Potential of siRNA-Bearing Subtilosomes in the Treatment of Diethylnitrosamine-Induced Hepatocellular Carcinoma.

Therapeutics, based on small interfering RNA (siRNA), have demonstrated tremendous potential for treating cancer. However, issues such as non-specific targeting, premature degradation, and the intrinsic toxicity of the siRNA, have to be solved before they are ready for use in translational medicines. To address these challenges, nanotechnology-based tools might help to shield siRNA and ensure its specific delivery to the target site. Besides playing a crucial role in prostaglandin synthesis, the cyclo-oxygenase-2 (COX-2) enzyme has been reported to mediate carcinogenesis in various types of cancer, including hepatocellular carcinoma (HCC). We encapsulated COX-2-specific siRNA in Bacillus subtilis membrane lipid-based liposomes (subtilosomes) and evaluated their potential in the treatment of diethylnitrosamine (DEN)-induced hepatocellular carcinoma. Our findings suggested that the subtilosome-based formulation was stable, releasing COX-2 siRNA in a sustained manner, and has the potential to abruptly release encapsulated material at acidic pH. The fusogenic property of subtilosomes was revealed by FRET, fluorescence dequenching, content-mixing assay, etc. The subtilosome-based siRNA formulation was successful in inhibiting TNF-α expression in the experimental animals. The apoptosis study indicated that the subtilosomized siRNA inhibits DEN-induced carcinogenesis more effectively than free siRNA. The as-developed formulation also suppressed COX-2 expression, which in turn up-regulated the expression of wild-type p53 and Bax on one hand and down-regulated Bcl-2 expression on the other. The survival data established the increased efficacy of subtilosome-encapsulated COX-2 siRNA against hepatocellular carcinoma.

Amphotericin B Nano-Assemblies Circumvent Intrinsic Toxicity and Ensure Superior Protection in Experimental Visceral Leishmaniasis with Feeble Toxic Manifestation.

In spite of its high effectiveness in the treatment of both leishmaniasis as well as a range of fungal infections, the free form of the polyene antibiotic amphotericin B (AmB) does not entertain the status of the most preferred drug of choice in clinical settings. The high intrinsic toxicity of the principal drug could be considered the main impedance in the frequent medicinal use of this otherwise very effective antimicrobial agent. Taking into consideration this fact, the pharma industry has introduced many novel dosage forms of AmB to alleviate its toxicity issues. However, the limited production, high cost, requirement for a strict cold chain, and need for parenteral administration are some of the limitations that explicitly compel professionals to look for the development of an alternate dosage form of this important drug. Considering the fact that the nano-size dimensions of drug formulation play an important role in increasing the efficacy of the core drug, we employed a green method for the development of nano-assemblies of AmB (AmB-NA). The as-synthesized AmB-NA manifests desirable pharmacokinetics in the treated animals. The possible mechanistic insight suggested that as-synthesized AmB-NA induces necrosis-mediated cell death and severe mitochondrial dysfunction in L. donovani promastigotes by triggering depolarization of mitochondrial membrane potential. In vivo studies demonstrate a noticeable decline in parasite burden in the spleen, liver, and bone marrow of the experimental BALB/c mice host. In addition to successfully suppressing the Leishmania donovani, the as-formed AmB-NA formulation also modulates the host immune system with predominant Th1 polarization, a key immune defender that facilitates the killing of the intracellular parasite.

Patho-Physiology of Aging and Immune-Senescence: Possible Correlates With Comorbidity and Mortality in Middle-Aged and Old COVID-19 Patients.

During the last 2 years, the entire world has been severely devastated by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic (COVID-19) as it resulted in several million deaths across the globe. While the virus infects people indiscriminately, the casualty risk is higher mainly in old, and middle-aged COVID-19 patients. The incidences of COVID-19 associated co-morbidity and mortality have a great deal of correlation with the weakened and malfunctioning immune systems of elderly people. Presumably, due to the physiological changes associated with aging and because of possible comorbidities such as diabetes, hypertension, obesity, cardiovascular, and lung diseases, which are more common in elderly people, may be considered as the reason making the elderly vulnerable to the infection on one hand, and COVID-19 associated complications on the other. The accretion of senescent immune cells not only contributes to the deterioration of host defense, but also results in elevated inflammatory phenotype persuaded immune dysfunction. In the present review, we envisage to correlate functioning of the immune defense of older COVID-19 patients with secondary/super infection, increased susceptibility or aggravation against already existing cancer, infectious, autoimmune, and other chronic inflammatory diseases. Moreover, we have discussed how age-linked modulations in the immune system affect therapeutic response against administered drugs as well as immunological response to various prophylactic measures including vaccination in the elderly host. The present review also provides an insight into the intricate pathophysiology of the aging and the overall immune response of the host to SARS-CoV-2 infection. A better understanding of age-related immune dysfunction is likely to help us in the development of targeted preemptive strategies for deadly COVID-19 in elderly patients.

Chaperone Like Attributes of Biogenic Fluorescent Gold Nanoparticles: Potential to Alleviate Toxicity Induced by Intermediate State Fibrils Against Neuroblastoma Cells.

In general, neurodegenerative disorders have a great deal of correlation with the misfolded as well as aggregated forms of protein-based macromolecules. Among various species formed during the aggregation process, protein oligomers have been classified as most toxic entities against several types of living cells. A series of chemicals have been developed to inhibit protein aggregation as a measure to regulate neurodegenerative diseases. Recently, various classes of nanoparticles have also been reported to inhibit protein aggregation. In the present study, we synthesized fluorescent gold nanoparticles (B-AuNPs) employing Olax scandens leaf extract. Next, an in vitro study was performed to assess the effect of as-synthesized B-AuNPs on the aggregation behavior of the ovalbumin (OVA) and other related model proteins. We performed an extensive study to elucidate anti-amyloidogenic properties of nano-sized entities and established that small-sized B-AuNPs manifest chaperone potential against protein aggregation. Further, we exploited as-synthesized B-AuNPs as a mean to prevent protein aggregation mediated toxicity in neuroblastoma cells.

Desmoid Tumor of Rectus Abdominis Presenting with Grey-Turner's and Cullen's Sign: A Report of a Rare Case.

Desmoid tumor of rectus abdominis presenting with Grey-Turner's and Cullen's sign is rare. Herein, we report desmoid tumor of rectus abdominis in a 64-year-old multiparous female who presented with ecchymosis involving left flank and around the umbilicus. Histopathological examination of biopsy from the tumor confirmed the diagnosis of the desmoid tumor. She was referred to a surgeon for radical resection.