and use with other medicine: a review].

Caused by endocrine disorder, hyperplasia of mammary glands(HMG) tends to occur in the young with increasing incidence, putting patients at the risk of cancer and threatening the health of women. Therefore, the prevention and treatment of HMG is attracting more and more attention. Amid the modernization of traditional Chinese medicine(TCM), many scholars have found that Chinese patent medicine has unique advantages and huge potential in treatment of endocrine disorder. Particularly, Chinese patent medicine with the function of blood-activating and mass-dissipating, such as Xiaojin Pills and Xiaozheng Pills, has been commonly used in clinical treatment of HMG, which features multiple targets, obvious efficacy, small side effect, and ease of taking and carrying around. Clinical studies have found that the combination of Chinese patent medicine with other medicine can not only improve the efficacy and relieve symptoms such as hyperplasia and pain but also reduce the toxic and side effects of western medicine. Therefore, based on precious pharmacological research and clinical research, this study reviewed the mechanisms of blood-activating mass-dissipating Chinese patent medicine alone and in combination with other medicine, such as regulating levels of in vivo hormones and receptors, promoting apoptosis, inhibiting angiogenesis, improving hemorheology indexes, enhancing immunity, and boosting antioxidant ability. In addition, limitations and problems were summarized. Thereby, this study is expected to lay a theoretical basis for the further study and clinical application of blood-activating mass-dissipating Chinese patent medicine alone or in combination with other medicine against HMG.

Dihydroartemisinin elicits immunogenic death through ferroptosis-triggered ER stress and DNA damage for lung cancer immunotherapy.

BACKGROUND: The immunosuppressive microenvironment of lung cancer serves as an important endogenous contributor to treatment failure. The present study aimed to demonstrate the promotive effect of DHA on immunogenic cell death (ICD) in lung cancer as well as the mechanism. METHODS: The lewis lung cancer cells (LLC), A549 cells and LLC-bearing mice were applied as the lung cancer model. The apoptosis, ferroptosis assay, western blotting, immunofluorescent staining, qPCR, comet assay, flow cytometry, confocal microscopy, transmission electron microscopy and immunohistochemistry were conducted to analyze the functions and the underlying mechanism. RESULTS: An increased apoptosis rate and immunogenicity were detected in DHA-treated LLC and tumor grafts. Further findings showed DHA caused lipid peroxide (LPO) accumulation, thereby initiating ferroptosis. DHA stimulated cellular endoplasmic reticulum (ER) stress and DNA damage simultaneously. However, the ER stress and DNA damage induced by DHA could be abolished by ferroptosis inhibitors, whose immunogenicity enhancement was synchronously attenuated. In contrast, the addition of exogenous iron ions further improved the immunogenicity induced by DHA accompanied by enhanced ER stress and DNA damage. The enhanced immunogenicity could be abated by ER stress and DNA damage inhibitors as well. Finally, DHA activated immunocytes and exhibited excellent anti-cancer efficacy in LLC-bearing mice. CONCLUSIONS: In summary, the current study demonstrates that DHA triggers ferroptosis, facilitating the ICD of lung cancer thereupon. This work reveals for the first time the effect and underlying mechanism by which DHA induces ICD of cancer cells, providing novel insights into the regulation of the immune microenvironment for cancer immunotherapy by Chinese medicine phytopharmaceuticals.

[Kaiqiao Jieyin acupuncture combined with repetitive transcranial magnetic stimulation for post-stroke aphasia: a randomized controlled trial].

OBJECTIVE: To observe the effect of Kaiqiao Jieyin acupuncture (acupuncture for opening orifices and relieving aphasia) combined with repetitive transcranial magnetic stimulation (rTMS) on language ability and daily life communication ability in patients with post-stroke aphasia (PSA). METHODS: Fifty-six patients with PSA were randomly divided into an observation group and a control group, 28 cases in each group. Both groups received routine symptomatic treatment. The control group was treated with speech rehabilitation training and rTMS. On the basis of the treatment in the control group, the observation group was treated with Kaiqiao Jieyin acupuncture at the speech area Ⅰ, Fengchi (GB 20), Tongli (HT 5), Lianquan (CV 23), Panglianquan (Extra), etc. Panglianquan (Extra) on both sides were connected to electroacupuncture, with intermittent wave, 2 Hz in frequency. The above treatment was performed once a day for 5 consecutive days, followed by 2 days of rest for 2 weeks. The scores of western aphasia battery (WAB, including scores of spontaneous speech, auditory comprehension, repetition, naming and score of aphasia quotient [AQ]) and communication abilities in daily living (CADL) in the two groups were compared before and after treatment. RESULTS: After treatment, the spontaneous speech, auditory comprehension, repetition, naming scores and AQ scores in both groups were higher than those before treatment (P<0.05), and the increase in the observation group was greater than the control group (P<0.05). The CADL scores of the two groups were higher than those before treatment (P<0.05). CONCLUSION: Kaiqiao Jieyin acupuncture combined with rTMS can improve the language ability and daily life communication ability of PSA patients.

A new modified pterocarpan glycoside from Sophora flavescens.

Sophora flavescens is a widely used traditional Chinese herbal medicine. In this work, a new pterocarpan glycoside, kurarinol C (1) together with six known compounds, sophoracarpan A (2), trifohrhizin-6'-monoacetate (3), trifohrhizin (4), maackiain (5), (6S,6aS,11aR）-6α-methoxy-pterocarpin (6), L-maackiain (7) were isolated from the roots of S. flavescens. Among them, compounds 2 and 6 were discovered from S. flavescens for the first time. Their chemical structures were elucidated on the basis of extensive NMR and MS analyses. Furthermore, the antioxidant activities of these compounds were evaluated by the ABTS and DPPH free radical scavenging assay. Three compounds (5, 6, 7) exhibited stronger antioxidant capacity against the ABTS enzyme at 20 µg/mL (scavenging rates > 55%).

Icotinib, an EGFR tyrosine kinase inhibitor, as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma: a multicenter, open-label, single-arm, phase II study (ICAPE).

The survival benefit of icotinib (an oral epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor) in patients with advanced lung cancer has been confirmed in several studies. This study (ICAPE) evaluated the efficacy of icotinib as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma. Patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma were enrolled in the multicenter, open-label, single-arm, phase II study. Eligible patients received oral icotinib 125 mg thrice daily for 1.5 years after complete surgical resection. The primary endpoint was disease-free survival (DFS). Between March 2014 and January 2018, 79 patients were enrolled. The median follow-up time was 39.7 months with a median DFS and overall survival (OS) of 41.4 months (95% CI: 33.6-51.8) and 67.0 months (95% CI: 21.2-not reached [NR]), respectively. The 1-year, 3-year, and 5-year OS rates were 100%, 83.3%, and 61.7%, respectively. No significant difference was found in the median DFS between patients with Bcl-2 interacting mediator of cell death (BIM) mutant-type and wild-type (NR vs. 41.7 months; p = 0.75). No significant difference was found in the median DFS according to EGFR mutation types. Icotinib as adjuvant therapy demonstrated a favorable survival benefit in patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma, indicating that icotinib might be a promising treatment option for this patient population. The optimal adjuvant duration of icotinib is still not clear and needs more incoming data to answer.

Systematic elucidation of the bioactive alkaloids and potential mechanism from Sophora flavescens for the treatment of eczema via network pharmacology.

ETHNOPHARMACOLOGY RELEVANCE: Sophora flavescens is a frequently used traditional Chinese medicine (TCM) for the treatment of skin disorders, diarrhea, vaginal itching and inflammatory diseases. In particular, the root of S. flavescens combination with other herbs mainly treat eczema ailment in the clinical applications. However, a holistic network pharmacology approach to understanding the mechanism by which alkaloids in S. flavescens treat eczema has not been pursued. AIM OF THE STUDY: To examine the network pharmacological potential effect of S. flavescens on eczema, we studied the alkaloids, performed protein targets prediction and investigated interacting signal pathways. Furthermore, animal experiment was carried out to evaluate its efficacy and real-time quantitative polymerase chain reactions (RT-qPCR) analysis was explored the mechanism of action. MATERIALS AND METHODS: The detail information on alkaloids from S. flavescens were obtained from a handful of public databases on the basis of oral bioavailability (OB ≥ 30%) and drug-likeness (DL ≥ 0.18). Then, correlations between compounds and protein targets were linked using the STRING database, and targets associated with eczema were gathered by the GeneCards database. Human genes were identified and subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) functional enrichment analysis. Particularly, matrine, the crucial alkaloid from S. flavescens, was estimated using a 2,4-dinitrochlorobenzene (DNCB)-induced eczema Kunming (KM) mice model, administered (50 mg/kg and 10 mg/kg) to mice for 22 days. On the last day, the activities of serum tumor necrosis factor α (TNF-α), interleukin-4 (IL-4) and histopathologic examinations were determined. For further to elucidate the mechanisms, the mRNA levels of TNF-α, STAT3, TP53, AKT1, IL-6, JUN and EGFR in dorsal skin tissues were also tested. RESULTS: Network analysis collected and identified 35 alkaloids from S. flavescens. Among them, in total 10 dominating alkaloids, including matrine, oxymatrine, sophoridine, sophocarpine, oxysophocarpine, allomatrine, sophoramine, anagyrine, cytisine and N-methylcytisine. And 71 related targets were provided of alkaloids for the treatment of eczema from S. flavescens. Furthermore, matrine dose-dependently (50 or 10 mg/kg, 22 days, apply to dorsal skin) remarkable decreased the serum levels of TNF-α and IL-4, and significantly alleviated the skin lesions. The effects of 50 mg/kg of matrine were almost identical to those of 200 mg/kg of the positive drug dexamethasone (DXM). The further RT-qPCR analyses could reveal that matrine down-regulate TNF-α, STAT3 and TP53 at transcriptional level in dorsal skin tissues. CONCLUSION: Pharmacological network analysis can utilize to illuminate the pharmacodynamic substances and the potential molecular mechanism of S. flavescens for treating eczema. Matrine, as the crucial alkaloid from S. flavescens, could be a promising drug candidate for the treatment of eczema ailment.

Mechanism of blood-activating and mass-dissipating Chinese patent medicine against hyperplasia of mammary glands and use with other medicine: a review / 中国中药杂志

Caused by endocrine disorder, hyperplasia of mammary glands(HMG) tends to occur in the young with increasing incidence, putting patients at the risk of cancer and threatening the health of women. Therefore, the prevention and treatment of HMG is attracting more and more attention. Amid the modernization of traditional Chinese medicine(TCM), many scholars have found that Chinese patent medicine has unique advantages and huge potential in treatment of endocrine disorder. Particularly, Chinese patent medicine with the function of blood-activating and mass-dissipating, such as Xiaojin Pills and Xiaozheng Pills, has been commonly used in clinical treatment of HMG, which features multiple targets, obvious efficacy, small side effect, and ease of taking and carrying around. Clinical studies have found that the combination of Chinese patent medicine with other medicine can not only improve the efficacy and relieve symptoms such as hyperplasia and pain but also reduce the toxic and side effects of western medicine. Therefore, based on precious pharmacological research and clinical research, this study reviewed the mechanisms of blood-activating mass-dissipating Chinese patent medicine alone and in combination with other medicine, such as regulating levels of in vivo hormones and receptors, promoting apoptosis, inhibiting angiogenesis, improving hemorheology indexes, enhancing immunity, and boosting antioxidant ability. In addition, limitations and problems were summarized. Thereby, this study is expected to lay a theoretical basis for the further study and clinical application of blood-activating mass-dissipating Chinese patent medicine alone or in combination with other medicine against HMG.

[Mechanism of anti-hyperplasia of mammary glands of Xihuang Pills blood-entering component based on UPLC-Q-TOF-MS and network pharmacology].

In this study, based on network pharmacology and molecular docking method, the mechanism of anti-hyperplasia of mammary glands of Xihuang Pills blood-entering components was explored, and the efficacy and key targets of Xihuang Pills blood-entering components were experimentally verified by MCF-10A proliferation model of human mammary epithelial cells. In order to clarify the material basis and mechanism of Xihuang Pills in realizing anti-hyperplasia of mammary glands, the blood-entering components of Xihuang Pills were qualitatively analyzed by UPLC-Q-TOF-MS, and 22 blood-entering components were identified. By taking the blood-entering components as the research object, the network pharmacology prediction and molecular docking verification were carried out, and finally, three key targets were screened out, namely JAK1, SRC, and CDK1. In vitro experiments show that Xihuang Pills can inhibit the proliferation of MCF-10A cells, promote the apoptosis of MCF-10A cells, and reduce the expression of JAK1, SRC, and CDK1 targets in cells. To sum up, Xihuang Pills can promote the apoptosis of mammary epithelial cells by regulating the expression of JAK1, SRC, and CDK1 and then play an anti-hyperplasia role, which provides an experimental basis for clarifying the material basis of Xihuang Pills for anti-hyperplasia effect.

[Chinese medicinal formulae treat inflammatory bowel diseases through maintaining gut flora homeostasis].

Inflammatory bowel disease(IBD) is a chronic and recurrent inflammatory disorder of the gut, including Crohn's disease(CD) and ulcerative colitis(UC). The occurrence and development of IBD involves multiple pathogenic factors, and the dybiosis of gut flora is recognized as an important pathogenic mechanism of IBD. Therefore, restoring and maintaining the balance of gut flora including bacteria and fungi has become an effective option for IBD treatment. Based on the theoretical basis of the interaction between gut flora and IBD, this paper followed the principle of clinical syndrome differentiation for IBD therapy by traditional Chinese medicine(TCM), and summarized several Chinese medicinal formulae commonly used in IBD patients with large intestine damp-heat syndrome, intermingled heat and cold syndrome, spleen deficiency and dampness accumulation syndrome, spleen and kidney yang deficiency syndrome, liver stagnation and spleen deficiency syndrome, and severe heat poisoning syndrome. The therapeutic and regulatory effects of Shaoyao Decoction, Qingchang Suppository, Wumei Pills, Banxia Xiexin Decoction, Shenling Baizhu Powder, Lizhong Decoction, Sishen Pills, Tongxie Yaofang, Baitouweng Decoction, Gegen Qinlian Decoction, and Houttuyniae Herba prescriptions on gut flora of IBD patients were emphasized as well as the mechanisms. This study found that Chinese medicinal formulae increased the abundance of Bacteroidetes, Bifidobacteria, Lactobacillus, and other beneficial bacteria producing short-chain fatty acids, and reduced the abundance of Enterobacteriaceae and other harmful bacteria to restore the balance of gut flora, thus treating IBD. Confronting the recalcitrance and high recurrence of IBD, Chinese medicinal formulae provide new opportunities for IBD treatment through intervening dysbiosis of gut flora.

Iron/photoredox dual catalysis for acyl nitrene-based C-O bond formation towards phthalides.

This paper describes iron/photoredox dual-catalyzed acyl nitrene formation and the use of acyl nitrene in constructing various C-O bonds towards phthalides. The developed reaction starts from N-methoxyl-2-alkylbenzamides. Mechanism surveys suggest the reaction involves iron nitrene-based hydrogen atom abstraction (HAA), radical-polar crossover and O-nucleophilic SN1. Distinctively, the often-reported radical rebound in previous publications is not observed. The reaction represents the first example on acyl nitrene-based synthesis of phthalides. Moreover, it also serves as a supplement for the synthesis of marketed medicines such as 3-butylphthalides (NBP), thalidomide, Pomalyst and Otezia.

Dihydroartemisinin remodels macrophage into an M1 phenotype via ferroptosis-mediated DNA damage.

Lung cancer recruits tumor-associated macrophages (TAMs) massively, whose predominantly pro-tumor M2 phenotype leads to immunosuppression. Dihydroartemisinin (DHA) has been proven to remodel TAM into an anti-tumor M1 phenotype at certain concentrations in the present study, which was hypothesized to facilitate anti-lung cancer immunotherapy. However, how DHA remodels the TAM phenotype has not yet been uncovered. Our previous work revealed that DHA could trigger ferroptosis in lung cancer cells, which may also be observed in TAM thereupon. Sequentially, in the current study, DHA was found to remodel TAM into the M1 phenotype in vitro and in vivo. Simultaneously, DHA was observed to trigger ferroptosis in TAM and cause the DNA damage response and NF-κB activation. Conversely, the DHA-induced DNA damage response and NF-κB activation in TAM were attenuated after the inhibition of ferroptosis in TAM using an inhibitor of ferroptosis. Importantly, a ferroptosis inhibitor could also abolish the DHA-induced phenotypic remodeling of TAM toward the M1 phenotype. In a nutshell, this work demonstrates that DHA-triggered ferroptosis of TAM results in DNA damage, which could activate downstream NF-κB to remodel TAM into an M1 phenotype, providing a novel strategy for anti-lung cancer immunotherapy. This study offers a novel strategy and theoretical basis for the use of traditional Chinese medicine monomers to regulate the anti-tumor immune response, as well as a new therapeutic target for TAM phenotype remodeling.