Whole-protein enteral nutrition formula supplementation reduces Escherichia and improves intestinal barrier function in HIV-infected immunological nonresponders.

People living with human immunodeficiency virus (PLWH) have persistent malnutrition, intestinal barrier dysfunction, and gut microbial imbalance. The interplay between gut microbiota and nutrients is involved in the immune reconstitution of PLWH. To evaluate the effects of whole-protein enteral nutrition formula supplementation on T-cell levels, intestinal barrier function, nutritional status, and gut microbiota composition in human immunodeficiency virus (HIV)-infected immunological nonresponders (INRs) who failed to normalize CD4+ T-cell counts, with a number <350 cells/µL, a pilot study was carried out in 13 HIV-infected INRs undergoing antiretroviral therapy who received a 3-month phase supplementation of 200 mL/200 kcal/45 g whole-protein enteral nutrition formula once daily. Our primary endpoint was increased CD4+ T-cell counts. Secondary outcome parameters were changes in intestinal barrier function, nutritional status, and gut microbiota composition. We showed that CD4+ T-cell counts of HIV-infected INRs increased significantly after the 3-month supplementation. Dietary supplementation for 3 months improved the intestinal barrier function and nutritional status of HIV-infected INRs. Furthermore, the enteral nutrition formula significantly decreased the relative abundance of Escherichia at the genus level and increased the alpha diversity of gut microbiota in HIV-infected INRs. The findings demonstrated that the whole-protein enteral nutrition formula aids in reducing Escherichia and improving intestinal barrier function in HIV-infected INRs. This study provides insight into the role of nutrients in the improvement of immune reconstitution in HIV-infected INRs. This study is registered in the Chinese Clinical Trial Registry (Document No. ChiCTR2000037839; http://www.chictr.org.cn/index.aspx).

In silico identification of natural compounds against SARS-CoV-2 main protease from Chinese herbal medicines.

Aims: To determine natural compounds with inhibitory effects toward SARS-CoV-2 Mpro from Chinese herbal medicines. Materials & methods: ∼1200 natural compounds from 19 Chinese herbal medicines were collected. Computational methods including molecular docking, drug-likeness assessment, molecular dynamics simulation and molecular mechanics Poisson-Boltzmann surface area analysis were combined to obtain potent inhibitors against SARS-CoV-2 Mpro. Results: Top 20 compounds mainly originated from Ranunculus ternatus and Picrasma quassioides exhibited low binding free energies which below -9.0 kcal/mol. Compounds Japonicone G and Picrasidine T were obtained with favorable drug-likeness. Moreover, the complex of Japonicone G and Mpro had prominent stability. Conclusion: Natural compound Japonicone G is highly promising as a potent inhibitor against SARS-CoV-2 for further study.

Impact of lockdown policies during the COVID-19 outbreak on a trauma center of a tertiary hospital in China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a major and costly public health emergency. AIM: To investigate the impact of China's lockdown policies during the COVID-19 outbreak on the level I trauma center of a tertiary comprehensive hospital of Traditional Chinese Medicine. METHODS: All patients admitted to our trauma center during a lockdown in 2020 and the same period in 2019 were enrolled. We collected data on demographics, daily visits, injury type, injury mechanism, injury severity score, and patient management for comparative analysis. RESULTS: The total number of patients in the trauma center of our hospital decreased by 50.38% during the COVID-19 Lockdown in 2020 compared to the same period in 2019. The average number of trauma visits per day in 2019 was 47.94, compared to 23.79 in 2020. Comparing the patients' demographic data, loss of employment was the most predominate characteristic in 2020 compared to 2019, while there was no significant difference in gender, age, and marital status between both periods. During the lockdown period, the proportion of traffic accident-related injuries, injuries due to falls greater than 1.5 m, and mechanical injuries decreased significantly, whereas the proportion of injuries caused by falls less than 1.5 m, cuts, assault, bites, and suicidal tendencies and other injuries increased relatively. In addition, the proportion of patients with minor injuries increased and serious injuries decreased during the lockdown. The hospitalization rate increased significantly, and there was no significant difference in emergency surgery and death rates. CONCLUSION: The lockdown policies during the COVID-19 outbreak significantly altered the number and mechanism of traumatic events in our hospital, which can be monitored regularly. Our results suggest that mandatory public health prevention and control measures by the government can reduce the incidence of traumatic events and the severity of traumatic injuries. Emergency surgery and mortality rates remain high, increased because of factors such as family injury and penetrating injury, and hospitalization rates have increased significantly. Therefore, our trauma center still needs to be fully staffed. Finally, from the perspective of the injury mechanism, indoor trauma is a major risk during a lockdown, and it is particularly important to develop prevention strategies for such trauma to reduce the medical burden of the next catastrophic epidemic.

Discovery of 3CLpro inhibitor of SARS-CoV-2 main protease.

Coronavirus main protease (3CLpro), a special cysteine protease in coronavirus family, is highly desirable in the life cycle of coronavirus. Here, molecular docking, ADMET pharmacokinetic profiles and molecular dynamics (MD) simulation were performed to develop specific 3CLpro inhibitor. The results showed that the 137 compounds originated from Chinese herbal have good binding affinity to 3CLpro. Among these, Cleomiscosin C, (+)-Norchelidonine, Protopine, Turkiyenine, Isochelidonine and Mallotucin A possessed prominent drug-likeness properties. Cleomiscosin C and Turkiyenine exhibited excellent pharmacokinetic profiles. Furthermore, the complex of Cleomiscosin C with SARS-CoV-2 main protease presented high stability. The findings in this work indicated that Cleomiscosin C is highly promising as a potential 3CLpro inhibitor, thus facilitating the development of effective drugs for COVID-19.

In this work, computer aided drug design technology was used to study the main protease 3CLpro of novel coronavirus, and functional small molecules with inhibitory effects on novel coronavirus were screened from the compound library of natural products. The results showed that Cleomiscosin C is highly promising as a potential 3CLpro inhibitor with prominent binding affinity, pharmacokinetic profiles and stability.

AAV-glycine receptor α3 alleviates CFA-induced inflammatory pain by downregulating ERK phosphorylation and proinflammatory cytokine expression in SD rats.

BACKGROUND: Glycine receptors (GlyRs) play key roles in the processing of inflammatory pain. The use of adeno-associated virus (AAV) vectors for gene therapy in human clinical trials has shown promise, as AAV generally causes a very mild immune response and long-term gene transfer, and there have been no reports of disease. Therefore, we used AAV for GlyRα1/3 gene transfer in F11 neuron cells and into Sprague-Dawley (SD) rats to investigate the effects and roles of AAV-GlyRα1/3 on cell cytotoxicity and inflammatory response. METHODS: In vitro experiments were performed using plasmid adeno-associated virus (pAAV)-GlyRα1/3-transfected F11 neurons to investigate the effects of pAAV-GlyRα1/3 on cell cytotoxicity and the prostaglandin E2 (PGE2)-mediated inflammatory response. In vivo experiment, the association between GlyRα3 and inflammatory pain was analyzed in normal rats after AAV-GlyRα3 intrathecal injection and after complete Freund's adjuvant (CFA) intraplantar administration. Intrathecal AAV-GlyRα3 delivery into SD rats was evaluated in terms of its potential for alleviating CFA-induced inflammatory pain. RESULTS: The activation of mitogen-activated protein kinase (MAPK) inflammatory signaling and neuronal injury marker activating transcription factor 3 (ATF-3) were evaluated by western blotting and immunofluorescence; the level of cytokine expression was measured by ELISA. The results showed that pAAV/pAAV-GlyRα1/3 transfection into F11 cells did not significantly reduce cell viability or induce extracellular signal-regulated kinase (ERK) phosphorylation or ATF-3 activation. PGE2-induced ERK phosphorylation in F11 cells was repressed by the expression of pAAV-GlyRα3 and administration of an EP2 inhibitor, GlyRαs antagonist (strychnine), and a protein kinase C inhibitor. Additionally, intrathecal AAV-GlyRα3 administration to SD rats significantly decreased CFA-induced inflammatory pain and suppressed CFA-induced ERK phosphorylation, did not induce obvious histopathological injury but increased ATF-3 activation in dorsal root ganglion (DRGs). CONCLUSIONS: Antagonists of the prostaglandin EP2 receptor, PKC, and glycine receptor can inhibit PGE2-induced ERK phosphorylation. Intrathecal AAV-GlyRα3 administration to SD rats significantly decreased CFA-induced inflammatory pain and suppressed CFA-induced ERK phosphorylation, did not significantly induce gross histopathological injury but elicited ATF-3 activation. We suggest that PGE2-induced ERK phosphorylation can be modulated by GlyRα3, and AAV-GlyRα3 significantly downregulated CFA-induced cytokine activation.

Schaftoside inhibits 3CLpro and PLpro of SARS-CoV-2 virus and regulates immune response and inflammation of host cells for the treatment of COVID-19.

It is an urgent demand worldwide to control the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) are key targets to discover SARS-CoV-2 inhibitors. After screening 12 Chinese herbal medicines and 125 compounds from licorice, we found that a popular natural product schaftoside inhibited 3CLpro and PLpro with IC50 values of 1.73 ± 0.22 and 3.91 ± 0.19 µmol/L, respectively, and inhibited SARS-CoV-2 virus in Vero E6 cells with EC50 of 11.83 ± 3.23 µmol/L. Hydrogen-deuterium exchange mass spectrometry analysis, quantum mechanics/molecular mechanics calculations, together with site-directed mutagenesis indicated the antiviral activities of schaftoside were related with non-covalent interactions with H41, G143 and R188 of 3CLpro, and K157, E167 and A246 of PLpro. Moreover, proteomics analysis and cytokine assay revealed that schaftoside also regulated immune response and inflammation of the host cells. The anti-inflammatory activities of schaftoside were confirmed on lipopolysaccharide-induced acute lung injury mice. Schaftoside showed good safety and pharmacokinetic property, and could be a promising drug candidate for the prevention and treatment of COVID-19.

Correction: A Telehealth-Delivered Tai Chi Intervention (TaiChi4Joint) for Managing Aromatase Inhibitor-Induced Arthralgia in Patients With Breast Cancer During COVID-19: Longitudinal Pilot Study.

[This corrects the article DOI: 10.2196/34995.].

A pharmacokinetic-pharmacodynamic study to elucidate the cardiovascular protective constituents in Danhong Injection.

Danhong Injection (DHI) is one of the most popular Chinese medicine formulations to treat cardiovascular diseases. However, the effective components of DHI have not been well addressed. In the present study, a pharmacokinetics-pharmacodynamics (PK-PD) approach was employed to elucidate the effective compounds of DHI for the first time. Firstly, the cardiovascular protective effect of DHI was demonstrated on an adrenaline-induced acute blood stasis rat model by echocardiography and histopathology. Secondly, the levels of four blood stasis-related cytokines in plasma were examined by ELISA. Thirdly, the plasma concentrations of 10 compounds in DHI were determined using UHPLC-Q-Orbitrap-MS. Finally, PK-PD profiles were established to describe the relationship between compound concentrations and cytokine levels in plasma at 0-12 h following DHI administration. The results showed that DHI attenuated cardiovascular injury and regulated IL-2, cTnT, VEGF, and VEGFR-1. Except for the endogenous metabolites cytidine and uridine, danshensu, rosmarinic acid, and salvianolic acid B exhibited the highest plasma exposure. PK-PD correlation analysis indicated that concentrations of salvianolic acid A, caffeic acid, and ferulic acid were negatively correlated with the level of cTnT, while the concentration of salvianolic acid A was negatively correlated with the level of IL-2. These compounds may contribute to the cardiovascular protective effect of DHI.

A Telehealth-Delivered Tai Chi Intervention (TaiChi4Joint) for Managing Aromatase Inhibitor-Induced Arthralgia in Patients With Breast Cancer During COVID-19: Longitudinal Pilot Study.

BACKGROUND: Estrogen receptor-positive breast cancer is the most common type of breast cancer in postmenopausal women. Aromatase inhibitors (AIs) are the endocrine therapy of choice recommended for these patients. Up to 50% of those treated with an AI develop arthralgia, often resulting in poor adherence and decreased quality of life. OBJECTIVE: The study is a single-arm longitudinal pilot study aiming to evaluate the safety, feasibility, acceptability, and potential efficacy of TaiChi4Joint, a remotely delivered 12-week tai chi intervention designed to relieve AI-induced joint pain. METHODS: Women diagnosed with stage 0-III breast cancer who received an AI for at least 2 months and reported arthralgia with a ≥4 score on a 0 to 10 scale for joint pain were eligible for study enrollment. Participants were encouraged to join tai chi classes delivered over Zoom three times a week for 12 weeks. Program engagement strategies included using a private Facebook study group and a Box cloud for archiving live class recordings. The program uses SMS text messaging and emails with periodic positive quotes and evidence-based information on tai chi for facilitating community bonding and class attendance. Participants were invited to complete the following assessments at baseline and at 1-, 2-, and 3-month intervals from study enrollment: Brief Pain Inventory, Western Ontario and McMaster University Osteoarthritis Index (WOMAC), The Australian Canadian Osteoarthritis Hand Index (AUSCAN), Fatigue Symptom Inventory, Hot Flash Related Daily Interference Scale (HFRDIS), Pittsburgh Sleep Quality Index (PSQI), and Center for Epidemiological Studies-Depression (CES-D). RESULTS: A total of 55 eligible patients were invited to participate, and 39 (71%) consented and completed the baseline assessments. Participants attended 61% (median) of the suggested classes, with no tai chi-related adverse events reported. Of the 39 participants, 22 completed the 3-month follow-up assessment with a 56% retention rate. Study participants reported improvement from baseline compared to 3 months as follows (paired t test): Brief Pain Inventory (P<.001), AUSCAN pain subscale (P=.007), AUSCAN function subscale (P=.004), Fatigue Symptom Inventory (P=.004) and PSQI (P<.001), and HFRDIS (P=.02) and CES-D (P<.001). In particular, for our primary end point of interest, improvements in hip and knee symptoms, measured by WOMAC's three subscales, were clinically meaningful and statistically significant when adjusted for multiple comparisons from baseline to 3 months post intervention. CONCLUSIONS: The COVID-19 global pandemic has resulted in the need to rethink how mind-body therapies can be delivered. This study demonstrated the feasibility, acceptability, and potential efficacy of a telehealth-based tai chi intervention for reducing AI-induced arthralgia. The intervention decreased patient-reported pain and stiffness, and improved sleep quality and depressive symptoms. Fully powered, large, telehealth-based tai chi trials for AI-associated arthralgia are needed considering our promising findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT04716920; https://www.clinicaltrials.gov/ct2/show/NCT04716920.

Mucosal-associated invariant T cells: A cryptic coordinator in HIV-infected immune reconstitution.

Human immunodeficiency virus type 1 (HIV-1) infection causes considerable morbidity and mortality worldwide. Although antiretroviral therapy (ART) has largely transformed HIV infection from a fatal disease to a chronic condition, approximately 10%-40% of HIV-infected individuals who receive effective ART and sustain long-term viral suppression still cannot achieve optimal immune reconstitution. These patients are called immunological nonresponders, a state associated with poor clinical prognosis. Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved unconventional T-cell subset defined by expression of semi-invariant αß T-cell receptor (TCR), which recognizes metabolites derived from the riboflavin biosynthetic pathway presented on major histocompatibility complex-related protein-1. MAIT cells, which are considered to act as a bridge between innate and adaptive immunity, produce a wide range of cytokines and cytotoxic molecules upon activation through TCR-dependent and TCR-independent mechanisms, which is of major importance in defense against a variety of pathogens. In addition, MAIT cells are involved in autoimmune and immune-mediated diseases. The number of MAIT cells is dramatically and irreversibly decreased in the early stage of HIV infection and is not fully restored even after long-term suppressive ART. In light of the important role of MAIT cells in mucosal immunity and because microbial translocation is inversely associated with CD4+ T-cell counts, we propose that MAIT cells participate in the maintenance of intestinal barrier integrity and microbial homeostasis, thus further affecting immune reconstitution in HIV-infected individuals.

Natural triterpenoids from licorice potently inhibit SARS-CoV-2 infection.

Introduction: The COVID-19 global epidemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a great public health emergency. Discovering antiviral drug candidates is urgent for the prevention and treatment of COVID-19. Objectives: This work aims to discover natural SARS-CoV-2 inhibitors from the traditional Chinese herbal medicine licorice. Methods: We screened 125 small molecules from Glycyrrhiza uralensis Fisch. (licorice, Gan-Cao) by virtual ligand screening targeting the receptor-binding domain (RBD) of SARS-CoV-2 spike protein. Potential hit compounds were further evaluated by ELISA, SPR, luciferase assay, antiviral assay and pharmacokinetic study. Results: The triterpenoids licorice-saponin A3 (A3) and glycyrrhetinic acid (GA) could potently inhibit SARS-CoV-2 infection, with EC50 of 75 nM and 3.17 µM, respectively. Moreover, we reveal that A3 mainly targets the nsp7 protein, and GA binds to the spike protein RBD of SARS-CoV-2. Conclusion: In this work, we found GA and A3 from licorice potently inhibit SARS-CoV-2 infection by affecting entry and replication of the virus. Our findings indicate that these triterpenoids may contribute to the clinical efficacy of licorice for COVID-19 and could be promising candidates for antiviral drug development.

A network pharmacology-based strategy to explore the pharmacological mechanisms of Antrodia camphorata and antcin K for treating type II diabetes mellitus.

BACKGROUND: Diabetes mellitus is a chronic carbohydrate metabolism disorder, which could develop a series of complications and thus lead to poor quality of life or even mortality. Antrodia camphorata is a rare parasitic fungus and has been proven to be effective for treating type II diabetes. PURPOSE: This study aims to evaluate the anti-diabetic activities of A. camphorata and its main compound antcin K, as well as to demonstrate the mechanisms. STUDY DESIGN AND METHODS: Network pharmacology was used to explore the potential targets of 12 major compounds of A. camphorata on diabetes. The core targets were analyzed by protein-protein interactions and the key pathways were enriched by Kyoto Encyclopedia of Genes and Genomes (KEGG). The anti-diabetic effects of A. camphorata and antcin K were evaluated using a high-fat diet (HFD)-induced diabetic mice model and oral glucose tolerance test (OGTT). The mRNA expressions were assessed using qPCR. RESULTS: Network pharmacology revealed 17 core targets between the 12 compounds and diabetes. The insulin resistance and NF-κB signaling pathways were enriched using KEGG. Five insulin resistance-related targets were focused on and antcin K (1/2) was discovered in the compound-target-pathway network. In vivo studies exhibited that A. camphorata and antcin K could dose-dependently reduce blood levels of glucose and lipids, decrease serum levels of insulin and leptin, and increase serum levels of adiponectin in HFD mice (p < 0.05). The mechanism could be through modulating the expressions of Tnfα, Il6, and Pparγ. The OGTT test also showed the down-regulatory effects of A. camphorata and antcin K on blood glucose. CONCLUSION: This study demonstrates that A. camphorata and its major compound antcin K possess potent anti-diabetic effects. The mechanism may be through the insulin resistance pathway.

Antifungal Biphenyl Derivatives from Sorbus pohuashanensis Leaves Infected by Alternaria tenuissi and Their Effect against Crop Pathogens.

Eight natural biphenyl-type phytoalexins exhibiting antifungal effect were isolated from the leaves of Sorbus pohuashanensis, which invaded by Alternaria tenuissi, and their growth inhibition rate towards A. tenuissi were 50.3 %, 54.0 %, 66.4 %, 58.8 %, 48.5 %, 51.0 %, 33.3 %, and 37.0 %, respectively. In vivo activity assay verified the protective effect of these natural biphenyls on tobacco leaves. The observation of mycelial morphology revealed that these compounds possessed adverse effects on mycelial growth of A. tenuissi. Subsequently, the most potent active compounds, 3',4',5'-trimethoxy[1,1'-biphenyl]-4-ol (3) and 3,4,4',5-tetramethoxy-1,1'-biphenyl (4), were conducted to the further antifungal evaluation and showed significant activity against the other four crop pathogens, Fusarium graminearum, Helminthosporium maydis, Sclerotinia sclerotiorum, and Exserohilum turcicum. Further, the structure-activity relationships and biosynthesis of these compounds were speculated in this work.

Glabrone as a specific UGT1A9 probe substrate and its application in discovering the inhibitor glycycoumarin.

UDP-glucuronosyltransferase 1A9 (UGT1A9) is one of the most important UGT isoforms, and plays an important role in the metabolic elimination of therapeutic drugs via glucuronidation. Herbal medicines affecting the activity of UGT1A9 may influence the metabolism of related drugs, thus causing herb-drug interactions and even adverse effects. However, few methods are available to evaluate the activity of UGT1A9. In this study, a natural product glabrone was discovered as an isoform-specific probe substrate for UGT1A9. The Vmax and Km values of glabrone were 362.6 nmol/min/mg protein and 17.2 µM for human liver microsomes (HLMs), and 382.3 nmol/min/mg protein and 16.6 µM for recombinant human UGT1A9, respectively. Glabrone 7-O-glucuronide, the UGT1A9 metabolite of glabrone, was prepared by using a plant glucuronosyltransferase UGT88D1, and the structure was identified by NMR spectroscopy. Using glabrone as a probe, we established a rapid HPLC method to screen UGT1A9 inhibitors from 54 natural products isolated from the Chinese herbal medicine licorice. Among them, glycycoumarin was found as a potent UGT1A9 inhibitor with an IC50 value of 6.04 µM. In rats, the pretreatment of glycycoumarin (4 mg/kg, i.p.) for 3 days could remarkably increase the plasma concentrations of dapagliflozin while decrease the concentrations of dapagliflozin-O-glucuronide after administration of dapagliflozin (1 mg/kg, i.v.), which is mainly metabolized by UGT1A9. The results indicated the potential risk of herb-drug interactions between licorice and UGT1A9-metabolizing drugs.

Phytochemistry and cardiovascular protective effects of Huang-Qi (Astragali Radix).

Huang-Qi (Astragali Radix) is an herbal tonic widely used in China and many other countries. It is derived from the roots of Astragalus membranaceus and A. membranaceus var. mongholicus and shows potent cardiovascular protective effects. In this article, we comprehensively reviewed 189 small molecules isolated from the two Astragalus species and discussed the interspecies chemical differences. Moreover, we summarized the pharmacological activities and mechanisms of action of Huang-Qi and its major bioactive compounds for the treatment of cardiovascular diseases. This review covers 171 references published between February 1983 and March 2020.

Terpenoids from the medicinal mushroom Antrodia camphorata: chemistry and medicinal potential.

Covering: up to February 2020Antrodia camphorata is a medicinal mushroom endemic to Taiwan for the treatment of intoxication, liver injury, cancer, and inflammation. Owing to its rare occurrence and potent pharmacological activities, efforts have been devoted to identify its bioactive constituents, especially terpenoids. Since 1995, a total of 162 terpenoids including triterpenoids, meroterpenoids, sesquiterpenoids, diterpenoids, and steroids have been characterized. The ergostane-type triterpenoids (antcins) and meroterpenoids (antroquinonols) are characteristic constituents of A. camphorata. The terpenoids show anti-cancer, hepatoprotective, anti-inflammatory, anti-diabetic, and neuroprotective activities. This review summarizes the research progress on terpenoids in A. camphorata during 1995-2020, including structural diversity, resources, biosynthesis, pharmacological activities, metabolism, and toxicity. The medicinal potential of the terpenoids is also discussed.

Pre-Digested Protein Enteral Nutritional Supplementation Enhances Recovery of CD4+ T Cells and Repair of Intestinal Barrier in HIV-Infected Immunological Non-Responders.

AIDS patients with immune non-response are prone to malnutrition, intestinal barrier damage, thus aggravating chronic immune activation and inflammation. However, nutritional interventions targeting malnutrition may be beneficial to restore immune function, improve clinical outcomes, and reduce mortality remains largely unclear. This work aimed to evaluate the efficacy of a nutritional supplement in HIV-infected immune non-responders (INRs). The subjects received oral supplementation of a pre-digested protein nutrition formula for three months. We show that the CD4+ T and CD8+ T cell counts were significantly increased after supplementation of the pre-digested enteral nutritional supplement. Among all pro-inflammatory cytokines in the serum, only IL-1ß level was significantly decreased, while TNF-ß was significantly increased (P < 0.05). The levels of intestinal mucosal damage markers, diamine oxidase (DAO), D-lactic acid (D-lactate), and lipopolysaccharide (LPS), decreased significantly (P < 0.05) after the nutritional intervention. Moreover, at month 3 after the intervention, the body weight, body mass index, albumin, and hemoglobin of all subjects were significantly increased (P < 0.05). The correlation analysis demonstrated a significantly negative correlation of CD4+ T cell count with levels of DAO (r = -0.343, P = 0.004), D-lactate (r = -0.250, P = 0.037), respectively, and a significantly positive correlation of IL-1ß level with levels of DAO (r = 0.445, P < 0.001), D-lactate (r = 0.523, P < 0.001), and LPS (r = 0.622, P < 0.001). We conclude that the pre-digested enteral nutrition supplement is effective for HIV-infected INRs.

Simultaneous determination of 35 constituents and elucidation of effective constituents in a multi-herb Chinese medicine formula Xiaoer-Feire-Kechuan.

Xiaoer-Feire-Kechuan (XFK) is an 11-herb Chinese medicine formula to treat cough and pulmonary inflammation. The complicated composition rendered its chemical analysis and effective-component elucidation. In this study, we combined quantitative analysis and bioactivity test to reveal the anti-inflammatory constituents of XFK. First, UPLC-DAD and UHPLC/Q-Orbitrap-MS methods were established and validated to quantify 35 analytes (covering 9 out of 11 herbs) in different XFK formulations. Parallel reaction monitoring mode built in Q-Orbitrap-MS was used to improve the sensitivity and selectivity. Then, anti-inflammatory activities of the 35 analytes were analyzed using in vitro COX-2 inhibition assay. Finally, major analytes forsythosides H, I, A (8-10), and baicalin (15) (total contents varied from 21.79 to 91.20 mg/dose in different formulations) with significant activities (inhibitory rate ≥ 80%) were proposed as the anti-inflammatory constituents of XFK. The present study provided an effective strategy to discover effective constituents of multi-herb formulas.

Combination therapy with B7H3-redirected bispecific antibody and Sorafenib elicits enhanced synergistic antitumor efficacy.

Rationale: Current traditional treatment options are frequently ineffective to fight against ovarian cancer due to late diagnosis and high recurrence. Therefore, there is a vital need for the development of novel therapeutic agents. B7H3, an immune checkpoint protein, is highly expressed in various cancers, representing it a promising target for cancer immunotherapy. Although targeting B7H3 by bispecific T cell-engaging antibodies (BiTE) has achieved successes in hematological malignancies during recent years, attempts to use them for the treatment of solid cancers are less favorable, in part due to the heterogeneity of tumors. Sorafenib is an unselective inhibitor of multiple kinases currently being tested in clinical trials for several tumors, including ovarian cancer which showed limited activity and inevitable side effect for ovarian cancer treatment. However, it is able to enhance antitumor immune response, which indicates sorafenib may improve the efficiency of immunotherapy. Methods: We evaluated the expression of B7H3 in ovarian cancer using online database and validated its expression of tumor tissues by immunohistochemistry staining. Then, B7H3 expression and the effects of sorafenib on ovarian cancer cell lines were determined by flow cytometry. In addition, 2D and 3D ovarian cancer models were established to test the combined therapeutic effect in vitro. Finally, the efficiency of B7H3×CD3 BiTE alone and its combination with sorafenib were evaluated both in vitro and in vivo. Results: Our data showed that B7H3 was highly expressed in ovarian cancer compared with normal samples. Treatment with sorafenib inhibited ovarian cancer cell proliferation and induced a noticeable upregulation of B7H3 expression level. Further study suggested that B7H3×CD3 BiTE was effective in mediating T cell killing to cancer cells. Combined treatment of sorafenib and B7H3×CD3 BiTE had synergistic anti-tumor effects in ovarian cancer models. Conclusions: Overall, our study indicates that combination therapy with sorafenib and B7H3×CD3 BiTE may be a new therapeutic option for the further study of preclinical treatment of OC.

Prenylated Phenolic Compounds from the Aerial Parts of Glycyrrhiza uralensis as PTP1B and α-Glucosidase Inhibitors.

Glycyrrhiza uralensis (liquorice) is a well-known medicinal plant. Its roots and rhizomes are used as the popular Chinese herbal medicine Gan-Cao. An ethanol extract of the aerial parts of G. uralensis showed antidiabetic effects on db/db mice. It decreased the blood glucose level by 30.3% and increased the serum insulin level by 41.8% compared to the control group. Eighty-six phenolic compounds (1-86) were obtained from the aerial parts, including the new prenylated isoflavanones (1-5), isoflavans (6-9), and a 2-phenylbenzofuran (10). The structures were identified by NMR and HRESIMS data analyses, and the absolute configurations were established by comparing the calculated and experimental ECD spectroscopic data. Compounds 2, 6, and 10 inhibited PTP1B with IC50 values of 5.9, 6.7, and 5.3 µM, respectively. Compound 2 and the known compounds glycycoumarin (76) and glyurallin A (79) inhibited α-glucosidase with IC50 values of 20.1, 0.1, and 0.3 µM, respectively. Compound 4 at 10 µM increased the glucose uptake rate to 95% in an insulin resistance HepG2 cell model (p < 0.01).