Current Status and Prospects of Camrelizumab, A Humanized Antibody Against Programmed Cell Death Receptor 1.

BACKGROUND: Camrelizumab, which was launched in China on May 29, 2019, is a humanized anti-programmed cell death-1 (PD-1) antibody. It is used for the treatment of complicated or refractory classic Hodgkin's lymphoma with at least second-line chemotherapy. On March 4, 2020, camrelizumab was approved as a second-line drug in China for the treatment of advanced hepatocellular carcinoma. Currently, camrelizumab is undergoing clinical research for advanced solid tumors such as liver cancer, gastric cancer, esophageal cancer, and lung cancer, and all have shown clinical efficacy. OBJECTIVE: This review describes preclinical studies on camrelizumab and its efficacy and safety in clinical studies in various tumors. METHODS: A literature search was conducted on basic research and clinical trials of camrelizumab determined its pharmacology, toxicology, pharmacokinetic properties, and current clinical research status. We also analyzed the difference between camrelizumab and other PD-1 antibodies. RESULTS: The results of preclinical studies show that camrelizumab binds to the PD-1 receptor and has stable anti-tumor activity in a dose-dependent manner. Clinical studies show that camrelizumab has therapeutic effects on a variety of tumors. The incidence of adverse reactions with camrelizumab is low, with most being mild, reversible, and predictable. CONCLUSION: This review summarizes the current status of preclinical and clinical studies on camrelizumab. Current research confirms that camrelizumab alone or in combination with other drugs shows significant anti-cancer activity and a low incidence of adverse reactions. However, further studies are needed to verify the application potential of camrelizumab in a variety of tumors.

Double C-N bond cleavages of N-alkyl 4-oxopiperidinium salts: access to unsymmetrical tertiary sulfonamides.

In this paper, regiospecific, double intraannular C-N bond cleavages of N-alkyl 4-oxopiperidinium salts are presented. The reaction sequence involves a charge-transfer complex, in situ formed between sulfonyl chloride and N-methylmorpholine, which induces S-Cl bond homolysis of sulfonyl chloride, yielding a reactive sulfonyl radical that further induces the double C-N bond cleavages of N-alkyl 4-oxopiperidinium salt. The secondary amine thus produced was trapped by sulfonyl chloride to yield the desired sulfonamide product. The key feature of this protocol is that two intraannular C-N bonds of the 4-oxopiperidine ring are cleaved in one step under metal- and oxidant-free conditions.

MARVELD1 attenuates arsenic trioxide-induced apoptosis in liver cancer cells by inhibiting reactive oxygen species production.

BACKGROUND: Arsenic trioxide (As2O3) is widely used for the treatment of acute promyelocytic leukemia (APL), and more recently, has also been applied to solid tumors. However, there are a fraction of patients with solid tumors, such as liver cancer, who respond to As2O3 treatment poorly. The underlying mechanisms for this remain unclear. METHODS: We determined the suitable concentration of drugs by IC50. Cell Counting Kit-8 (CCK-8) and flow cytometry were used to analyze the apoptosis. Morphological changes of the cells were observed by laser scanning confocal microscopy. Furthermore, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. Quantitative polymerase chain reaction (qPCR) and Western blot tests were conducted to detect the mRNA and protein levels in different groups. Finally, a xenograft tumor assay and histopathological analysis were performed to evaluate the MARVELD1 function in cell proliferation and apoptosis. RESULTS: Here, we show that MARVELD1 enhances the therapeutic effects of epirubicin, while inducing the strong resistance of liver cancer cells to As2O3 treatment. We further demonstrate that the As2O3-induced apoptosis was inhibited by MARVELD1 overexpression (24 h Vector vs. MARVELD1 =30.58% vs. 17.41%, P<0.01; 48 h Vector vs. MARVELD1 =46.50% vs. 21.02%, P<0.01), possibly through inhibiting ROS production by enhancing TRXR1 expression. In vivo, we found a significantly increased size (Vector vs. MARVELD1 =203.90±21.92 vs. 675.70±37.84 mm3, P<0.001) and weight (Vector vs. MARVELD1 =0.19±0.02 vs. 0.58±0.05 g, P<0.001) of tumors with high expression of MARVELD1 after As2O3 treatment. Consistently, a higher expression of MARVELD1 predicted a poor prognosis for liver cancer patients. CONCLUSIONS: Our data identified a unique role of MARVELD1 in As2O3-induced apoptosis and As2O3 cancer therapy resistance.

Study on the mechanism of the interaction between acteoside and pepsin using spectroscopic techniques.

The interaction of acteoside with pepsin has been investigated using fluorescence spectra, UV/vis absorption spectra, three-dimensional (3D) fluorescence spectra and synchronous fluorescence spectra, along with a molecular docking method. The fluorescence experiments indicate that acteoside can quench the intrinsic fluorescence of pepsin through combined quenching at a low concentration of acteoside, and static quenching at high concentrations. Thermodynamic analysis suggests that hydrogen bonds and van der Waal's forces are the main forces between pepsin and acteoside. According to the theory of Förster's non-radiation energy transfer, the binding distance between pepsin and acteoside was calculated to be 2.018 nm, which implies that energy transfer occurs between acteoside and pepsin. In addition, experimental results from UV/vis absorption spectra, 3D fluorescence spectra and synchronous fluorescence spectra imply that pepsin undergoes a conformation change when it interacts with acteoside.

Flavonoid of Drynaria fortunei protects against acute renal failure.

The flavonoid fraction (FF) from Drynaria fortunei was investigated to determine its biological activity expression in three acute renal failure animal models. Guinea pigs received 100 mg/kg of gentamicin (GM group), 100 mg/kg of GM plus 10 mg/kg of FF (GMFF group), 10 mg/kg of FF (FF group) or saline (saline group) intramuscularly for 14 days. The blood urea nitrogen (BUN) and creatinine levels were found to be significantly higher in the GM group (22.70+/-3.84 mg/dL, 0.68+/-0.05 mg/dL) than in the GMFF group (17.10+/-1.04 mg/dL, 0.58+/-0.09 mg/dL), the FF group (17.40+/-1.01 mg/dL, 0.49+/-0.20 mg/dL) and the saline group (17.50+/-1.22 mg/dL, 0.50+/-0.02 mg/dL). Mice were treated once with 6 mg/kg of mercuric chloride, followed by 10 mg/kg of FF or saline. On days 3, 4 and 5, BUN and creatinine levels were found to be significantly higher in the HgCl2-saline group (74.00+/-39.20 mg/dL, 59.30+/-31.20 mg/dL, 74.00+/-37.30 mg/dL and 0.53+/-0.17 mg/dL, 0.48+/-0.15 mg/dL 0.33+/-0.15 mg/dL) than in the HgCl2-FF group (19.50+/-4.90 mg/dL, 43.00+/-26.30 mg/dL, 38.50+/-13.80 mg/dL and 0.23+/-0.05 mg/dL, 0.30+/-0.12 mg/dL, 0.15+/-0.06 mg/dL).After surgery for 5/6-nephrectomy, ten mice received FF at a dose of 10 mg/kg/day and eight received saline for 42 days. The saline group survived for 12-62 days and the FF group survived for 20-320 days. The FF group had a significantly longer survival time than the saline group (p<0.05). Regeneration of kidney tubular cells and significantly enlarged convoluted tubules were noted in the pathology study of the FF group. In conclusion, the present study suggests that FF prevents nephrotoxicity, improves kidney function and promotes kidney primary epithelial tubular cell regeneration.

Flavanoid of Drynaria fortunei protects against gentamicin ototoxicity.

A flavanoid fraction (FF) from Drynaria fortunei, was investigated to see if it has the protective and ameliorative effects against gentamicin (GM) ototoxicity in guinea pigs (n = 36). Eleven (GM-group) animals received GM 100 mg/kg/day. Eleven (GMFF-group) animals received the same dose of GM but 2 days prior were dosed with FF (10 mg/kg/day) for 2 weeks. Seven (S-group) animals received saline and seven (FF-group) animals received the same dose of FF as the GMFF-group. The thresholds of tone-burst auditory evoked response (ABR) at 2 k, 8 k, and 32 k Hz were determined to be as follows: GM-group: 90 dB, 92 dB and 72 dB, GMFF-group: 30 dB, 37 dB and 38 dB, FF-group: 28 dB, 25 dB and 29 dB, S-group: 30 dB, 28 dB and 39 dB. The GM-group had a significantly higher hearing threshold than the other groups (p < 0.05). The GMFF- and FF-groups had hearing thresholds similar to the S-groups (p > 0.1). Repair of damaged hair cells was observed histologically. The percentage of the damaged outer hair cells (OHC) and inner hair cells (IHC) were determined to be as follows: GM-group: 43% and 20%, GMFF-group: 20% and 2%, FF-group: 9% and 2% and S-group: 4% and 1%. The GMFF-group showed less damage to the OHC (p > 0.05) and significantly less damage to the IHC (p < 0.05) than the GM-group. FF did not change the antimicrobial activity of GM and it did not show any intrinsic antibacterial effect. FF did not affect the kinetics of GM during the course of the experiment.