Anticancer polypyrrole-polyethylenimine drug-free nanozyme for precise B-cell lymphoma therapy.

As an alternative strategy for cancer treatment, the combination of cancer nanomedicine and immunotherapy is promising with regard to efficacy and safety; however, precise modulation of the activation of antitumor immunity remains challenging. Therefore, the aim of the present study was to describe an intelligent nanocomposite polymer immunomodulator, drug-free polypyrrole-polyethyleneimine nanozyme (PPY-PEI NZ), which responds to the B-cell lymphoma tumor microenvironment, for precision cancer immunotherapy. Earlier engulfment of PPY-PEI NZs in an endocytosis-dependent manner resulted in rapid binding in four different types of B-cell lymphoma cells. The PPY-PEI NZ effectively suppressed B cell colony-like growth in vitro accompanied by cytotoxicity via apoptosis induction. During PPY-PEI NZ-induced cell death, mitochondrial swelling, loss of mitochondrial transmembrane potential (MTP), downregulation of antiapoptotic proteins, and caspase-dependent apoptosis were observed. Deregulated AKT and ERK signaling contributed to glycogen synthase kinase-3-regulated cell apoptosis following deregulation of Mcl-1 and MTP loss. Additionally, PPY-PEI NZs induced lysosomal membrane permeabilization while inhibiting endosomal acidification, partly protecting cells from lysosomal apoptosis. PPY-PEI NZs selectively bound and eliminated exogenous malignant B cells in a mixed culture system with healthy leukocytes ex vivo. While PPY-PEI NZs showed no cytotoxicity in wild-type mice, they provided long-term and efficient inhibition of the growth of B-cell lymphoma-driven nodules in a subcutaneous xenograft model. This study explores a potential PPY-PEI NZ-based anticancer agent against B-cell lymphoma.

Different Induction of PD-L1 (CD274) and PD-1 (CD279) Expression in THP-1-Differentiated Types 1 and 2 Macrophages.

BACKGROUND: Phorbol 12-myristate 13-acetate (PMA)-induced differentiation of human monocytic THP-1 cells is an experimental model for preparing resting macrophages (M0) for cell polarization toward the different functional specializations of macrophages. METHODS: In this study, we examined the expression of immune checkpoints by using flow cytometry following multicolor staining. The blockade of immune checkpoint by using neutralizing antibodies was performed to assess their role in PMA-induced THP-1-differentiated macrophages. RESULTS: Upon the inducible macrophage differentiation caused by PMA, increased expression levels of CD11b and CD68 were measured and characterized according to their adherent phenotype accompanied by the generation of cellular complexity. While the cell growth rate was abolished post-differentiation, some cells underwent cell death. Notably, we found increases in the expression of programmed cell death protein 1, also known as PD-1 (CD279), and its ligand PD-L1 (CD274), mainly in differentiated M0 (CD68+CD11b+) macrophages. However, neutralizing PD-L1/PD-1 neither blocked THP-1 cell differentiation toward macrophages nor inhibited macrophage polarization in M1 and M2. In specializing macrophages, a decrease both in CD274 and CD279 was found in M2. CONCLUSION: These results revealed the inducible expression of PD-L1/PD-1 in PMA-induced THP-1-differentiated M0 macrophages followed by a decrease in M2 macrophages.

Carnosic Acid Alleviates Levodopa-Induced Dyskinesia and Cell Death in 6-Hydroxydopamine-lesioned Rats and in SH-SY5Y Cells.

The present study investigated the impact of carnosic acid (CA) from rosemary on the levodopa (L-dopa)-induced dyskinesia (LID) in rats treated with 6-hydroxydopamine (6-OHDA). To establish the model of LID, 6-OHDA-lesioned rats were injected intraperitoneally with 30 mg/kg L-dopa once a day for 36 days. Rats were daily administrated with 3 or 15 mg/kg CA by oral intubation prior to L-dopa injection for 4 days. Rats pretreated with CA had reduced L-dopa-induced abnormal involuntary movements (AIMs) and ALO scores (a sum of axial, limb, and orofacial scores). Moreover, the increases of dopamine D1-receptor, p-DARPP-32, ΔFosB, p-ERK1/2, and p-c-Jun ser63, along with the decrease in p-c-Jun ser73, induced by L-dopa in 6-OHDA-treated rats were significantly reversed by pretreatment with CA. In addition, we used the model of SH-SY5Y cells to further examine the neuroprotective mechanisms of CA on L-dopa-induced cytotoxicity. SH-SY5Y cells were treated with CA for 18 h, and then co-treated with 400 µM L-dopa for the indicated time points. The results showed that pretreatment of CA attenuated the cell death and nuclear condensation induced by L-dopa. By the immunoblots, the reduction of Bcl-2, p-c-Jun ser73, and parkin and the induction of cleaved caspase 3, cleaved Poly (ADP-ribose) polymerase, p-ERK1/2, p-c-Jun ser63, and ubiquitinated protein by L-dopa were improved in cells pretreated with CA. In conclusion, CA ameliorates the development of LID via regulating the D1R signaling and prevents L-dopa-induced apoptotic cell death through modulating the ERK1/2-c-Jun and inducing the parkin. This study suggested that CA can be used to alleviate the adverse effects of LID for PD patients.

Antiviral activity of Portulaca oleracea L. against influenza A viruses.

ETHNOPHARMACOLOGICAL RELEVANCE: Portulaca oleracea L. is used not only as an edible potherb but also as a traditional remedy to assuage the symptoms of various diseases. The water extract of P. oleracea (WEPO) has been found to effectively alleviate the signs and symptoms of pandemic influenza A virus (IAV) infection. However, the anti-IAV activity of WEPO is still unclear. AIM OF STUDY: In this study, we aimed to elucidate the anti-IAV activity of WEPO and investigate the potential mechanisms underlying the anti-H1N1 activity. MATERIALS AND METHODS: The cytotoxicity of WEPO and other Chinese herbs was measured using the cell viability test. The anti-IAV activity of WEPO was determined using the plaque reduction assay, real-time reverse transcription-polymerase chain reaction, and immunofluorescence assay. The virucidal activity of WEPO was determined by labeling the virus and using the time-dependent virucidal activity assay. RESULTS: The half-maximal effective concentration of WEPO for A/WSN/1933 (H1N1) was very low, with a high selectivity index. The production of circulating H1N1 and H3N2 was suppressed by WEPO. Additionally, the antiviral activity of WEPO was observed in the early stage of IAV infection. Furthermore, WEPO inhibited the binding of virus to cells and exhibited good virucidal activity, significantly decreasing the viral load within 10 min to prevent viral infection. CONCLUSIONS: We demonstrate the anti-IAV activity of WEPO and strongly recommend the use of WEPO, as an herbal regimen, to prevent and treat H1N1 infection at an early stage.

Persistent nasal carriers of Acinetobacter baumannii in long-term-care facilities.

BACKGROUND: Acinetobacter baumannii and Staphylococcus aureus have persisted as 2 major pathogens worldwide. AIM: We designed a prevalence study to investigate the prevalence of nasal carriage of S aureus and A baumannii in long-term-care facilities (LCTFs) and their collaborative community hospitals. In addition, we aimed to clarify persistent or nonpersistent carriage of the 2 organisms among residents of LTCFs. METHODS: We performed a prevalence study concerning nasal carriers of A baumannii and S aureus in 3 LTCFs and 1 collaborative community hospital. RESULTS: Seventy subjects were enrolled and clustered into 3 groups: the elderly sick group (n = 24), the elderly healthy group (n = 33), and the healthy health care worker group (n = 13). Nasal samples were collected, and the nuc and mecA genes of S aureus and the blaOXA gene of A baumannii were analyzed by polymerase chain reaction. Among the 3 groups, the rate of nasal carriage of S aureus was approximately 0%-15%. However, the rate for A baumannii was approximately 54%-92%. Notably, the persistent carrier rate of A baumannii in the elderly sick group was 83.3% (20 out of 24) despite a 12.5% (3 out of 24) rate of carbapenem-resistant A baumannii. CONCLUSIONS: We emphasized that the persistent nasal carriage of A baumannii in LTCFs could be another portal of exit to cause A baumannii infection in Taiwan.