Chloroquine delivery to erythrocytes in Plasmodium berghei-infected mice using antibody-bearing liposomes as drug vehicles

Suitability of anti-erythrocyte F(ab')2-bearing liposomes as vehicles for chloroquine in the treatment of chloroquine resistantPlasmodium berghei infections in mice has been examined. Free chloroquine or chloroquine encapsulated in antibody-free liposomes failed to show much effect on the resistant infections, but the same doses of this drug after being encapsulated in antibody-bearing liposomes exhibited a significant inhibitory effect on this infection. These results indicate that chloroquine delivery in antibody targeted liposomes may help in the successful treatment of the chloroquine resistant malarial infections

KSHV Genome Replication and Maintenance

Kaposi’s sarcoma associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8) is a major etiological agent for multiple severe malignancies in immunocompromised patients. KSHV establishes lifetime persistence in the infected individuals and displays two distinct life cycles, generally a prolonged passive latent, and a short productive or lytic cycle. During latent phase, the viral episome is tethered to the host chromosome and replicates once during every cell division. Latency-associated nuclear antigen (LANA) is a predominant multifunctional nuclear protein expressed during latency, which plays a central role in episome tethering, replication and perpetual segregation of the episomes during cell division. LANA binds cooperatively to LANA binding sites (LBS) within the terminal repeat (TR) region of the viral episome as well as to the cellular nucleosomal proteins to tether viral episome to the host chromosome. LANA has been shown to modulate multiple cellular signaling pathways and recruits various cellular proteins such as chromatin modifying enzymes, replication factors, transcription factors and cellular mitotic framework to maintain a successful latent infection. Although many other regions within the KSHV genome can initiate replication, KSHV TR is important for latent DNA replication and possible segregation of the replicated episomes. Binding of LANA to LBS favors the recruitment of various replication factors to initiate LANA dependent DNA replication. In this review, we discuss the molecular mechanisms relevant to KSHV genome replication, segregation, and maintenance of latency

Chloroquine encapsulated in malaria-infected erythrocyte-specific antibody-bearing liposomes effectively controls chloroquine-resistant Plasmodium berghei infections in mice

The suitability of liposomes as drug carriers in the treatment of drug-resistant rodent malaria was examined after covalently attaching F(ab')2 fragments of a mouse monoclonal antibody (MAb), MAb F10, raised against the host cell membranes isolated from the Plasmodium berghei-infected mouse erythrocytes, to the liposome surface. The antibody-bearing liposomes thus formed specifically recognized the P. berghei-infected mouse erythrocytes under both in vitro and in vivo conditions. No such specific binding of the liposomes with the infected cells was observed when MAb F10 was replaced by another mouse monoclonal antibody, MAb D2. Upon loading with the antimalarial drug chloroquine, the MAb F10-bearing liposomes effectively controlled not only the chloroquine-susceptible but also the chloroquine-resistant P. berghei infections in mice. The chloroquine delivered in these liposomes intravenously at a dosage of 5 mg/kg of body weight per day on days 4 and 6 postinfection completely cured the animals (75 to 90%) of chloroquine-resistant P. berghei infections. These results indicate that selective homing of chloroquine to malaria-infected erythrocytes may help to cure the chloroquine-resistant malarial infections with low doses of chloroquine

Anti-tuberculosis drug induced hepatotoxicity: a study from Himalayan region

Background: Tuberculosis (TB) is the infection of global health concern. The management of TB is a 6-month course of anti-TB drugs. Compliance is crucial for curing TB. Adverse effects often affect the compliance negatively. One of the adverse effects affecting TB treatment outcome is anti-TB drug induced hepatotoxicity (DIH). Therefore, the purpose of this study was to assess the incidence of anti-TB DIH and its associated factors among newly diagnosed TB patients.Methods: A single centre prospective study was conducted from January-December 2020. All patients who were newly-diagnosed for TB, started anti-TB medication and diagnosed with drug-induced liver injury during anti-tubercular treatment included in the study.Results: Total of four hundred and ninety-two (492) TB patients taking anti-TB drugs were involved in this study with male predominance and maximum in the age group of 30-45 years. Smear-positive pulmonary TB accounted for 66.9% of all cases. During the study period, 9.3% TB patients developed anti-TB DIH. Among the cases of anti-TB DIH, female patients account for 52%. Patients with extra-pulmonary TB (n=23), low BMI (n=16), alcohol consumption (n=21) had developed anti-TB DIH. The time interval from the initiation of treatment to the onset of hepatotoxicity was 16-45 days.Conclusion: The chances of hepatotoxicity among TB patients taking anti-TB drugs are always there. Thus, it is necessary to monitor liver function in patients receiving anti-TB drugs routinely

The NMDA receptor GluN2C subunit controls cortical excitatoryinhibitory balance, neuronal oscillations and cognitive function

Despite strong evidence for NMDA receptor (NMDAR) hypofunction as an underlying factor for cognitive disorders, the precise roles of various NMDAR subtypes remains unknown. The GluN2Ccontaining NMDARs exhibit unique biophysical properties and expression pattern, and lower expression of GluN2C subunit has been reported in postmortem brains from schizophrenia patients. We found that loss of GluN2C subunit leads to a shift in cortical excitatory-inhibitory balance towards greater inhibition. Specifically, pyramidal neurons in the medial prefrontal cortex (mPFC) of GluN2C knockout mice have reduced mEPSC frequency and dendritic spine density and a contrasting higher frequency of mIPSCs. In addition a greater number of perisomatic GAD67 puncta was observed suggesting a potential increase in parvalbumin interneuron inputs. At a network level the GluN2C knockout mice were found to have a more robust increase in power of oscillations in response to NMDAR blocker MK- 801. Furthermore, GluN2C heterozygous and knockout mice exhibited abnormalities in cognition and sensorimotor gating. Our results demonstrate that loss of GluN2C subunit leads to cortical excitatoryinhibitory imbalance and abnormal neuronal oscillations associated with neurodevelopmental disorders

Targeting IκappaB kinases for cancer therapy

The inhibitory kappa B kinases (IKKs) and IKK related kinases are crucial regulators of the pro-inflammatory transcription factor, nuclear factor kappa B (NF-κB). The dysregulation in the activities of these kinases has been reported in several cancer types. These kinases are known to regulate survival, proliferation, invasion, angiogenesis, and metastasis of cancer cells. Thus, IKK and IKK related kinases have emerged as an attractive target for the development of cancer therapeutics. Several IKK inhibitors have been developed, few of which have advanced to the clinic. These inhibitors target IKK either directly or indirectly by modulating the activities of other signaling molecules. Some inhibitors suppress IKK activity by disrupting the protein-protein interaction in the IKK complex. The inhibition of IKK has also been shown to enhance the efficacy of conventional chemotherapeutic agents. Because IKK and NF-κB are the key components of innate immunity, suppressing IKK is associated with the risk of immune suppression. Furthermore, IKK inhibitors may hit other signaling molecules and thus may produce off-target effects. Recent studies suggest that multiple cytoplasmic and nuclear proteins distinct from NF-κB and inhibitory κB are also substrates of IKK. In this review, we discuss the utility of IKK inhibitors for cancer therapy. The limitations associated with the intervention of IKK are also discussed

Emerging Roles and Potential Applications of Non-Coding RNAs in Cervical Cancer

Cervical cancer (CC) is a preventable disease using proven interventions, specifically prophylactic vaccination, pervasive disease screening, and treatment, but it is still the most frequently diagnosed cancer in women worldwide. Patients with advanced or metastatic CC have a very dismal prognosis and current therapeutic options are very limited. Therefore, understanding the mechanism of metastasis and discovering new therapeutic targets are crucial. New sequencing tools have given a full visualization of the human transcriptome’s composition. Non-coding RNAs (NcRNAs) perform various functions in transcriptional, translational, and post-translational processes through their interactions with proteins, RNA, and even DNA. It has been suggested that ncRNAs act as key regulators of a variety of biological processes, with their expression being tightly controlled under physiological settings. In recent years, and notably in the past decade, significant effort has been made to examine the role of ncRNAs in a variety of human diseases, including cancer. Therefore, shedding light on the functions of ncRNA will aid in our better understanding of CC. In this review, we summarize the emerging roles of ncRNAs in progression, metastasis, therapeutics, chemoresistance, human papillomavirus (HPV) regulation, metabolic reprogramming, diagnosis, and as a prognostic biomarker of CC.We also discussed the role of ncRNA in the tumor microenvironment and tumor immunology, including cancer stem cells (CSCs) in CC.We also address contemporary technologies such as antisense oligonucleotides, CRISPR–Cas9, and exosomes, as well as their potential applications in targeting ncRNAs to manage CC