Hydroxychloroquine (HCQ) is an antimalarial drug also used in treating autoimmune diseases. Its antiviral activity was demonstrated in restricting HIV infection in vitro ; however, the clinical implications remain controversial. Infection with dengue virus (DENV) is a global public health problem, and we lack an antiviral drug for DENV. Here, we evaluated the anti-DENV potential of treatment with HCQ. Immunofluorescence assays demonstrated that HCQ could inhibit DENV serotype 1–4 infection in vitro . RT-qPCR analysis of HCQ-treated cells showed induced expression of interferon (IFN)-related antiviral proteins and certain inflammatory cytokines. Mechanistic study suggested that HCQ activated the innate immune signaling pathways of IFN-β, AP-1, and NFκB. Knocking down mitochondrial antiviral signaling protein (MAVS), inhibiting TANK binding kinase 1 (TBK1)/inhibitor-κB kinase ɛ (IKKɛ), and blocking type I IFN receptor reduced the efficiency of HCQ against DENV-2 infection. Furthermore, HCQ significantly induced cellular production of reactive oxygen species (ROS), which was involved in the host defense system. Suppression of ROS production attenuated the innate immune activation and anti-DENV-2 effect of HCQ. In summary, HCQ triggers the host defense machinery by inducing ROS- and MAVS-mediated innate immune activation against DENV infection and may be a candidate drug for DENV infection.

Cervical cancer is a common gynecological malignancy, accounting for 10% of all gynecological cancers. Recently, targeted therapy for cervical cancer has shown unprecedented advantages. Several studies have shown that ubiquitin conjugating enzyme E2 (UBE2C) is highly expressed in a series of tumors, and participates in the progression of these tumors. However, the possible impact of UBE2C on the progression of cervical squamous cell carcinoma (CESC) remains unclear. Here, we carried out tissue microarray analysis of paraffin-embedded tissues from 294 cervical cancer patients with FIGO/TNM cancer staging records. The results indicated that UBE2C was highly expressed in human CESC tissues and its expression was related to the clinical characteristics of CESC patients. Overexpression and knockdown of UBE2C enhanced and reduced cervical cancer cell proliferation, respectively, in vitro. Furthermore, in vivo experiments showed that UBE2C regulated the expression and activity of the mTOR/PI3K/AKT pathway. In summary, we confirmed that UBE2C is involved in the process of CESC and that UBE2C may represent a molecular target for CESC treatment.

Extraintestinal pathogenic Escherichia coli (ExPEC) strains hold the responsibility for the majority of E. coli infections. Numerous extraintestinal virulence factors (VFs) were possessed by ExPEC which are involved in the pathogenesis of infection. However, the effect of comorbidities or infection syndrome in the association of VFs and mortality remains inconclusive. This study addressed whether specific sequence type (ST) and VFs of extended-spectrum beta-lactamase-producing E. coli (ESBL-EC) are associated with different outcomes in patients with bloodstream infection. 121 adults from southern Taiwan with ESBL-EC bloodstream infections were enrolled during a 6-year period. Demographic data, including infection syndromes, underlying disease and outcomes, were collected. The virulence factors in isolates were analyzed by PCR and multilocus sequence typing analyses were also performed. Positivity for the virulence genes iha, hlyD, sat, iutA, fyuA, malX, ompT, and traT was associated with ST131 positivity (P < 0.05). Some ESBL-EC virulence genes associated with urinary tract infection (UTI) were revealed. Positivity for ST405 and the virulence genes iroN and iss were significantly associated with increased 30-day mortality (death within 30 days) on univariate analysis (P < 0.05). Independent risk factors of 30-day mortality in bacteremic patients with UTI included underlying chronic liver disease and malignancy. ST131 was borderline associated with 30-day mortality. Independent risk factors associated with 30-day mortality among bacteremic patients without UTI included comorbidities and iroN positivity. In bacteremic patients with UTI, and the ST131 clone was borderline associated with mortality. Positivity for the virulence gene iroN may be linked to mortality in bacteremic patients without UTI.

Metformin activates type I interferon signaling against HCV via activation of adenosine monophosphate-activated protein kinase Metformin activates type I interferon signaling against HCV via activation of adenosine monophosphate-activated protein kinase

Tripartite motif (TRIM) protein TRIM5 of the primate species restricts replication of HIV and other retroviruses. Whereas primates have a single TRIM5 gene, the corresponding locus in the mouse has expanded during evolution, now containing more than eight related genes. Owing to the complexity of the genomic organization, a mouse homolog of TRIM5 has not been fully studied thus far. In the present study, we report that Trim12c (formerly Trim12-2) encodes a TRIM5-like protein with a ubiquitin ligase activity. Similar to the primate TRIM5, TRIM12c is expressed in the cytoplasm as a punctate structure and induced upon IFN and pathogen stimulation in macrophages and dendritic cells. We show that TRIM12c interacts with TRAF6, a key protein in the pathogen recognition receptor signaling, and reciprocally enhances their ubiquitination, leading to cooperative activation of IFN and NF-κB pathways. This study identifies TRIM12c as a mouse TRIM5 equivalent, critical for host innate immunity.

Primary squamous cell carcinoma (SCC) of the ovary in humans is rare. Most cases represent a malignant transformation of ovarian teratoma, Brenner tumor, or endometriosis. The etiology of this cancer remains largely unknown. Human papillomavirus (HPV) infection is a critical factor that induces tumor formation, particularly cervical cancer. Therefore, this study aimed to evaluate the association of HPV with malignant transformation of mature cystic teratoma (MCT) into SCC of the ovary. The samples included four formalin-fixed paraffin-embedded SCC-MCT tissues and their adjacent tissues from the cervix to the ovaries, 12 cases of benign teratoma ovarian tissues (dermoid tissues), and 11 cases of benign nonteratoma ovarian tissues (nondermoid tissues). The two squamous carcinoma tissues of the cervix were used as control samples. HPV was detected by immunohistochemistry (IHC) with anti-HPV capsid or E6 (HPV type 16/18) antibodies and in situ hybridization (ISH) with three sets of genotyping probes, HPV types 6/11, 16/18, and 31/33. IHC revealed HPV infection associated with the four cases of SCC-MCT and the two cases of control cervical cancer samples. Importantly, HPV was also detected in adjacent reproductive tissues of the SCC-MCT cases, which suggested that the viral particles might spread in an ascending route through the fallopian tubes, endometrium, endocervix, and cervix to the ovaries. ISH revealed HPV type 16/18 in all SCC-MCT cases and HPV type 31/33 in two, with no HPV type 6/11 in any SCC-MCT cases. However, compared with the SCC-MCT cases, the lower detection rates of HPV in dermoid cysts and nondermoid tissues suggested that HPV might not be associated with normal ovarian tissues or benign ovarian teratomas. Our data suggest that high-risk HPV infection might be a causal factor that induces malignant transformation of MCT into SCC of the ovary, although further investigation is still required.