HDAC Inhibition Increases CXCL12 Secretion to Recruit Natural Killer Cells in Peripheral T Cell Lymphoma.

Peripheral T cell lymphoma (PTCL) is a heterogeneous and aggressive disease with a poor prognosis. Histone deacetylase (HDAC) inhibitors have shown inhibitory effects on PTCL. A better understanding of the therapeutic mechanism underlying the effects of HDAC inhibitors could help improve treatment strategies. Here, we found that high expression of HDAC3 is associated with poor prognosis in PTCL. HDAC3 inhibition suppressed lymphoma growth in immunocompetent mice but not in immunodeficient mice. HDAC3 deletion delayed the progression of lymphoma, reduced the lymphoma burden in the thymus, spleen, and lymph nodes, and prolonged the survival of mice bearing MNU-induced lymphoma. Furthermore, inhibiting HDAC3 promoted the infiltration and enhanced the function of natural killer (NK) cells. Mechanistically, HDAC3 mediated ATF3 deacetylation, enhancing its transcriptional inhibitory activity. Targeting HDAC3 enhanced CXCL12 secretion through an ATF3-dependent pathway to stimulate NK cell recruitment and activation. Finally, HDAC3 suppression improved the response of PTCL to conventional chemotherapy. Collectively, this study provides insights into the mechanism by which HDAC3 regulates ATF3 activity and CXCL12 secretion, leading to immune infiltration and lymphoma suppression. Combining HDAC3 inhibitors with chemotherapy may be a promising strategy for treating PTCL. Key words: Histone deacetylases (HDACs), Natural killer (NK) cells, Peripheral T cell lymphoma (PTCL).

Correction: Dong et al. Identification of the Trace Components in BopuzongJian and Macleaya cordata Extract Using LC-MS Combined with a Screening Method. Molecules 2021, 26, 3851.

The article in question [...].

Prediction of Human Pharmacokinetics of E0703, a Novel Radioprotective Agent, Using Physiologically Based Pharmacokinetic Modeling and an Interspecies Extrapolation Approach.

E0703, a new steroidal compound optimized from estradiol, significantly increased cell proliferation and the survival rate of KM mice and beagles after ionizing radiation. In this study, we characterize its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model. The preclinical PK of E0703 was studied in mice and Rhesus monkeys. Asian human clearance (CL) values for E0703 were predicted from various allometric methods. The human PK profiles of E0703 (30 mg) were predicted by the PBPK model in Gastro Plus software 9.8 (SimulationsPlus, Lancaster, CA, USA). Furthermore, tissue distribution and the human PK profiles of different administration dosages and forms were predicted. The 0.002 L/h of CL and 0.005 L of Vss in mice were calculated and optimized from observed PK data. The plasma exposure of E0703 was availably predicted by the CL using the simple allometry (SA) method. The plasma concentration-time profiles of other dosages (20 and 40 mg) and two oral administrations (30 mg) were well-fitted to the observed values. In addition, the PK profile of target organs for E0703 exhibited a higher peak concentration (Cmax) and AUC than plasma. The developed E0703-PBPK model, which is precisely applicable to multiple species, benefits from further clinical development to predict PK in humans.

Cardiac glycosides from Streblus asper with potential antiviral activity.

Ten undescribed cardiac glycosides, strasperosides A-J, together with twelve known analogues, were isolated from Streblus asper Lour. Their structures were elucidated on the basis of spectroscopic analysis, electronic circular dichroism data, and chemical methods. These cardiac glycosides showed diversity in steroid skeleton and sugar moiety. Strasperosides A and B are a pair of unusual stereoisomers featuring different orientation of the lactone motif. Ten cardiac glycosides demonstrated potent antiviral effects on HSV-1 in vitro with the IC50 values from 0.19 ± 0.08 to 1.03 ± 0.25 µM and the therapeutic indices from 66.61 ± 5.08 to 326.75 ± 11.75.

FGF1 reduces cartilage injury in osteoarthritis via regulating AMPK/Nrf2 pathway.

Osteoarthritis (OA) is a systemic joint degenerative disease involving a variety of cytokines and growth factors. In this study, we investigated the protective effect of fibroblast growth factor 1 (FGF1) knockdown on OA and its underlying mechanisms in vitro. In addition, we evaluated the effect of FGF1 knockout on the destabilization of the medial meniscus (DMM) and examined the anterior and posterior cruciate ligament model in vivo. FGF1 affects OA cartilage destruction by increasing the protein expression of Nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), which is associated with the phosphorylation of AMPK and its substrates. Our study showed that FGF1 knockdown could reverse the oxidative damage associated with osteoarthritis. Nrf2 knockdown eliminated the antioxidant effect of FGF1 knockdown on chondrocytes. Furthermore, AMPK knockdown could stop the impact of FGF1 knockdown on osteoarthritis. These findings suggested that FGF1 knockdown could effectively prevent and reverse osteoarthritis by activating AMPK and Nrf2 in articular chondrocytes.

Initial suction drainage decreases severe postoperative complications after pancreatic trauma: A cohort study.

BACKGROUND: Few studies have addressed the question of which drain types are more beneficial for patients with pancreatic trauma (PT). AIM: To investigate whether sustained low negative pressure irrigation (NPI) suction drainage is superior to closed passive gravity (PG) drainage in PT patients. METHODS: PT patients who underwent pancreatic surgery were enrolled consecutively at a referral trauma center from January 2009 to October 2021. The primary outcome was defined as the occurrence of severe complications (Clavien-Dindo grade ≥ Ⅲb). Multivariable logistic regression was used to model the primary outcome, and propensity score matching (PSM) was included in the regression-based sensitivity analysis. RESULTS: In this study, 146 patients underwent initial PG drainage, and 50 underwent initial NPI suction drainage. In the entire cohort, a multivariable logistic regression model showed that the adjusted risk for severe complications was decreased with NPI suction drainage [14/50 (28.0%) vs 66/146 (45.2%); odds ratio (OR), 0.437; 95% confidence interval (CI): 0.203-0.940]. After 1:1 PSM, 44 matched pairs were identified. The proportion of each operative procedure performed for pancreatic injury-related and other intra-abdominal organ injury-related cases was comparable in the matched cohort. NPI suction drainage still showed a lower risk for severe complications [11/44 (25.0%) vs 21/44 (47.7%); OR, 0.365; 95%CI: 0.148-0.901]. A forest plot revealed that NPI suction drainage was associated with a lower risk of Clavien-Dindo severity in most subgroups. CONCLUSION: This study, based on one of the largest PT populations in a single high-volume center, revealed that initial NPI suction drainage could be recommended as a safe and effective alternative for managing complex PT patients.

6-Methoxydihydrosanguinarine exhibits cytotoxicity and sensitizes TRAIL-induced apoptosis of hepatocellular carcinoma cells through ROS-mediated upregulation of DR5.

6-methoxydihydrosanguinarine (6-MS), a natural benzophenanthridine alkaloid extracted from Macleaya cordata (Willd.) R. Br, has shown to trigger apoptotic cell death in cancer cells. However, the exact mechanisms involved have not yet been clarified. The current study reveals the underlying mechanisms of 6-MS-induced cytotoxicity in hepatocellular carcinoma (HCC) cells and investigates whether 6-MS sensitizes TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis. 6-MS was shown to suppress cell proliferation and trigger cell cycle arrest, DNA damage, and apoptosis in HCC cells. Mechanisms analysis indicated that 6-MS promoted reactive oxygen species (ROS) generation, JNK activation, and inhibits EGFR/Akt signaling pathway. DNA damage and apoptosis induced by 6-MS were reversed following N-acetyl-l-cysteine (NAC) treatment. The enhancement of PARP cleavage caused by 6-MS was abrogated by pretreatment with JNK inhibitor SP600125. Furthermore, 6-MS enhanced TRAIL-mediated HCC cells apoptosis by upregulating the cell surface receptor DR5 expression. Pretreatment with NAC attenuated 6-MS-upregulated DR5 protein expression and alleviated cotreatment-induced viability reduction, cleavage of caspase-8, caspase-9, and PARP. Overall, our results suggest that 6-MS exerts cytotoxicity by modulating ROS generation, EGFR/Akt signaling, and JNK activation in HCC cells. 6-MS potentiates TRAIL-induced apoptosis through upregulation of DR5 via ROS generation. The combination of 6-MS with TRAIL may be a promising strategy and warrants further investigation.

Cobalt-Catalyzed Chemo- and Stereoselective Arylative Carbocyclization of 1,6-Allenynes.

Different from the well-investigated enynes, transition-metal-catalyzed carbocyclization reactions of allenynes are more attractive as a result of the unique structure and versatile reactivity of allenes. Herein, we report the first cobalt-catalyzed highly chemo- and stereoselective arylative carbocyclization of 1,6-allenynes with arylboronic acids, affording five-membered carbocycles and heterocycles with moderate to high yields, broad substrate scope, and wide functional group compatibility. Moreover, several mechanistic experiments were conducted to gain insight into the reaction process.

Seasonal malaria chemoprevention in Africa and China's upgraded role as a contributor: a scoping review.

BACKGROUND: Children under five are the vulnerable population most at risk of being infected with Plasmodium parasites, especially in the Sahel region. Seasonal malaria chemoprevention (SMC) recommended by World Health Organization (WHO), has proven to be a highly effective intervention to prevent malaria. Given more deaths reported during the COVID-19 pandemic than in previous years due to the disruptions to essential medical services, it is, therefore, necessary to seek a more coordinated and integrated approach to increasing the pace, coverage and resilience of SMC. Towards this end, fully leverage the resources of major players in the global fight against malaria, such as China could accelerate the SMC process in Africa. METHODS: We searched PubMed, MEDLINE, Web of Science, and Embase for research articles and the Institutional Repository for Information Sharing of WHO for reports on SMC. We used gap analysis to investigate the challenges and gaps of SMC since COVID-19. Through the above methods to explore China's prospective contribution to SMC. RESULTS: A total of 68 research articles and reports were found. Through gap analysis, we found that despite the delays in the SMC campaign, 11.8 million children received SMC in 2020. However, there remained some challenges: (1) a shortage of fully covered monthly courses; (2) lack of adherence to the second and third doses of amodiaquine; (3) four courses of SMC are not sufficient to cover the entire malaria transmission season in areas where the peak transmission lasts longer; (4) additional interventions are needed to consolidate SMC efforts. China was certified malaria-free by WHO in 2021, and its experience and expertise in malaria elimination can be shared with high-burden countries. With the potential to join the multilateral cooperation in SMC, including the supply of quality-assured health commodities, know-how transfer and experience sharing, China is expected to contribute to the ongoing scale-up of SMC. CONCLUSIONS: A combination of necessary preventive and curative activities may prove beneficial both for targeted populations and for health system strengthening in the long run. More actions are entailed to promote the partnership and China can be one of the main contributors with various roles.

Application of SHAP for Explainable Machine Learning on Age-Based Subgrouping Mammography Questionnaire Data for Positive Mammography Prediction and Risk Factor Identification.

Mammography is considered the gold standard for breast cancer screening. Multiple risk factors that affect breast cancer development have been identified; however, there is an ongoing debate regarding the significance of these factors. Machine learning (ML) models and Shapley Additive Explanation (SHAP) methodology can rank risk factors and provide explanatory model results. This study used ML algorithms with SHAP to analyze the risk factors between two different age groups and evaluate the impact of each factor in predicting positive mammography. The ML model was built using data from the risk factor questionnaires of women participating in a breast cancer screening program from 2017 to 2021. Three ML models, least absolute shrinkage and selection operator (lasso) logistic regression, extreme gradient boosting (XGBoost), and random forest (RF), were applied. RF generated the best performance. The SHAP values were then applied to the RF model for further analysis. The model identified age at menarche, education level, parity, breast self-examination, and BMI as the top five significant risk factors affecting mammography outcomes. The differences between age groups ranked by reproductive lifespan and BMI were higher in the younger and older age groups, respectively. The use of SHAP frameworks allows us to understand the relationships between risk factors and generate individualized risk factor rankings. This study provides avenues for further research and individualized medicine.

Discovery of the Quinoxalinone-B(C6F5)3·H2O Combo as a Photocatalyst by Acidochromism Strategy: Aerobic Oxidation of Alcohol, Alkene, and Thiols.

Modification of photocatalyst reactivity through intermolecular interactions represents a straightforward and convenient strategy for catalyst designation. Herein, we reported that upon the addition of B(C6F5)3·H2O, the oxidation potential of quinoxalinone increased remarkably, enabling the photoredox aerobic oxidation of alcohol, thiols, and alkenes toward carbonyl compounds and dithioethers under visible light conditions. Mechanistic studies, including X-ray structure analysis, cyclic voltammetry, electron paramagnetic resonance measurements, UV-vis absorption, and fluorescence spectra, revealed that the quinoxalinone-B(C6F5)3·H2O combo could serve as a versatile photocatalyst for both energy transfer and single electron transfer processes.

Catalytic asymmetric interrupted Attanasi reaction: access to fused 2,3-dihydropyrroles with vicinal quaternary carbons.

The first catalytic asymmetric interrupted Attanasi reaction has been established. Under the catalysis of a bifunctional organocatalyst, the condensation of cyclic ß-keto esters with azoalkenes readily occurred, delivering a variety of bicyclic fused 2,3-dihydropyrroles with vicinal quaternary stereogenic centers in good yields and with good to excellent enantioselectivities (27 examples, up to 96% yield and 95% ee).

Complications during CT-Guided Lung Nodule Localization: Impact of Needle Insertion Depth and Patient Characteristics.

Although widely used, CT-guided lung nodule localization is associated with a significant risk of complications, including pneumothorax and pulmonary hemorrhage. This study identified potential risk factors affecting the complications associated with CT-guided lung nodule localization. Data from patients with lung nodules who underwent preoperative CT-guided localization with patent blue vital (PBV) dye at Shin Kong Wu Ho-Su Memorial Hospital, Taiwan, were retrospectively collected. Logistic regression analysis, the chi-square test, and the Mann-Whitney test were used to analyze the potential risk factors for procedure-related complications. We included 101 patients with a single nodule (49 with pneumothorax and 28 with pulmonary hemorrhage). The results revealed that men were more susceptible to pneumothorax during CT-guided localization (odds ratio: 2.48, p = 0.04). Both deeper needle insertion depth (odds ratio: 1.84, p = 0.02) and nodules localized in the left lung lobe (odds ratio: 4.19, p = 0.03) were associated with an increased risk of pulmonary hemorrhage during CT-guided localization. In conclusion, for patients with a single nodule, considering the needle insertion depth and patient characteristics during CT-guided localization procedures is probably important for reducing the risk of complications.

Inflammation and coagulation abnormalities via the activation of the HMGB1­RAGE/NF­κB and F2/Rho pathways in lung injury induced by acute hypoxia.

High­altitude acute hypoxia is commonly associated with respiratory cardiovascular diseases. The inability to adapt to acute hypoxia may lead to cardiovascular dysfunction, lung injury and even death. Therefore, understanding the molecular basis of the adaptation to high­altitude acute hypoxia may reveal novel therapeutic approaches with which to counteract the detrimental consequences of hypoxia. In the present study, a high­altitude environment was simulated in a rat model in order to investigate the role of the high mobility group protein­1 (HMGB1)/receptor for advanced glycation end products (RAGE)/NF­κB and F2/Rho signaling pathways in lung injury induced by acute hypoxia. It was found that acute hypoxia caused inflammation through the HMGB1/RAGE/NF­κB pathway and coagulation dysfunction through the F2/Rho pathway, both of which may be key processes in acute hypoxia­induced lung injury. The present study provides new insight into the molecular basis of lung injury induced by acute hypoxia. The simultaneous activation of the HMGB1/RAGE/NF­κB and F2/Rho signaling pathways plays a critical role in hypoxia­induced inflammatory responses and coagulation abnormalities, and provides a theoretical basis for the development of potential therapeutic strategies.

Catabolism of Dictyophora indusiata Polysaccharide and Its Impacts on Gut Microbial Composition during In Vitro Digestion and Microbial Fermentation.

Dictyophora indusiata is one of the most famous edible mushrooms in China. D. indusiata polysaccharide (DP) has attracted increasing attention because of its multiple beneficial effects. In this study, the in vitro simulated digestion and microbial fermentation were designed to reveal the potential catabolic property of DP and its impacts on the modulation of gut microbial composition. The results showed that the reducing sugar content, total polysaccharides content, molecular weight, and rheological property of DP were not significantly altered under in vitro simulated digestive conditions. However, the molecular weight, apparent viscosity, and total polysaccharides content of indigestible DP (DPI) significantly decreased during in vitro fecal fermentation, and the reducing sugar content and the release of free monosaccharides notably increased, suggesting that DP could be degraded and used by gut microbiota. Additionally, the relative abundances of several beneficial bacteria, such as Bacteroides, Catenibacterium, Parabacteroides, and Megamonas, increased significantly, indicating that DP can regulate the composition and abundance of gut microbiota. Moreover, DP could also promote the production of SCFAs, thus changing the acid-base environment of the large intestine. The results of this study are beneficial for deeply clarifying the catabolic behavior of DP in the gastrointestinal tract, which can provide a theoretical basis for developing microbiota-directed products based on DP.

Evaluating the contact anatomy and contact bone volume of spinal screws using a novel drilled surface image.

Intraoperative navigation systems have been widely applied in spinal fusion surgery to improve the implantation accuracy of spinal screws using orthogonal tomographic and surface-rendering imaging. However, these images contain limited anatomical information and no information on bone volume contact by the implanted screw, which has been proven to affect the stability of implanted screws. This study proposed a novel drilled surface imaging technique that displays anatomical integration properties to calculate the contact bone volume (CBV) of the screws implanted along an implantation trajectory. A cylinder was used to represent the area traversed by the screws, which was manually rotated and translated to a predetermined implantation trajectory according to a vertebra model obtained using computed tomography (CT) image volumes. The drilled surface image was reconstructed by interpolating the CT numbers at the predefined sampling points on the cylinder surface. The anatomical integration property and CBV of the screw implanted along the transpedicular trajectory (TT) and cortical bone trajectory (CBT) were evaluated and compared. The drilled surface image fully revealed the contact anatomical structure of the screw under the trajectories, improving the understanding of the anatomical integration of the screw and surrounding tissues. On average, the CBV of the CBT was 30% greater than that of the TT. The proposed drilled surface image may be applied in preoperative planning and integrated into intraoperative navigation systems to evaluate the anatomical integration and degree of bone contact of the screw implanted along a trajectory.

Elucidation of Non-Intentionally Added Substances from Plant Fiber/Plastic Composites by UPLC-QTOF/MS.

Plant fiber/plastic composites (PPCs) have been widely used in food contact materials (FCMs) for many benefits, such as their claimed better environmental footprint compared to conventional plastics. However, their safety is still not fully understood and must be comprehensively evaluated. Non-volatiles extracted from six PPCs with different plant fibers and polymer matrices were characterized by employing ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry in combination with various spectral libraries and manual elucidation, taking into account spectral similarity and characteristic product ions. A total of 115 compounds were tentatively identified, 50 of which were oligomers or their derivatives from the sample with polylactic acid (PLA) and polybutylene adipate terephthalate (PBAT) as the polymer matrix, and some of them were Cramer rules class III substances based on the threshold of toxicological concern (TTC). Seven reaction products between PLA and PBAT monomers, as well as four derivatives of melamine, were elucidated and well detailed for the first time. In addition, bisphenol S was detected in all samples even though its origin remains to be further explored. Isoprothiolane, as an insecticide and fungicide used to control a range of rice pests, was identified in the sample with rice husk as fillers, experimentally confirming the presence of agrochemicals in samples containing plant fibers.

Multiple portions enteral nutrition and chyme reinfusion of a blunt bowel injury patient with hyperbilirubinemia undergoing open abdomen: A case report.

Blunt bowel injury (BBI) is relatively rare but life-threatening when delayed in surgical repair or anastomosis. Providing enteral nutrition (EN) in BBI patients with open abdomen after damage control surgery is challenging, especially for those with discontinuity of the bowel. Here, we report a 47-year-old male driver who was involved in a motor vehicle collision and developed ascites on post-trauma day 3. Emergency exploratory laparotomy at a local hospital revealed a complete rupture of the jejunum and then primary anastomosis was performed. Postoperatively, the patient was transferred to our trauma center for septic shock and hyperbilirubinemia. Following salvage resuscitation, damage control laparotomy with open abdomen was performed for abdominal sepsis, and a temporary double enterostomy (TDE) was created where the anastomosis was ruptured. Given the TDE and high risk of malnutrition, multiple portions EN were performed, including a proximal portion EN support through a nasogastric tube and a distal portion EN via a jejunal feeding tube. Besides, chyme delivered from the proximal portion of TDE was injected into the distal portion of TDE via a jejunal feeding tube. Hyperbilirubinemia was alleviated with the increase in chyme reinfusion. After 6 months of home EN and chyme reinfusion, the patient finally underwent TDE reversal and abdominal wall reconstruction and was discharged with a regular diet. For BBI patients with postoperative hyperbilirubinemia who underwent open abdomen, the combination of multiple portions EN and chyme reinfusion may be a feasible and safe option.

8-oxo-dGTP curbs tumor development via S phase arrest and AIF-mediated apoptosis.

Oxidative stress can attack precursor nucleotides, resulting in nucleic acid damage in cells. It remains unclear how 8-oxo-dGTP and 8-oxoGTP, oxidized forms of dGTP and GTP, respectively, could affect DNA or RNA oxidation levels and tumor development. To address this, we intravenously administered 8-oxo-dGTP and 8-oxoGTP to wild-type and MTH1-knockout mice. 8-oxoGTP administration increased frequency of tumor incidence, which is more prominent in MTH1-knockout mice. However, 8-oxo-dGTP treatment rather reduced tumor development regardless of the mouse genotype. The tumor suppressive effects of 8-oxo-dGTP were further confirmed using xenograft and C57/6J-ApcMin/Nju mouse models. Mechanistically, 8-oxo-dGTP increased the 8-oxo-dG contents in DNA and DNA strand breakage, induced cell cycle arrest in S phase and apoptosis mediated by AIF, eventually leading to reduced tumor incidence. These results suggest distinct roles of 8-oxo-dGTP and 8-oxoGTP in tumor development.