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Osteoarthritis (OA) is a complicated disorder that is the most prevalent chronic degenerative joint disease nowadays. Pudilan Tablets (PDL) is a prominent traditional Chinese medicine formula used in clinical settings to treat chronic inflammatory illnesses. However, there is currently minimal fundamental research on PDL in the therapy of joint diseases. As a result, this study looked at the anti-inflammatory and anti-OA properties of PDL in vitro and in vivo, as well as the mechanism of PDL in the treatment of OA. We investigated the anti-OA properties of PDL in OA mice that were generated by monosodium iodoacetate (MIA). All animals were administered PDL (2 g/kg or 4 g/kg) or the positive control drug, indomethacin (150 mg/kg), once daily for a total of 28 days starting on the day of MIA injection. The CCK-8 assay was used to test the vitality of PDL-treated RAW264.7 cells in vitro. RAW264.7 cells that had been activated with lipopolysaccharide (LPS) were used to assess the anti-inflammatory properties of PDL. In the MIA-induced OA model mice, PDL reduced pain, decreased OA-induced cartilage damages and degradation, decreased production of pro-inflammatory cytokines in serum, and suppressed IL-1β, IL-6, and TNF-α mRNA expression levels in tibiofemoral joint. In RAW264.7 cells, PDL treatment prevented LPS-induced activation of the ERK/Akt signaling pathway and significantly decreased the levels of inflammatory cytokines, such as IL-1β, IL-6, and TNF-α. In conclusion, these results suggest that PDL is involved in combating the development and progression of OA, exerts a powerful anti-inflammatory effect on the knee joint, and may be a promising candidate for the treatment of OA. [ABSTRACT FROM AUTHOR]

BsAb (bispecific antibody)-armed oncolytic viruses (OVs) are effective in regulating tumor microenvironment. However, oHSV2 (oncolytic herpes simplex virus type 2) expressing immune checkpoints targeting BsAb molecules are not reported. Here, we generated oHSV2-armed PD-L1/CD3 BsAb and established pharmacodynamic evaluation models, which suggested that our oHSV2-BsAb molecules have an improved oncolytic potency in vitro and in vivo. The oHSV2 viruses armed with BsAb molecules targeting programmed cell death ligand 1 (PD-L1)/CD3 or CD19/CD3 (oHSV2-PD-L1/CD3-BsAb or oHSV2-CD19/mCD3-BsAb) were constructed; besides inducing oncolysis in virus-infected tumor cells, the modified oncolytic virus oHSV2-PD-L1/CD3-BsAb can also activate peripheral blood mononuclear cells (PBMCs) by releasing PD-L1/CD3 BsAb and thereby induce PBMC-mediated killing of PD-L1-positive tumor cells, regardless of PD-L1 expression level. The expressed PD-L1/CD3 BsAb can upregulate the activation markers of T cells in PBMCs and induce different cytokine secretion. The activation of T cells and the enrichment of related immune regulatory pathways are further confirmed by proteomics. It also demonstrated that the OVs or PBMCs could upregulate PD-L1 expression on the surface of tumor cells through transforming "cold tumors" with low PD-L1 expression into "hot tumors" with high PD-L1 expression, which can facilitate the targeting of BsAb molecules and enhance the effect of oncolysis. oHSV2-PD-L1/CD3-BsAb or oHSV2-CD19/mCD3-BsAb showed an enhanced oncolytic effect in vitro and in vivo compared to backbone virus oHSV2-GFP. Our results showed that the newly designed oHSV2-BsAb had enhanced therapeutic effects against solid tumors and provided a new option of immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Selectively replicating herpes simplex virus-2 (HSV-2) vector is a promising treatment for cancer therapy. The insertion of multiple transgenes into the viral genome has been performed to improve its oncolytic activity. Methods: Herein, we simultaneously constructed five "armed" oncolytic viruses (OVs), designated oHSV2-IL12, -IL15, GM-CSF, -PD1v, and IL7 × CCL19. These OVs delete the ICP34.5 and ICP47 genes with the insertion of transgenes into the deleted ICP34.5 locus. The anti-tumor efficacy in vivo was tested in the syngeneic 4T1 and CT26 tumor-bearing mice model. Results: The OVs showed comparable oncolytic capability in vitro. The combination therapy of oHSV2-IL12, -IL15, GM-CSF, -PD1v, and IL7 × CCL19 exhibited the highest tumor inhibition efficacy compared with the treatment of single OV or two OVs combination. Conclusions: The OVs armed with different transgenes combination therapy also named 5-valent oHSV2 (also called cocktail therapy) might be an effective therapeutic strategy for solid tumors. [ABSTRACT FROM AUTHOR]

Reliable animal models are required for understanding the molecular events of gastric tumor growth and metastasis. Tracing techniques based on iRFP720 may optimize the noninvasive monitoring of tumors in vivo. The present study established a human gastric adenocarcinoma cell line BGC823-iRFP720-GFP (abbreviated as BGC823-iRFP) that stably expressed iRFP720 and green fluorescent protein (GFP) by piggyBac transposon system. The monoclonal cell line BGC823-iRFP was isolated under puromycin selection. The cell morphology and proliferation ability of BGC823-iRFP cells in vitro were similar to that of the BGC823 cells. The iRFP720 and GFP expressions were confirmed by laser confocal microscopy and Cytation™ 5. Hematoxylin and eosin staining, immunohistochemical analysis, and animal experiments also revealed that BGC823-iRFP exhibited no significant changes in morphology, growth kinetics, and tumorigenicity in vivo. IVIS Lumina III imaging indicated that the iRFP720 signals of the BGC823-iRFP cells could be used to evaluate the antitumor efficacy of oncolytic viruses and chemotherapy drugs. Therefore, the BGC823-iRFP cells would be a useful tool for gastric cancer research and antitumor drug evaluation. [ABSTRACT FROM AUTHOR]

Oncolytic virotherapy is a new and safe therapeutic strategy based on the inherent cytotoxicity of oncolytic viruses and their ability to replicate and spread within tumors in a selective manner. In a previous study, a new type of oncolytic herpes simplex virus type 2 (oHSV-2, named OH2) was constructed to treat human cancers. That study demonstrated that OH2 is genetically and biologically stable. Its antitumor activity was maintained, even after passaging the virus for >20 generations. To advance OH2 into a clinical trial, a systematic preclinical safety evaluation was performed, which included: an acute toxicity test of OH2 in BALB/c mice; repeated dose toxicity tests of OH2 in BALB/c mice and cynomolgus monkeys; and biodistribution assays of OH2 in BALB/c mice, tumor-bearing mice, tumor-bearing nude mice, and cynomolgus monkeys. The results of this preclinical safety evaluation of OH2 indicate that OH2 is safe and suitable for clinical trials. [ABSTRACT FROM AUTHOR]

• A comprehensive preclinical safety evaluation was conducted for oHSV2-PD-L1/CD3-BsAb. • Preclinical safety evaluation indicated that oHSV2-PD-L1/CD3-BsAb is safe and suitable for clinical trials. • oHSV2-PD-L1/CD3-BsAb has obtained approval to initiate Phase I clinical trials in the United States (FDA IND: 28717). Oncolytic virotherapy is an emerging and safe therapeutic approach based on the inherent cytotoxicity of oncolytic viruses and their ability to replicate and spread within tumors in a selective manner. We constructed a new type of oncolytic herpes simplex virus armed with Bispecific Antibody (BsAb) molecules targeting PD-L1/CD3 (oHSV2-PD-L1/CD3-BsAb) to treat human malignancies. We demonstrated the anti-tumor efficacy of oHSV2-PD-L1/CD3-BsAb. To move forward with clinical trials of oHSV2-PD-L1/CD3-BsAb, we conducted a comprehensive preclinical safety evaluation, including hemolysis test, anaphylaxis test, repeated dose toxicity test in cynomolgus monkeys, biodistribution in cynomolgus monkeys and tissue cross-reactivity of PD-L1/CD3-BsAb with human and cynomolgus monkey tissues in vitro. Our preclinical safety evaluation indicated that oHSV2-PD-L1/CD3-BsAb is safe and suitable for clinical trials. After undergoing a thorough evaluation by the United States Food and Drug Administration (FDA), oHSV2-PD-L1/CD3-BsAb has successfully obtained approval to initiate Phase I clinical trials in the United States (FDA IND: 28717). [ABSTRACT FROM AUTHOR]