Some novel antileishmanial compounds inhibit normal cell cycle progression of Leishmania donovani promastigotes and exhibits pro-oxidative potential

In the midst of numerous setbacks that beclouds the fight against leishmaniasis; a neglected tropical disease, the search for new chemotherapeutics against this disease is of utmost importance. Leishmaniasis is a disease closely associated with poverty and endemic in Africa, Asia, southern Europe and the Americas. It is caused by parasites of the genus Leishmania and transmitted by a sandfly vector. In this study, we evaluated the antileishmanial potency of eighteen pathogen box compounds and elucidated their biosafety and possible mechanisms of action against Leishmania donovani promastigotes and amastigotes in vitro. IC50s range of 0.12±0.15 to >6.25 μg/ml and 0.13±0.004 to >6.25μg/ml were observed for the promastigotes and amastigotes, respectively. We demonstrated the ability of some of the compounds to cause cytocidal effect on the parasites, induce increased production of reactive oxygen species (ROS), disrupt the normal parasite morphology and cause the accumulation of parasites at the DNA synthesis phase of the cell cycle. We recommend a further in vivo study on these compounds to validate the findings.

COVID-19 Syndrome: Nexus with Herbivory and Exposure Dynamics for Monitoring Livestock Welfare and Agro-Environment

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a public health emergency that turns the year 2020–2021 into annus horribilis for millions of people across international boundaries. The interspecies transmission of this zoonotic virus and mutated variants are aided by exposure dynamics of infected aerosols, fomites and intermediate reservoirs. The spike in the first, second and third waves of coronavirus confirms that herd immunity is not yet reached and everyone including livestock is still vulnerable to the infection. Of serious concern are the communitarian nature of agrarians in the livestock sector, aerogenous spread of the virus and attendant cytocidal effect in permissive cells following activation of pathogen recognition receptors, replication cycles, virulent mutations, seasonal spike in infection rates, flurry of reinfections and excess mortalities that can affect animal welfare and food security. As the capacity to either resist or be susceptible to infection is influenced by numerous factors, identifying coronavirus-associated variants and correlating exposure dynamics with viral aerosols, spirometry indices, comorbidities, susceptible blood types, cellular miRNA binding sites and multisystem inflammatory syndrome remains a challenge where the lethal zoonotic infections are prevalent in the livestock industry, being the hub of dairy, fur, meat and egg production. This review provides insights into the complexity of the disease burden and recommends precision smart-farming models for upscaling biosecurity measures and adoption of digitalised technologies (robotic drones) powered by multiparametric sensors and radio modem systems for real-time tracking of infectious strains in the agro-environment and managing the transition into the new-normal realities in the livestock industry.

Cytotoxic Effects of Arsenite in Combination With Gamabufotalin Against Human Glioblastoma Cell Lines

Glioblastoma is a fatal primary malignant brain tumor, and the 5-year survival rate of treated glioblastoma patients still remains <5%. Considering the sustained development of metastasis, tumor recurrence, and drug resistance, there is an urgent need for the novel therapeutic approaches to combat glioblastoma. Trivalent arsenic derivative (arsenite, AsIII) with remarkable clinical efficacy in leukemia has been shown to exert cytocidal effect against glioblastoma cells. Gamabufotalin, an active bufadienolide compound, also shows selective cytocidal effect against glioblastoma cells, and has been suggested to serve as a promising adjuvant therapeutic agent to potentiate therapeutic effect of conventional anticancer drugs. In order to gain novel insight into therapeutic approaches against glioblastoma, the cytotoxicity of AsIII and gamabufotalin was explored in the human glioblastoma cell lines U-87 and U-251. In comparison with U-251 cells, U-87 cells were highly susceptible to the two drugs, alone or in combination. More importantly, clinically achieved concentrations of AsIII combined with gamabufotalin exhibited synergistic cytotoxicity against U-87 cells, whereas showed much less cytotoxicity to human normal peripheral blood mononuclear cells. G2/M cell cycle arrest was induced by each single drug, and further augmented by their combination in U-87 cells. Downregulation of the expression levels of cdc25C, Cyclin B1, cdc2, and survivin was observed in U-87 cells treated with the combined regimen and occurred in parallel with G2/M arrest. Concomitantly, lactate dehydrogenase leakage was also observed. Intriguingly, SB203580, a specific inhibitor of p38 MAPK, intensified the cytotoxicity of the combined regimen in U-87 cells, whereas wortmannin, a potent autophagy inhibitor, significantly rescued the cells. Collectively, G2/M arrest, necrosis and autophagy appeared to cooperatively contribute to the synergistic cytotoxicity of AsIII and gamabufotalin. Given that p38 MAPK serves an essential role in promoting glioblastoma cell survival, developing a possible strategy composed of AsIII, gamabufotalin, and a p38 MAPK inhibitor may provide novel insight into approaches designed to combat glioblastoma.

Potentiation of Cisplatin Activity in Colorectal Cancer Cells by Lovastatin

Cisplatin (CIS) is an anticancer drugs used in the treatment of several solid tumors with nephrotoxicity as its main toxic effect. The current study was directed to assess the role of hypolipidemic drug (lovastatin) on sensitization of human colorectal cancer cells (HCT -116) to the action of CIS. This study assessed the action of lovastatin on sensitization of colorectal cancer cells to cisplatin by examining cisplatin cytotoxicity, cisplatin cellular uptake and P-glycoprotein (P-gp) activity in presence and absence of Lovastatin 10 and 30 ug/ml. Lovastatin treatment at dose level of 10 and 30 µg/ml potentiated the cytocidal effect of cisplatin against the growth of HCT-116 cells with IC50 7.3 and 5.4 µg/ml, respectively compare to 18 µg/ml after treatment with cisplatin alone. Moreover, lovastatin increased the uptake of cisplatin into colorectal cancer cells with marked inhibition of P-glycoprotein pump. On conclusion Lovastatin treatment increases the antiproliferative activity of cisplatin against the growth of colorectal cancer cells due to inhibition the activity P-glycoprotein pump with marked increase in its cellular uptake.

Photochemical generation of the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) radical from caged nitroxides by near-infrared two-photon irradiation and its cytocidal effect on lung cancer cells

Novel caged nitroxides (nitroxide donors) with near-infrared two-photon (TP) responsive character, 2,2,6,6-tetramethyl-1-(1-(2-(4-nitrophenyl)benzofuran-6-yl)ethoxy)piperidine (2a) and its regioisomer 2b, were designed and synthesized. The one-photon (OP) (365 ± 10 nm) and TP (710–760 nm) triggered release (i.e., uncaging) of the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) radical under air atmosphere were discovered. The quantum yields for the release of the TEMPO radical were 2.5% (2a) and 0.8% (2b) in benzene at ≈1% conversion of 2, and 13.1% (2a) and 12.8% (2b) in DMSO at ≈1% conversion of 2. The TP uncaging efficiencies were determined to be 1.1 GM at 740 nm for 2a and 0.22 GM at 730 nm for 2b in benzene. The cytocidal effect of compound 2a on lung cancer cells under photolysis conditions was also assessed to test the efficacy as anticancer agents. In a medium containing 100 μg mL−1 of 2a exposed to light, the number of living cells decreased significantly compared to the unexposed counterparts (65.8% vs 85.5%).

The Development of Oncolytic Adenovirus Therapy in the Past and Future - For the Case of Pancreatic Cancer

Pancreatic cancer is an aggressive malignant disease and the efficacy of current treatments for unresectable diseases is quite limited despite recent advances. Gene therapy /virotherapy strategies may provide new options for the treatment of various cancers including pancreatic cancer. Oncolytic adenovirus shows an antitumoral effect via its intratumoral amplification and strong cytocidal effect in a variety of cancers and it has been employed for the development of potent oncolytic virotherapy agents for pancreatic cancer. Our ultimate goal is to develop an oncolytic adenovirus enabling the treatment of patients with advanced or spread diseases by systemic injection. Systemic application of oncolytic therapy mandates more efficient and selective gene delivery and needs to embody sufficient antitumor effect even with limited initial delivery to the tumor location. In this review, the current status of oncolytic adenoviruses from the viewpoints of vector design and potential strategies to overcome current obstacles for its clinical application will be described. We will also discuss the efforts to improve the antitumor activity of oncolytic adenovirus, in in vivo animal models, and the combination therapy of oncolytic adenovirus with radiation and chemotherapy.