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In seasonal breeders, photoperiods regulate the levels of circulatory melatonin, a well-known immunomodulator and an antioxidant. Melatonin is known to play a complex physiological role in maintaining the immune homeostasis by affecting cytokine production in immunocompetent cells. In this study, we have quantified seasonal and temporal variations in immunocompetent cytokines-IL-2, IL-6, and TNF-α-and circulatory corticosterone along with in- vitro proliferation of bone marrow-derived granulocyte macrophage-colony forming unit (CFU-GM) progenitor cells of a tropical seasonal breeder Funambulus pennanti (northern palm squirrel). Transient variations in antioxidant status of seasonal breeders might be due to the fluctuations associated with immunity and inflammation. Further, to establish a direct immunomodulatory effect of photoperiod, we recorded the LPS-induced oxidative and inflammatory responses of squirrels by housing them in artificial photoperiodic chambers mimicking summer and winter seasons respectively. We observed a marked variation in cytokines level, melatonin, and corticosterone , and CFU-GM cell proliferation during summer and winter seasons. High Peripheral melatonin levels directly correlated with cytokine IL-2 levels, and inversely correlated with TNF-α, and circulatory corticosterone level. LPS-challenged squirrels housed in short photoperiod (10L:14D; equivalent to winter days) showed a marked reduction in the components of the inflammatory cascade, CRP, TNF-α, IL-6, NOx, NF-κB, Cox-2, and PGES, with an overall improvement in antioxidant status when compared to squirrels maintained under a long photoperiod (16L:8D; equivalent to summer days). Our results underline the impact of seasonality, photoperiod, and melatonin in maintaining an intrinsic redox-immune homeostasis which helps the animal to withstand environmental stresses.

Ampicillin is one of the most commonly prescribed antibiotics against intra-renal infections. Prolonged use of ampicillin has been found to be associated with a high rate of free-radical ge...

3051 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload to tumors. Previous clinical trials demonstrated that almost all patients formed anti-drug-antibodies (ADAs) to LMB-100 that made administration beyond cycle 2 ineffective. Tofacitinib is an oral JAK inhibitor that prevented formation of ADAs against a closely related immunotoxin in pre-clinical studies. The primary objective of the dose escalation cohort was assessment of safety and tolerability of LMB-100 given with tofacitinib to patients with mesothelin-expressing solid tumors. The primary objective of the expansion cohort was to determine whether co-administration of tofacitinib delays formation of neutralizing LMB-100 ADAs. Methods: Patients (n = 13) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 mcg/kg) and co-treated with oral tofacitinib for the first 10 days of the cycle (10 mg BID). Results: Dose level 1 of LMB-100 was started at 100 mcg/kg one dose level below the single agent MTD. Dose escalation to 140 mcg/kg (dose level 2) resulted in DLTs in 2 of the 3 patients treated: grade 3 cardiac toxicity and grade 4 hyponatremia, both attributed to capillary leak syndrome. Ultimately, 7 patients were treated at dose level 1 without DLTs and 100 mcg/kg was chosen as the LMB-100 dose for the expansion cohort. The last of 6 patients treated in the expansion cohort developed grade 4 pericardial effusion leading to early closure of the study for toxicity. No objective responses were seen. Of the 8 patients who received two cycles of treatment at MTD, 4 met prespecified criteria for ADA prevention, and 2 patients who went on to receive cycle 3 had detectable LMB-100 plasma drug levels after administration. Conclusions: LMB-100 was unable to be co-administered safely with tofacitinib. ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence. Clinical trial information: NCT04034238.

The neuroendocrine hormone melatonin and molecular chaperones (heat shock proteins) are evolutionarily conserved molecules that play an important role in protecting organisms from abiotic and biotic stressors. Environmental temperature and seasonality modulates immunity which impacts the overall health of animals. Most studies in relation to thermal stress are based on animals inhabiting temperate zones however, the substantial effect of climatic stress on tropical animals is less explored. Therefore, in this study we focused on the immunosuppressive effect of cold environment on a seasonally breeding tropical rodent and highlighted the importance of melatonin and HSF-1/Hsp-70 in regulating immunity. Animals were exposed to different temperatures with or without melatonin treatment. Our results suggest that, low temperature elicited cold-associated stress in animals marked by reduced body weight, decreased TLC/LC count in the blood and increased corticosterone production which was central to all immune alterations. Cold temperature also increased the oxidative stress which further induced apoptosis in the immune cells and activated stress response molecular chaperones HSF-1/HSP-70. Exogenous melatonin treatment not only ameliorated cold-induced immune suppression but also upregulated the expression of HSF-1 and HSP-70 in the immune cells thereby preventing protein unfolding and cell death. Thus, we conclude that melatonin and molecular chaperones synergistically alleviated immune suppression and could emerge as a promising combination therapy to target temperature stress in animals while boosting immunity.

A majority of cellular diseases, independent of their origin, are characterized by a dramatic increase in Reactive Oxygen Species (ROS) in response to stress. In most cases, the uncontrolled detrimental ROS outburst is difficult to handle for the cellular machinery and eventually leads to cell mortality. In this study, we compare the antioxidant efficacy of quercetin and melatonin to find out a better alternative against lipopolysaccharide (LPS) induced tissue injury by oxidative stress in Funambulus pennanti. Transient exposure to LPS significantly increased ROS generation and lipid peroxidation levels in bone marrow mononuclear cells (MNCs) and spleen which was further corroborated by decreased activities of SOD, CAT and Gpx enzymes. It also downregulate the expression of cellular oxidative stress response proteins Nrf-2 and HO-1 in spleen and decreases the proliferation of bone marrow derived Granulocyte macrophage-colony forming unit cells (GM-CFU). Both melatonin and quercetin pre-treatments rescued these effects, however, our results indicated that the efficacy of melatonin to overcome oxidative stress was significantly better than quercetin. Our findings support the idea that melatonin is a better antioxidant and immunomodulator as compared to other alternatives and perhaps may be employed in the development of effective therapeutics against ROS dominated diseases.