Use of the improved tug-of-war acupuncture for promoting cartilage repair by inducing macrophage polarization in knee osteoarthritis.

Introduction: Knee osteoarthritis (KOA) is a type of joint disease causing degenerative changes that are challenging to treat. The improved tug-of-war acupuncture (BHZF) can improve joint pain in KOA. However, the associated mechanism has not been validated. Methods: The KOA rabbit model was established. After the surgery, the improved BHZF was provided as an intervention, and the animals were euthanized after 2 weeks. Histopathological changes in the synovium and cartilage were observed on hematoxylin & eosin staining and Safranin O-Fast Green staining. Synovial fluid and serum samples were collected to assess the presence of cytokines using the enzyme-linked immunosorbent assay. The expression of M1 macrophage (CD86) and M2 macrophage (ARG1) markers in the cartilage and synovium was detected via immunohistochemistry and immunofluorescence assays. Results: The improved BHZF could reduce KOA-related pain and inhibit joint swelling. Further, it significantly maintained the morphology of articular chondrocytes in KOA and reduced the decomposition of the cartilage matrix. Then, it significantly reduced the expression of CD86-positive cells (P < 0.05), and increased the expression of ARG1-positive cells in the cartilage and synovium (P < 0.05). Moreover, it significantly decreased the expression of inflammatory factors interleukin (IL)-1 beta and tumor necrosis factor-alpha in the serum and synovial fluid (P < 0.05), and significantly increased the expression levels of anti-inflammatory cytokines IL-4 and IL-10 (P < 0.05). Conclusions: The improved BHZF can relieve pain and improve cartilage damage by regulating macrophage polarization in KOA.

Deciphering the Effects of 2D Black Phosphorus on Disrupted Hematopoiesis and Pulmonary Immune Homeostasis Using a Developed Flow Cytometry Method.

As an emerging two-dimensional nanomaterial with promising prospects, mono- or few-layer black phosphorus (BP) is potentially toxic to humans. We investigated the effects of two types of BPs on adult male mice through intratracheal instillation. Using the flow cytometry method, the generation, migration, and recruitment of immune cells in different organs have been characterized on days 1, 7, 14, and 21 post-exposure. Compared with small BP (S-BP, lateral size at ∼188 nm), large BP (L-BP, lateral size at ∼326 nm) induced a stronger stress lymphopoiesis and B cell infiltration into the alveolar sac. More importantly, L-BP dramatically increased peripheral neutrophil (NE) counts up to 1.9-fold on day 21 post-exposure. Decreased expression of the CXCR4 on NEs, an important regulator of NE retention in the bone marrow, explained the increased NE release into the circulation induced by L-BP. Therefore, BP triggers systemic inflammation via the disruption of both the generation and migration of inflammatory immune cells.

Chinese Herbal Medicine Adjusting Brain Microenvironment via Mediating Central Nervous System Lymphatic Drainage in Alzheimer's Disease.

Due to its complex pathogenesis and lack of effective therapeutic methods, Alzheimer's disease (AD) has become a severe public health problem worldwide. Recent studies have discovered the function of central nervous system lymphatic drainage, which provides a new strategy for the treatment of AD. Chinese herbal medicine (CHM) has been considered as a cure for AD for hundreds of years in China, and its effect on scavenging ß-amyloid protein in the brain of AD patients has been confirmed. In this review, the mechanism of central nervous system lymphatic drainage and the regulatory functions of CHM on correlation factors were briefly summarized. The advances in our understanding regarding the treatment of AD via regulating the central lymphatic system with CHM will promote the clinical application of CHM in AD patients and the discovery of new therapeutic drugs.

[Effect of moxibustion on the expression of microglia and brain-derived neurotrophic factor protein in the spinal cord of rats with myofascial pain syndrome].

OBJECTIVE: To observe the effect of moxibustion at myofascial trigger points on microglia activation and the expression of brain-derived neurotrophic factor (BDNF) in the spinal cord of rats with myofascial pain syndrome (MPS), so as to explore the central mechanism of the analgesic effect of moxibustion. METHODS: Twenty-four male SD rats were randomly divi-ded into control, model and moxibustion groups (n=8 in each group). The MPS model was established by strinking on fascia musculares and eccentric exercise. Rats in the moxibustion group were treated with mild moxibustion at myofascial trigger point for 15 min, once daily for 7 days. The thermal withdrawal latency (TWL) of rats was measured with a hot stabbing instrument. The pathological changes of the rat medial femoris muscle were observed after H.E. staining. The expressions of microglia marker (OX-42) and BDNF in the spinal dorsal horn were detected by immunohistochemistry and Western blot, separately. RESULTS: After modeling, the TWL of both the model and the moxibustion groups were significantly down-regulated (P<0.01)，and were significantly decreased in contrast to that of the control group (P<0.01). After treatment and compared with the model group, the TWL of the moxibustion group was significantly increased (P<0.01) in the moxibustion group. Rat's muscle fibers of the control group were uniform in thickness and arranged tightly and regularly. While in the model group, some fractures and connective structure tissue renewal, irregular arrangement, and inflammatory cell infiltration were seen. The morphology of muscle fibers in the moxibustion group was close to normal, and the arrangement was neat and orderly, with a small amount of inflammatory cell infiltration. Compared with the control group, the expression of OX-42 and BDNF in the spinal dorsal horn of rats in the model group was increased(P<0.01). Following the treatment, and in comparison with the model group, the expression of OX-42 and BDNF of moxibustion group was down-regulated(P<0.05). CONCLUSION: Moxibustion can significantly improve the injury of the medial femoral muscle and the TWL in MPS rats，which may be related to its effects in inhibiting the activation of spinal dorsal horn microglia and reducing the expression of BDNF.

Biodegradable Nanocomposite with Dual Cell-Tissue Penetration for Deep Tumor Chemo-Phototherapy.

Chemo-phototherapy, as a promising cancer combination therapy strategy, has attracted widespread attention. However, the complex tumor microenvironment restricts the penetration depth of chemo-phototherapy agents in the tumor region. Here, biodegradable amphiphilic gelatin (AG) wrapped nanocomposite (PRDCuS@AG) composed of doxorubicin and copper sulfide (CuS)-loaded dendrimer is designed for deep tumor chemo-phototherapy. PR in PRDCuS@AG represents arginine-conjugated polyamidoamine dendrimer. PRDCuS@AG can rapidly biodegrade into PRDCuS by matrix metalloproteinases under near-infrared light irradiation. The resulted PRDCuS harbors dual cell-tissue penetration ability, which can effectively penetrate deep into the tumor tissue. In particular, PRDCuS@AG achieves photoacoustic imaging-guided synergistic chemo-phototherapy with 97% of tumor inhibition rate. Moreover, PRDCuS@AG can further degrade into 3 nm ultrasmall CuS, which can be eliminated from the body after treatment to avoid side effects. This strategy provides an insight that the development of chemo-phototherapy agents with high penetration ability to overcome the limitation of current deep tumor therapy.

Black phosphorus for fighting antibiotic-resistant bacteria: What is known and what is missing.

Recently, two-dimensional black phosphorus (BP) nanomaterial has captured much attention due to its superb physiochemical and electronic properties and various promising biomedical applications. However, relatively few studies have explored its antimicrobial properties, particularly for targeting antibiotic-resistant pathogens. A comprehensive understanding of the bactericidal mechanisms of BP is essential for application of this material as an antimicrobial. This review discusses the physicochemical and electronic properties of BP that are relevant for antimicrobial applications, especially the unique characteristics that may play a role in overcoming drug resistance. The literature is discussed in the context of what is known and what information is missing. We also highlight the differences and advantages of BP over other two-dimensional nanomaterials (i.e., graphene oxide and molybdenum disulfide) for bactericidal activity. Finally, we analyze existing challenges and note topics that require future investigation to overcome current inadequacies, aiming to assist the safe development of BP-based nanotechnology for pathogen control.

Activation of Prodrugs by NIR-Triggered Release of Exogenous Enzymes for Locoregional Chemo-photothermal Therapy.

Enzymes have been used to direct the conversion of prodrugs in cancer therapy. However, non-specific distribution of endogenous enzymes seriously hinders their bioapplications. Herein, we developed a near-infrared-triggered locoregional chemo-photothermal therapy based on the exogenous enzyme delivery and remolded tumor mivroenvironment. The catalytic efficiency of enzymes was enhanced by the hyperthermia, and the therapeutic efficacy of photothermal therapy (PTT) was improved owing to the inhibition of heat shock protein 90 by chemotherapeutics. The locoregional chemo-phototherapy achieved a one-time successful cure in 4T1 tumor-bearing mice model. Thus, a mutually reinforcing feedback loop between PTT and chemotherapy can be initiated by the irradiation, which holds a promising future in cancer therapy.

Biodegradable Poly(amino acid)-Gold-Magnetic Complex with Efficient Endocytosis for Multimodal Imaging-Guided Chemo-photothermal Therapy.

Gold complexes can serve as efficient photothermal converters for cancer therapy, but their non-biodegradability hinders clinical bioapplications. Although enormous effort has been devoted, the conventionally adopted synthetic methods of biodegradation are characterized by high cost and complicated procedures, which delay the process of further clinical translation of gold complexes. Here, we report a multifunctional poly(amino acid)-gold-magnetic complex with self-degradation properties for synergistic chemo-photothermal therapy via simple and green chemistry methods. Nanoparticles of ∼3 nm in the biodegradation product were observed in simulated body fluid in 4 days. The biodegradability mainly benefits from the weakened internal electrostatic interaction of the poly(amino acid) by the ions in simulated body fluid. It is demonstrated that the poly(amino acid)-gold-magnetic complex has great cellular endocytosis by taking advantage of the guanidine group in arginine and possesses multimodal imaging and efficient tumor ablation (94%). This study reports a possibility for gold-magnetic complexes composed of poly(amino acid) to serve as a biodegradable nanotherapeutic for clinical applications.

Successful treatment with rivaroxaban of cerebral venous thrombosis and bone marrow necrosis induced by pegaspargase: A case report and literature review.

RATIONALE: Pegaspargase has been used in the treatment of acute lymphoblastic leukemia with promising results. However, it has also been associated with several potentially serious complications, including thrombosis. Pegaspargase-induced cerebral venous thrombosis and bone marrow necrosis are very rare. PATIENT CONCERNS: A 50-year-old female developed headache, weakness of the right lower extremity, fever, and bone pain after chemotherapy including pegaspargase for the treatment of acute lymphoblastic leukemia. DIAGNOSES: Her imaging studies and bone marrow examinations were compatible with cerebral venous thrombosis and bone marrow necrosis. INTERVENTIONS: The patient received anticoagulation therapy with rivaroxaban. OUTCOMES: After treatment with rivaroxaban, she had a good outcome without major or minor bleeding. LESSONS: Clinicians should be aware of the very rare but possible induction of bone marrow necrosis during pegaspargase treatment when there is necrosis in other organs. Because of its greater safety and convenience, rivaroxaban gains popularity over traditional anticoagulant drugs.

Cryptotanshinone inhibits proliferation yet induces apoptosis by suppressing STAT3 signals in renal cell carcinoma.

It has been established that signal transducer and activator of transcription 3 serves as an oncoprotein in various human cancers; targeting it is therefore a reasonable approach for emerging cancer therapies. Cryptotanshinone, a natural compound extracted from the root of Salvia miltiorrhiza Bunge, has been identified as a potential STAT3 inhibitor. However, its functional role in renal cell carcinomas remains largely unknown. Therefore, we investigated the mode of action for cryptotanshinone. We found that cryptotanshinone substantially suppressed cancer cell growth while it promoted cell apoptosis by inhibiting the phosphorylation of STAT3 at Tyr705 and its blocking nuclear translocation. Coordinately, P-AKT, CyclinD1, C-MYC, MEKK2, and HGF were down-regulated and cell cycle progression was arrested at the G0/G1 phase, thereby attenuating cell proliferation. Moreover, the level of Cleaved-Caspase-3 was elevated while Bcl-2 and Survivin were down-regulated, accounting for the increased apoptosis. Furthermore, in vivo results revealed that cryptotanshinone effectively inhibits tumorigenesis in an A498-xenografted mouse model. Taken together, our data gives a more comprehensive understanding of how cryptotanshinone functions in renal cell carcinomas and demonstrates its potential as a powerful therapeutic approach to treat renal cell carcinomas.

Efficacy of Aidi Injection () on overexpression of P-glycoprotein induced by vinorelbine and cisplatin regimen in patients with non-small cell lung cancer.

OBJECTIVE: To investigate the efficacy of Aidi Injection () on overexpression of P-glycoprotein (P-gp) induced by vinorelbine and cisplatin (NP) regimen in patients with non-small cell lung cancer (NSCLC), and study the difference between intravenous administration and targeting intratumor administration of Aidi Injection with thoracoscope. METHODS: Totally 150 patients with NSCLC were randomly assigned to the control group, the intravenous group and the intratumor group by the random envelope method, 50 cases in each group. The patients were treated with NP regimen (2 cycles), NP regimen (2 cycles) plus Aidi intravenous injection, or NP regimen (2 cycles) plus Aidi intratumor injection with thoracoscope, respectively for 6 weeks. The clinical effificacy was observed based on Response Evaluation Criteria in Solid Tumors (RECIST) rules, the expression of P-gp in the tumor tissue was tested before, 3 and 6 weeks after treatment, the safety was evaluated by monitoring the toxicity in the process of treatment, and the progression-free survival (PFS) was measured. RESULTS: Fifteen cases dropped out because of the irreconcilable conditions which had no relationship with the treatment, 4 in the control group, 5 in the intravenous group, and 6 in the intratumor group, respectively. Compared with the control group, the response rates (complete remission + partial response) and the disease control rates (complete remission + partial response + stable disease) were significantly higher, the P-gp expressions were significantly decreased after 3 and 6 weeks of treatment, and the Kaplan-Meier survival curves of PFS were significantly longer in the intravenous and intratumor groups (P<0.05 or P<0.01), and the intratumor group showed better effects than the intravenous group (P<0.05 or P<0.01). Compared with the control group, the occurrences of rash, nausea and leukocytopenia were signifificantly decreased in the intravenous and intratumor groups (P<0.05), but without signifificant difference between the intravenous and intratumor groups (P>0.05). CONCLUSION: Aidi Injection not only improves the effificacy of NP regime, but also has the function of reducing adverse events and preventing against overexpression of P-gp induced by chemotherapy of NP regimen.

[Metabolomics Study on Non-Small Cell Lung Cancer Patients with Different Chinese Medical Syndromes].

OBJECTIVE: To study the relationship between Chinese medical syndrome types and metabolomics of non-small cell lung cancer (NSCLC) patients. METHODS: Totally 120 NSCLC patients were assigned to asthenia syndrome group and sthenia syndrome group, 60 in each group. Meanwhile, 60 cases of benign pulmonary nodules in physical examinations were recruited as the control group. Tumor tissues or benign pulmonary nodules tissues were obtained by thoracoscope. Changes of their metabolites were observed using gas chromatography-mass spectrometry (GC-MS). Their differences were studied using principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA). ROC curve analysis was performed in different metabolic compounds of sthenia and asthenia syndromes groups. The area under the curve (AUC) was calculated to evaluate the sensitivity of diagnosing syndrome types. RESULTS: Compared with the control group, difference existed in 16 compounds. Of them , contents of citric acid, pyruvic acid, alanine, choline phosphate, glycerol phosphate choline, linoleic acid, oleic acid, lactic acid, inositol were more in the two tumors group than in the control group. Difference existed in 10 compounds between the sthenia syndrome group and the asthenia syndrome group. Of them, citric acid, pyruvic acid, alanine, choline phosphate, glycerol phosphate choline, lactic acid, and inositol were more in the asthenia syndrome group than in the sthenia syndrome group. Contents of valine, glucose, and glutamine were more in the sthenia syndrome group than in the asthenia syndrome group. ROC curve analyses of different compounds indicated that AUC of lactic acid and glucose was more than 0.8 (P < 0.01); AUC of inositol, choline phosphate, and glycerol phosphate choline was more than 0.7 (P < 0.01); AUC of valine, citric acid, glutamine, alanine, and pyruvic acid was more than 0.6 (P < 0.05). CONCLUSIONS: There existed certain correlation between CM syndrome types and metabolomics of lung cancer. Lactic acid, glucose, inositol, choline phosphate, glycerol phosphate choline, valine, citric acid, glutamine, alanine, pyruvic acid were sensitive diagnostic compounds, and the first four kinds were most sensitive compounds.

[Effect-of Angong Niuhuang Pill on Th1/Th2 of cerebral infarction patients of phlegm-heat obstructing orifices in China and Indonesia].

OBJECTIVE: To observe the effect of Angong Niuhuang Pill (ANP) on Thl/Th2 in cerebral infarction patients and to explore the mechanism of phlegm-heat obstructing orifices. METHODS: Re- cruited were 30 cerebral infarction patients of phlegm-heat obstructing orifices syndrome (PHOOS) both in China and Indonesia. They were assigned to 4 groups according to the use of ANP, the Chinese treatment group, the Indonesia treatment group, the Chinese control group, and the Indonesia control group. Patients in the two control groups received conventional treatment, while those in the two treatment group additionally took ANP for 30 successive days. Their adverse reactions were observe, and levels of INF-γ and IL-4 were detected. RESULTS: The INF-γ level and the INF-γ/IL-4 ratio significantly decreased, and the IL-4 level increased after treatment in the four groups with statistical difference (P < 0.05). Compared with the control group after treatment in the same country, the INF-γ level and the INF-γ/IL-4 ratio were lower, and the IL-4 level was higher in the two treatment groups (P < 0.05). Compared with the two Chinese groups, the INF-γ level and the INF-γ/IL-4 ratio were higher, and the IL-4 level was lower in the two Indonesian groups (P < 0.05). There was no statistical difference in the post-treatment indices between the two treatment groups. CONCLUSIONS: ANP had moderating effect on Th1/Th2 in cerebral infarction pa- tients. Cerebral infarction patients of PHOOS might exist certain relation with Th1/Th2.

Effect of ginseng polysaccharides and dendritic cells on the balance of Th1/Th2 T helper cells in patients with non-small cell lung cancer.

OBJECTIVE: To investigate the effect of thorascopic administration.of ginseng polysaccharides (GPS) plus dendritic cells (DC) on T helper cell type 1/T helper cell type 2 (Th1/Th2) balance in patients with non-small cell lung cancer (NSCLC). METHODS: A total of 96 NSCLC patients were divided evenly into two groups. The control group was treated with DCs alone and the treatment group was treated with DCs plus GPS. After DCs and GPS were administered thoracoscopically, once a week, 4 times for 30 days, the patients' quality of life was measured with the Functional Assessment of Cancer Treatment-Lung (FACT-L) questionnaire before and after treatment. Serum interferon-γ (INF-γ), interleukin-4 (IL-4), IL-2 and IL-5 were examined before and after treatments. RESULTS: The level of Th1 cytokines (INF-γ, IL-2) and the ratio of Th1/Th2 cytokines (INF-γ/IL-4, IL-2/ IL-5) increased in both treatment groups, while Th2 cytokines (IL-4, IL-5) and FACT-L scores decreased (P < 0.01). Furthermore, after treatment Th1 cytokines (INF-γ, IL-2) and the ratio of Th1/Th2 cytokines (INF-γ/IL-4, IL-2/IL-5) were higher in the DCs + GPS group than in the control group (P < 0.05). Conversely, FACT-L scores and Th2 cytokines (IL-4, IL-5) were higher in the control group than in the DCs + GPS group (P < 0.05). CONCLUSION: The treatment regime of DCs plus GPS had a greater effect on NSCLC patients' immune function as compared with DCs alone. This was evident by increased expression of Th1 cytokines (INF-γ, IL-2) and the ratio of Th1/Th2 (INF-γ/IL-4, IL-2/IL-5), as well as by decreased FACT-L scores and the expression of Th2 cytokines (IL-4, IL-5).

[Research on the relationship between chinese medical syndrome types and Th1/Th2 in bronchioloalveolar carcinoma by thoracoscopic technique].

OBJECTIVE: To study the relationship between Chinese medical syndrome types of bronchioloalveolar carcinoma (BAC) and Th1/Th2. METHODS: Totally 60 BAC patients were syndrome typed as qi and yin deficiency syndrome (QYDS) and qi stagnation and phlegm-blood stasis syndrome (QSPSS), 30 cases in each group. Meanwhile, 30 subjects with benign pulmonary nodules were recruited as the control group. The contents of interferon-gamma (INF-gamma), interleukin 4 (IL-4), IL-2, and IL-5 were detected using thoracoscopic technique. RESULTS: As for Th1 (INF-gamma and IL-2), it was ranked from high to low as the control group > the QSPSS group > the QYDS group (P < 0.05). As for Th2 (IL-4 and IL-5), it was ranked from high to low as the QYDS group > the QSPSS group >the control group (P < 0.05). As for Th1/Th2 (INF-gamma/lL-4, IL-2/IL-5), it was ranked from high to low as the control group > the QSPSS group >the QYDS group (P < 0.05). CONCLUSIONS: Compared with the tissue of benign nodules, Th1 function in tumor tissue of BAC patients was weaker and Th2 function stronger. Chinese medical syndrome types of BAC had correlation with Th1/Th2. Patients of excess syndrome had stronger immunity with Th1/Th2 shifting left,while those of deficiency syndrome were predispose to humoral immunity with Thl/Th2 shifting right.

[Pathological changes of rectal cancer after irinotecan, 5-fluorouracil or combined short-term radiotherapy].

OBJECTIVE: To observe and evaluate the pathologic changes and curative effects of irinotecan (CPT-11), 5-fluorouracil (5-FU) and combined short-term radiotherapy before low-set rectal cancer operation so as to provide a theoretic basis for formulating a new effective adjuvant therapeutic regimen. METHODS: A total of 41 patients of low rectal cancer were treated with CPT-11, 5-FU therapy or CPT-11 plus 5-FU combined short-term radiotherapy from April 2002 to April 2009. They were divided into 2 groups according to different treatment schemes, including irinotecan group (n = 18) and irinotecan combined short-term radiotherapy group (n = 23). The pathologic changes before and after treatment were observed and the differences of two treatment approaches compared. RESULTS: Tumor cells had different degrees of degeneration and necrosis under microscope in two groups. Compared with computed tomographic findings before therapy, tumor sizes of two groups were reduced by an average of 33.1% (13.5 mm vs 20.2 mm) and 34.4% (12.8 mm vs 19.5 mm) respectively. Two groups were graded according to the RCRG (rectal cancer regression grade) score: RCRG1: 7 cases vs 18 cases, RCRG2: 4 cases vs 3 cases and RCRG3: 7 cases vs 2 cases. According to the pathologic evaluation standard, 3-degree necrosis, cell interstitial fibrosis and intimal thickening in vessels were observed in two groups: 7 cases vs 17 cases, 6 cases vs 17 cases and 3 cases vs 14 cases respectively (all P < 0.05). Five patients achieved complete pathological remission in the irinotecan combined short-term radiotherapy group. CONCLUSION: Based on the pathological changes and mitigation results after treatment, CPT-11 and 5-FU may be used as neoadjuvant drugs for rectal cancer. If the above two drugs can be used in combination with short-term radiation, the curative effect will be better.

[Changes of apoptosis, mitochondrion membrane potential and Ca2+ of hypothalamic neurons induced by high power microwave].

OBJECTIVE: To explore the injury effect and mechanism of hypothalamic neurons after high power microwave (HPM) exposure. METHODS: Primarily cultured hypothalamic neurons were exposed to 10 and 30 mW/cm(2) HPM, and the inverted phase contrast microscope (IPCM) and flow cytometry (FCM) were employed to detect the injury of cells and change of mitochondrion membrane potential (MMP) and Ca(2+) in the cytoplasm of neurons. RESULTS: The ratio of apoptosis was significantly higher than that of the sham exposure (P < 0.05) induced by 10 and 30 mW/cm(2) HPM and necrosis increased significantly (P < 0.05) in the group of 30 mW/cm(2) at 6 h after exposure. The content of Ca(2+) in the cytoplasm of neuron cells increased (P < 0.01) while MMP decreased significantly (P < 0.01) after radiation of 30 mW/cm(2) HPM at 6 h after exposure. CONCLUSION: Apoptosis is one of the major death ways of hypothalamic neurons. The overloading of Ca(2+) and the decline of MMP are involved in the process.