The effectiveness of high intensity laser therapy in the patients with lumbar disc herniation: A protocol of randomized placebo-controlled trial.

BACKGROUND: There is no consensus in existing literature on the pulse power, application time, frequency and the dose of energy of laser therapy for the patients. Therefore, we conducted this research for the assessment of safety and efficiency of ultrasound and high-intensity laser therapy (HILT) in the lumbar disc herniation (LDH) patients. METHODS: Our present research was approved by the institutional review board in the West China-Guangan Hospital. All the participants would acquire the written informed consent. From December 2020 to December 2021, we will conduct a prospective evaluation via a senior surgeon for 1 hundred LDH patients who plan to undergo the conservative treatment at our hospital. In this research, the inclusion criteria contained: the patients with lumbar disc herniation diagnosed by lumbar MRI; the patients with no history of trauma or congenital abnormalities; and the patients with sufficient psychological ability to understand and then answer the questions raised in assessment scale. The participants were randomly divided into the control group or HILT group after performing the examination of baseline. The main outcome was the pain score of visual analog scale. The other results contained the adverse effects, back range of motion as well as functional scores. CONCLUSIONS: We assumed that the HILT is as effective as the ultrasound therapy in treating pain for LDH. TRIAL REGISTRATION: This study protocol was registered in Research Registry (researchregistry5975).

Diosmetin reduces bone loss and osteoclastogenesis by regulating the expression of TRPV1 in osteoporosis rats.

BACKGROUND: Osteoporosis is a systemic skeletal disorder and occurs frequently in postmenopausal women and older men. This study aimed to examine whether diosmetin (DIO) can relieve estrogen deficiency-induced osteoporosis and to explore the underlying mechanisms of this potential effect. METHODS: Forty-nine Sprague-Dawley (SD) rats were divided into seven groups. Six groups underwent bilateral ovariectomy (OVX), while the sham group underwent ovarian exposure surgery. DIO and evodiamine were administered 3 days before surgery, and then subcutaneously every 3 days for 3 months in the following fashion: group I, DIO (100 mg/kg); group II, OVX; group III, OVX + DIO (50 mg/kg); group IV, OVX + DIO (100 mg/kg); group V, OVX + evodiamine (10 mg/kg) group; group VI, OVX + DIO (100 mg/kg) + evodiamine (10 mg/kg) group. Bone histopathological damage, bone loss, osteoclast production, and the expression level of transient receptor potential vanilloid 1 (TRPV1) were detected. RESULTS: Compared with the sham group, the expression of bone resorption-related genes, osteoclast-associated receptor (OSCAR) (1.00%±0.16% versus 4.5%±0.28%, **, P<0.01) and tartrate-resistant acid phosphatase (TRAP) (2.0%±0.6% versus 18.00±1.2%, ***, P<0.001), was increased significantly. The protein level of osteogenic marker proteins, osterix (Osx) (1.0%±0.1% versus 0.03%±0.01%, **, P<0.01) and type 1 collagen (COL1A1) (1.0%±0.13% versus 0.13%±0.05%, **, P<0.01) was decreased significantly with the increase of TRPV1 (1.0%±0.15% versus 2.89%±0.28%, **, P<0.01) protein level. Notably, DIO can alleviate some abnormal symptoms related to osteoporosis. CONCLUSIONS: DIO can relieve typical osteoporosis symptoms in an OVX osteoporosis rat model. The underlying mechanism may be associated with the downregulation of TRPV1.

Development of a novel TLR8 agonist for cancer immunotherapy.

Toll-like receptors (TLRs) are a family of proteins that recognize pathogen associated molecular patterns (PAMPs). Their primary function is to activate innate immune responses while also involved in facilitating adaptive immune responses. Different TLRs exert distinct functions by activating varied immune cascades. Several TLRs are being pursued as cancer drug targets. We discovered a novel, highly potent and selective small molecule TLR8 agonist DN052. DN052 exhibited strong in vitro cellular activity with EC50 at 6.7 nM and was highly selective for TLR8 over other TLRs including TLR4, 7 and 9. DN052 displayed excellent in vitro ADMET and in vivo PK profiles. DN052 potently inhibited tumor growth as a single agent. Moreover, combination of DN052 with the immune checkpoint inhibitor, selected targeted therapeutics or chemotherapeutic drugs further enhanced efficacy of single agents. Mechanistically, treatment with DN052 resulted in strong induction of pro-inflammatory cytokines in ex vivo human PBMC assay and in vivo monkey study. GLP toxicity studies in rats and monkeys demonstrated favorable safety profile. This led to the advancement of DN052 into phase 1 clinical trials.

Synergetic effect of dual co-catalysts on the activity of BiVO4 for photocatalytic carbamazepine degradation.

An efficient visible-light driven three components photocatalyst for carbamazepine (CBZ) degradation has been assembled by co-loading reduction cocatalyst Pt and oxidation cocatalyst Co3O4 (MnO x ) on BiVO4. The apparent rate constant of the three components photocatalyst Pt/BiVO4/Co3O4 for degradation of CBZ is 54 times that of Co3O4/BiVO4 and 2.5 times that of Pt/BiVO4, which shows a synergetic effect in the photocatalytic activity. The same synergetic effect is also observed for Pt/BiVO4/MnO x . The spatial separation of the reduction and oxidation cocatalysts could reduce the recombination of the photogenerated charges, which mainly accounts for the high photocatalytic activity of the three components photocatalyst. The photocatalytic intermediates of CBZ were detected by HPLC-ESI-MS, and a deductive degradation pathway of CBZ was proposed.

Involvement of glyceraldehyde-3-phosphate dehydrogenase in tumor necrosis factor-related apoptosis-inducing ligand-mediated death of thyroid cancer cells.

TNF-related apoptosis-inducing ligand (TRAIL) is cytotoxic to most thyroid cancer cell lines, including those originating from anaplastic carcinomas, implying TRAIL as a promising therapeutic agent against thyroid cancers. However, signal transduction in TRAIL-mediated apoptosis is not clearly understood. In addition to its well-known glycolytic functions, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional protein, including its surprising role as a mediator for cell death. In this study we explored the involvement of GAPDH in TRAIL-mediated thyroid cancer cell death. In follicular undifferentiated thyroid cells, S-nitrosylation and nuclear translocation of GAPDH appear to mediate TRAIL-induced cell death at least partially, as evidenced by pretreatment with N-nitro-L-arginine methyl ester, a competitive nitric oxide synthase inhibitor that partially but significantly attenuated TRAIL-induced apoptosis through the reduction of S-nitrosylation and nuclear translocation of GAPDH. In addition, GAPDH small interfering RNA partially prevented the apoptotic effect of TRAIL, although TRAIL-induced nitric oxide synthase stimulation and production of nitric oxide were not attenuated. Furthermore, nuclear localization of GAPDH was observed in another thyroid cancer cell line, KTC2, which is also sensitive to TRAIL, but not in those TRAIL insensitive cell lines: ARO, KTC1, and KTC3. These data indicate that nitric oxide-mediated S-nitrosylation of GAPDH and subsequent nuclear translocation of GAPDH might function as a mediator of TRAIL-induced cell death in thyroid cancer cells.

Different induction of GRP78 and CHOP as a predictor of sensitivity to proteasome inhibitors in thyroid cancer cells.

Proteasome inhibitors represent a novel class of antitumor agents with preclinical and clinical evidence of activity against hematological malignancies and solid tumors. Emerging lines of evidence suggest that the unfolded protein response is implicated in proteasome inhibitors-induced apoptosis. Glucose-regulated protein 78 kDa (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) as part of the unfolded protein response play critical roles in cell survival or death. Here we demonstrate that induction of GRP78 and CHOP are differently regulated upon proteasome inhibition in different thyroid cancer cell lines, and GRP78 levels as well as preferential induction of GRP78 or CHOP appears to be involved in the responsiveness. Insensitive ARO, 8305C, and 8505C cell lines inherently express relatively high levels of GRP78 compared with sensitive cell lines, and its levels are further up-regulated upon treatment with proteasome inhibitors. CHOP levels are dramatically induced in sensitive cell lines until 24 h after proteasome inhibition. On the other hand, only a slight increase is observed at 4 h in insensitive cell lines, and this increase is unable to be detected after 8 h. Insensitive cells are sensitized to proteasome inhibition by suppression of GRP78. Furthermore, suppression of CHOP induction or overexpression of GRP78 partially prevents proteasome inhibition-mediated cell death. Our study indicates a molecular mechanism by which the sensitivity of thyroid cancer cells is regulated by the level of GRP78 as well as preferential induction of GRP78 or CHOP upon treatment with proteasome inhibitors. Our experiments therefore suggest a novel approach toward sensitization of thyroid cancer cells to proteasome inhibitors.

[The inhibitory effect of vascular endothelial growth factor antisense oligonucleotides in angiogenesis of thyroid carcinoma].

OBJECTIVE: To investigate the inhibitive effect of antisense oligonucleotide (ASODN) on vascular endothelial growth factor (VEGF) expression and endothelial cell growth in thyroid carcinoma. METHODS: Targeted ASODN of VEGF was designed and synthesized, then transfected to TT (medullary thyroid carcinoma) cell line and the culture supernatant was collected in which ECV304 (endothelial cell line) was seeded. At the same time positive control [sense oligonucleotides (SODN) group] and normal control were set for comparison. Cell growth condition was observed under microscope. RT-PCR and immuocytochemistry were used for detection of VEGF mRNA and protein expression in TT cells. MTT assay was used for cell growth inhibition ratio (IR) of TT and ECV304 cells, flow cytometry (FCM) for apoptotic index (AI) of ECV304 cells and acridine orange/ethidium bromide (AO/EB) staining for apoptotic morphology of ECV304 cells. RESULTS: As compared with positive and normal control groups, VEGF mRNA and protein expressions in TT cells of ASODN transfection groups were obviously decreased (P < 0.01). Cell growth was not influenced apparently in ECV304 cells with direct ASODN administration, but ECV304 cell growth in ASODN conditioned medium was significantly inhibited and IR (0.21 +/- 0.03, 0.31 +/- 0.01, 0.42 +/- 0.22) was significantly higher than that of SODN group (0.05 +/- 0.03, P < 0.01), with the presence of apparent apoptosis. The effect mentioned above was in a dose-dependent manner. CONCLUSION: ASODN can suppress endothelial cell growth and inhibit tumor angiogenesis possibly by specifically blocking VEGF expression in thyroid carcinoma.

Synthesis and Biological Evaluation of Macrocyclized Betulin Derivatives as a Novel Class of Anti-HIV-1 Maturation Inhibitors.

A macrocycle provides diverse functionality and stereochemical complexity in a conformationally preorganized ring structure, and it occupies a unique chemical space in drug discovery. However, the synthetic challenge to access this structural class is high and hinders the exploration of macrocycles. In this study, efficient synthetic routes to macrocyclized betulin derivatives have been established. The macrocycle containing compounds showed equal potency compared to bevirimat in multiple HIV-1 antiviral assays. The synthesis and biological evaluation of this novel series of HIV-1 maturation inhibitors will be discussed.