From immune checkpoints to therapies: understanding immune checkpoint regulation and the influence of natural products and traditional medicine on immune checkpoint and immunotherapy in lung cancer.

Lung cancer is a disease of global concern, and immunotherapy has brought lung cancer therapy to a new era. Besides promising effects in the clinical use of immune checkpoint inhibitors, immune-related adverse events (irAEs) and low response rates are problems unsolved. Natural products and traditional medicine with an immune-modulating nature have the property to influence immune checkpoint expression and can improve immunotherapy's effect with relatively low toxicity. This review summarizes currently approved immunotherapy and the current mechanisms known to regulate immune checkpoint expression in lung cancer. It lists natural products and traditional medicine capable of influencing immune checkpoints or synergizing with immunotherapy in lung cancer, exploring both their effects and underlying mechanisms. Future research on immune checkpoint modulation and immunotherapy combination applying natural products and traditional medicine will be based on a deeper understanding of their mechanisms regulating immune checkpoints. Continued exploration of natural products and traditional medicine holds the potential to enhance the efficacy and reduce the adverse reactions of immunotherapy.

Research on different compound combinations of Realgar-Indigo naturalis formula to reverse acute promyelocytic leukemia arsenic resistance by regulating autophagy through mTOR pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: In China, the Chinese patent drug Realgar-Indigo naturalis Formula (RIF) is utilized for the therapy of acute promyelocytic leukemia (APL). Comprising four traditional Chinese herb-Realgar, Indigo naturalis, Salvia miltiorrhiza, and Pseudostellaria heterophylla-it notably includes tetra-arsenic tetra-sulfide, indirubin, tanshinone IIa, and total saponins of Radix Pseudostellariae as its primary active components. Due to its arsenic content, RIF distinctly contributes to the therapy for APL. However, the challenge of arsenic resistance in APL patients complicates the clinical use of arsenic agents. Interestingly, RIF demonstrates a high remission rate in APL patients, suggesting that its efficacy is not significantly compromised by arsenic resistance. Yet, the current state of research on RIF's ability to reverse arsenic resistance remains unclear. AIM OF THE STUDY: To investigate the mechanism of different combinations of the compound of RIF in reversing arsenic resistance in APL. MATERIALS AND METHODS: The present study utilized the arsenic-resistant HL60-PMLA216V-RARα cell line to investigate the effects of various RIF compounds, namely tetra-arsenic tetra-sulfide (A), indirubin (I), tanshinone IIa (T), and total saponins of Radix Pseudostellariae (S). The assessment of cell viability, observation of cell morphology, and evaluation of cell apoptosis were performed. Furthermore, the mitochondrial membrane potential, changes in the levels of PMLA216V-RARα, apoptosis-related factors, and the PI3K/AKT/mTOR pathway were examined, along with autophagy in all experimental groups. Meanwhile, we observed the changes about autophagy after blocking the PI3K or mTOR pathway. RESULTS: Tanshinone IIa, indirubin and total saponins of Radix Pseudostellariae could enhance the effect of tetra-arsenic tetra-sulfide down-regulating PMLA216V-RARα, and the mechanism was suggested to be related to inhibiting mTOR pathway to activate autophagy. CONCLUSIONS: We illustrated that the synergistic effect of different compound combinations of RIF can regulate autophagy through the mTOR pathway, enhance cell apoptosis, and degrade arsenic-resistant PMLA216V-RARα.

The role of Shenqi Fuzheng injection as adjuvant therapy for breast cancer: an overview of systematic reviews and meta-analyses.

BACKGROUND: Breast cancer (BC) is the most frequent malignancy in the world. Chemotherapy (CT) is a common treatment for BC but is accompanied by toxicity and side effects. Shenqi Fuzheng Injection (SFI) is an adjuvant therapy with promising results in improving efficacy and reducing toxicity in clinical studies. This overview of systematic reviews and meta-analysis (SRs/MAs) aimed to summarize the benefits and evaluate the quality of evidence supporting SFI adjuvant as CT for BC. METHODS: A systematic search for SRs/MAs of randomized controlled trials (RCTs) on SFI treatment for BC was performed by searching PubMed, Web of Science, EMbase, Cochrane Library, CNKI, Wanfang, VIP, and SinoMed databases from inception to October 1, 2022. The quality of SRs/MAs was evaluated using AMSTAR-2, PRISMA 2020, ROBIS, and GRADE by two reviewers. The corrected covered area (CCA) was used to quantify the degree of duplication of the original SRs/MAs. Finally, quantitative analysis of RCTs was conducted using RevMan 5.4 software. This study was registered with PROSPERO, CRD42022377290. RESULTS: Six SRs/MAs including 61 RCTs with 5593 patients were included in this study. Studies were published between 2015 and 2019, the original RCTs ranged from 7-49, with sample sizes ranging from 336-1989. The quantitative meta-analysis found that adjuvant CT of SFI improved the clinical response rate (RR=1.37, 95% CI=1.28, 1.46; P<0.00001) and the KPS score (RR=1.66, 95% CI 1.54, 1.79, P<0.00001) of patients with BC. In terms of immune function, CD3+ (SMD=1.51, 95% CI 0.91, 2.10; P<0.00001), CD4+ (SMD=1.87, 95% CI 1.18, 2.56; P<0.00001), CD4+/CD8+ (SMD=0.86, 95% CI 0.48, 1.23; P<0.00001), and NK cell levels (SMD=0.94, 95% CI 0.63, 1.24; P<0.00001) in the adjuvant CT group SFI were better than those with CT alone. Adverse reactions following SFI adjuvant CT showed reduced incidence of leukopenia (RR=0.53, 95% CI 0.46, 0.62; P<0.00001) and gastrointestinal reactions (RR=0.48, 95% CI 0.39, 0.58; P<0.00001). However, the GRADE results showed 'very low' to 'moderate' evidence for the 42 outcomes, without high-quality evidence supporting them, limited mainly by deficiencies in the design of RCTs (42/42, 100.00%), inconsistency (19/42, 45.24%), publication bias (41/42, 97.62%), and inaccuracy (3/42, 7.14%). The unsatisfactory results of AMSTAR-2, PRISMA 2020, and ROBIS were limited to lack of registration of study protocols, explanation of inclusion basis of RCTs, description of funding sources for the included studies, incomplete search strategy and screening process, addressing heterogeneity and sensitivity, and reporting potential conflicts of interest. CONCLUSION: Adjuvant CT with SFI for BC had better benefits and a lower risk of adverse events. The methodology and quality of the evidence are generally low, highlighting a need of greater attention during study implementation. More objective and high-quality studies are needed to verify the efficacy of adjuvant CT with SFI in clinical decision-making for BC.

Black phosphorus-incorporated novel Ti-12Mo-10Zr implant for multimodal treatment of osteosarcoma.

The repair and reconstruction of large bone defects after bone tumor resection is still a great clinical challenge. At present, orthopedic implant reconstruction is the mainstream treatment for repairing bone defects. However, according to clinical feedback, local tumor recurrence and nonunion of bone graft are common reasons leading to the failure of bone defect repair and reconstruction after bone tumor resection, which seriously threaten the physical and mental health of patients. On this basis, here the self-developed low modulus Ti-12Mo-10Zr alloy (TMZ) was chosen as substrate material. To improve its biological activity and osteointegration, calcium, oxygen, and phosphorus co-doped microporous coating was prepared on TMZ alloy by microarc oxidation (MAO). Then, black phosphorus (BP) nanosheets were incorporated onto MAO treated TMZ alloy to obtain multifunctional composites. The obtained BP-MAO-TMZ implant exhibited excellent photothermal effects and effective ablation of osteosarcoma cancer cells under the irradiation of 808 nm near infrared laser, while no photothermal or therapeutic effects were observed for TMZ alloy. Meanwhile, the structure/component bionic coating obtained after MAO treatment as well as the P-driven in situ biomineralization performance after incorporation of BP nanosheets endowed BP-MAO-TMZ implant with synergistic promoting effect on MC3T3-E1 osteoblasts' activity, proliferation and differentiation ability. This study is expected to provide effective clinical solutions for problems of difficult bone regeneration and tumor recurrence after tumor resection in patients with bone tumors and to solve a series of medical problems such as poor prognosis and poor postoperative quality of patients life with malignant bone tumors.

Clinical characteristics and prognostic analysis of Lung Cancer patients with Hypercoagulability: A single-center, retrospective, real-world study.

Objective: We explored the clinical regularity and prognosis of lung carcinoma (LC) patients with hypercoagulability, which is often associated with the occurrence and development of tumors. Methods: This retrospective study analyzed 624 LC patients diagnosed from 2010-2017 in the Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, China. Kaplan-Meier analysis was used to estimate survival and the log-rank test was used to identify differences in survival between groups. The predictive power of a hypercoagulation model was tested using receiver operating characteristic (ROC) curve analysis. Univariate and multivariate Cox regression analyses were performed to explore independent factors associated with survival. A logistic regression model was used to explore factors related to hypercoagulability. The diagnostic power of relevant influencing factors on hypercoagulability was tested using ROC curve analysis. Results: Of 624 patients in the study, 161(25.8%) had hypercoagulability and 463 did not (normal group). The overall survival (OS) of the hypercoagulability group was significantly lower than the normal group (P < 0.0001). The ROC curve showed that the predictive power of the hypercoagulability model was better than that of a single coagulation indicator (P < 0.01). Both univariate and multivariate Cox regression analyses showed that hypercoagulability was an independent factor affecting the prognosis of LC (P<0.0001). The results of the logistic regression analysis showed that clinical stage (P < 0.05), cytokeratin 19 fragment (Cyfra211) (P < 0.05), and the platelet-to-lymphocyte ratio (PLR) (P < 0.05) were positively correlated with hypercoagulability. When combining clinical stage, Cyfra211, and the PLR to predict hypercoagulability, the area under the ROC curve was 0.797 (P < 0.01). Conclusions: In LC, hypercoagulability is an independent factor associated with poor OS and could be a prognostic factor.

Electroacupuncture Ameliorates Cerebral Ischemic Injury by Inhibiting Ferroptosis.

Background: Our previous study found that electroacupuncture (EA) can promote the recovery of neurological functions, reduce the volume of cerebral infarction, and protect the neurovascular unit in middle cerebral artery occlusion (MCAO) rats. Some studies have shown that ferroptosis is closely related to ischemic stroke; however, whether EA plays a protective role by regulating ferroptosis is unknown. Objective: We aimed to investigate the inhibitory effects of EA on ferroptosis in MCAO rats. Methods: We used 36 adult male Sprague-Dawley rats in this study. MCAO rats were established according to the Zea method and treated with EA at a continuous wave of 2/100 Hz and ~2-4 V for 30 min for 7 consecutive days. We analyzed the coordinated motor deficit and volume of cerebral infarction in vivo through 9.4-tesla magnetic resonance imaging. Then, the ischemic brain tissue was isolated and the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and iron were determined. Western blotting and real-time quantitative PCR were performed to evaluate the expression of glutathione peroxidase 4 (GPX4), transferrin (Tf), transferrin receptor 1 (TfR1), and ferritin heavy chain 1 (FTH1). To confirm the results, we used a transmission electron microscope to observe the mitochondrial morphology. Results: EA intervention significantly decreased the oxidative stress level and inhibited ferroptosis. EA significantly improved coordinated motor deficit (P < 0.01) and decreased cerebral infarct volume (P < 0.01) in the EA + MCAO group, compared with the MCAO group. EA downregulated the level of MDA (P < 0.01) and total iron (P < 0.01) and upregulated the level of SOD (P < 0.01) and GSH (P < 0.01) in the EA + MCAO group, compared with the MCAO group. EA increased the levels of GPX4 and GPX4 mRNA (P < 0.01) and FTH1 and FTH1 mRNA (P < 0.05, P < 0.01), whereas it decreased the levels of Tf and Tf mRNA (P < 0.05, P < 0.01) and TfR1 and TfR1 mRNA (P < 0.01) in the EA + MCAO group, compared with the MCAO group. EA also promoted the recovery of mitochondrial morphology according to the mitochondrial classification system for the ischemic cerebral tissue. Conclusion: Our results indicate that EA can inhibit ferroptosis by regulating oxidative stress and iron-related proteins, thus conferring protection against MCAO in a rat model.

[Effect of electroacupuncture on neurovascular unit and Wnt/ß-catenin signaling in rats with cerebral ischemia].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Baihui" (GV20), "Shuigou" (GV26), etc. on the expressions of vascular endothelial growth factor (VEGF), collagen fibrillary acidic protein (GFAP), neuronal nucleus antigen(NeuN), ß-catenin and Axin2 protein and mRNA in rats with cerebral ischemia (CI), so as to explore its mechanism underlying improvement of ischemic stroke. METHODS: A total of 108 male SD rats were randomly divided into control, model and EA groups, which were further divided into 7 d, 14 d and 21 d subgroups, with 12 rats in each group. The CI model was established by occlusion of the middle cerebral artery. EA (2 Hz/100 Hz, 2-4 V) was applied to GV20, GV26, bilateral "Sanyinjiao" (SP6) and bilateral "Neiguan" (PC6) for 30 min, once daily (except Sundays) for 21 days at most. The neurological deficit score was evaluated according to Longa's methods. The cerebral infarction state was assessed by using a magnetic resonance T2 imaging system. The expression levels of neurovascular markers as VEGF,GFAP and NeuN, and ß-catenin and Axin2 protein and mRNA in the ischemic brain tissue were detected by using immunohistochemistry and quantitative real-time PCR, respectively. RESULTS: After modeling, the neurological deficit score and cerebral infarction size were significantly increased (P<0.01), and the expression of NeuN and Axin2 proteins and mRNAs were significantly and gradually decreased with time (day 7, 14 and 21) (P<0.01), whereas the expression levels of VEGF, GFAP, ß-catenin proteins and mRNAs were significantly increased on day 7, 14 and 21 in the model group relevant to the control group (P<0.01). Compared with the model group, the neurological deficit score, cerebral infarction size and the expressions of Axin2 protein and mRNA were significantly decreased on day 7, 14 and 21 (P<0.01), whereas the expression levels of VEGF, GFAP and NeuN and ß-catenin proteins and mRNAs were considerably up-regulated in the EA group on day 7, 14 and 21 (P<0.01). CONCLUSION: EA can protect the neurovascular units from injury, reduce the volume of cerebral infarction and improve the symptoms of neurological deficit in cerebral ischemic rats, which may be related to its effects in up-regulating ß-catenin expression and in down-regulating Axin2 expression to further activate classical Wnt/ ß-catenin signal pathway.

Huayu Wan Prevents Lewis Lung Cancer Metastasis in Mice via the Platelet Pathway.

OBJECTIVE: To study the mechanism of Huayu Wan on the metastasis of Lewis lung cancer in mice via the platelet pathway. METHOD: Construction of the lung metastasis model by injection of Lewis cells through the tail vein. The next day, 72 mice were randomly divided into the Huayu Wan group (HYW), the aspirin group, the control group, and the normal group . Treatment was given for 5 days per week for a total of 16 days. The size and distribution of lung metastases were observed. Thromboelastography was used to detect platelet function, flow cytometry was used to analyze platelet activation, and ELISA was used to detect platelet tumor metastasis-related factor expression. RESULT: Lung weight in the control group was significantly higher than that in the HYW group (P < 0.05). The distribution of lung metastases in the control group was obviously more than that in the HYW group. The thromboelastogram showed that the R value of the control group was significantly lower than the normal group, while the R values of the HYW and aspirin groups were higher than the control group (P < 0.05). Flow cytometry analysis showed that the expression of CD62P in platelet-rich plasma in the control group was significantly higher than that in the normal group, while the expression of CD62P in the HYW and aspirin groups was lower than that in the control group (P < 0.05). In addition, ELISA showed that the expression of VEGF, bFGF, and CD62P in serum of the HYW group was significantly decreased than the control group (P < 0.05), and the expression of VEGF and bFGF in serum of the aspirin group was significantly decreased than the control group (P < 0.05). CONCLUSION: The mechanism of Huayu Wan inhibiting the metastasis of lung cancer in mice may be related to the improvement of blood hypercoagulability, the inhibition of platelet activation, and the expression of VEGF, bFGF, and CD62P.

[Advances in the experimental mechanism of acupuncture in the treatment of Alzheimer's disease based on Wnt/ß-catenin pathway].

Alzheimer's disease is a neurodegenerative disease closely related to age, which is characterized by cognitive and memory impairment. Extensive studies have confirmed that Wnt/ß-catenin signal pathway is involved in the occurrence and development of Alzheimer's disease. With the characteristics of holistic concept and syndrome differentiation, acupuncture is widely used in clinic. Acupuncture plays a role in the treatment of Alzheimer's disease through the regulation of each target and the whole of the pathway. The author reviewed and combed the research on acupuncture treatment of Alzheimer's disease in recent years, and reviewed the regulatory effects of acupuncture on the important components of Wnt/ß-catenin signal pathway (Wnt protein, ß-catenin, glycogen synthase kinase-3ß) and whole, ATP-binding cassette subfamily B member 1 (ABCB1), low density lipoprotein receptor associated protein-1 (LRP-1)．.

[Research advances in neurovascular unit mechanism in acupuncture treatment of ischemic stroke].

Ischemic stroke is a type of clinical syndrome caused by brain blood supply disorders due to various cerebrovascular diseases, which lead to local cerebral ischemia, hypoxic necrosis, and corresponding neurological defects. In recent years, the neurovascular unit mechanism of ischemic stroke has been proposed in modern medicine. With the principles of syndrome differentiation-based treatment and holistic view in traditional Chinese medicine, acupuncture has the advantage of multi-target and multi-link effect and good clinical efficacy on this disease, and current studies have shown that acupuncture has a marked effect on each component and the whole of neurovascular unit. This article reviews the effect of acupuncture on the regulation of blood-brain barrier, astrocytes, microglial cells, neurons, and neurovascular units.

Drug "Pent-Up" in Hollow Magnetic Prussian Blue Nanoparticles for NIR-Induced Chemo-Photothermal Tumor Therapy with Trimodal Imaging.

The study reports a biocompatible smart drug delivery system based on a doxorubicin (DOX) blending phase-change material of 1-pentadecanol loaded hollow magnetic Prussian blue nanoparticles, resulting in HMNP-PB@Pent@DOX. The system possesses concentration-dependent high thermogenesis (>50 °C) when applying a near-infrared (NIR) laser irradiation only for 5 min. Furthermore, the system realizes near "zero release" of drug and is efficiently triggered by NIR for drug delivery in an "on" and "off" manner, thus inducing cell apoptosis in vitro and in vivo. Moreover, the system clearly indicates tumor site with trimodal imaging of magnetic resonance imaging, photoacoustic tomography imaging, and infrared thermal imaging. Furthermore, the system achieves efficient chemo-photothermal combined tumor therapy in vivo with 808 nm laser irradiation for 5 min at 1.2 W cm-2 , revealing the good tumor inhibition effect comparing with those of chemotherapy or photothermal therapy alone. The system is also confirmed to be biocompatible in regard to the mortality rate.

New lignans from the roots of Schisandra sphenanthera.

Nine new lignans (1-8, 13) and five known ones (9-12, 14) have been isolated from the roots of Schisandra sphenanthera and were tested for their capacity to scavenge 2,2-diphenyl-1-Picryl-hydrazyl (DPPH). Of these lignans tested, compounds 1, 7, 8 and 13 exhibited noteworthy antioxidant activity with IC50 values of 92, 115, 35 and 48 µg/mL, respectively. The anti-oxidative haemolysis of human red blood cells (RBCs) activity of the most active compound 8, which is similar to that of vitamin C, was evaluated.

Magnetic bioactive glass ceramic in the system CaO-P2O5-SiO2-MgO-CaF2-MnO2-Fe2O3 for hyperthermia treatment of bone tumor.

Magnetic bioactive glass ceramic (MG) in the system CaO-SiO(2)-P(2)O(5)-MgO-CaF(2)-MnO(2)-Fe(2)O(3) for hyperthermia treatment of bone tumor was synthesized. The phase composition was investigated by XRD. The magnetic property was measured by VSM. The in vitro bioactivity was investigated by simulated body fluid (SBF) soaking experiment. Cell growth on the surface of the material was evaluated by co-culturing osteoblast-like ROS17/2.8 cells with materials for 7 days. The results showed that MG contained CaSiO(3) and Ca(5)(PO(4))(3)F as the main phases, and MnFe(2)O(4) and Fe(3)O(4) as the magnetic phases. Under a magnetic field of 10,000 Oe, the saturation magnetization and coercive force of MG were 6.4 emu/g and 198 Oe, respectively. After soaking in SBF for 14 days, hydroxyapatite containing CO(3)(2-) was observed on the surface of MG. The experiment of co-culturing cells with material showed that cells could successfully attach and well proliferate on MG.