Serum protein profiles of patients with bacterial sepsis from the day of diagnosis until recovery/mortality were compared from early to late stages in response to severe sepsis using two dimensional electrophoresis. The proteins exhibiting changes during the course of sepsis (20‑28 day mortality) were selected and identified by matrix‑assisted laser desorption ionization‑time of flight‑tandem mass spectrometry. Among the proteins identified, haptoglobin (Hp), transthyretin (TTR), orosomucoid 1/α1 acid glycoprotein (ORM1), α1 antitrypsin (A1AT), serum amyloid A (SAA) and S100A9 exhibited differential expression patterns between survivors (S; n=6) and non‑survivors (NS; n=6), particularly during the early stages of sepsis. Expression factors (EFs), taken as the ratio between the NS and S during early stages, showed ratios of Hp, 0.39 (P≤0.012); TTR, 3.96 (P≤0.03); ORM1, 0.69 (P≤0.79); A1AT, 0.92 (P≤0.87) and SAA, 0.69 (P≤0.01). S100A9, an acute phase protein, exhibited an EF ratio of 1.68 (P≤0.004) during the end stages of sepsis. A delayed rise in levels was observed in Hp, A1AT, ORM1, S100A9 and SAA, whereas TTR levels increased during the early stages of sepsis in NS. Analysis of inflammatory responses in the early stages of sepsis revealed increased mRNA expression in leukocytes of interleukin (IL)‑6 (EF, 2.50), IL‑10 (EF, 1.70) and prepronociceptin (EF, 1.6), which is a precursor for nociceptin in NS compared with S, and higher Toll‑like receptor‑4 (EF, 0.30) levels in S compared with NS. Therefore, a weaker acute phase response in the early stages of sepsis in NS, combined with an inefficient inflammatory response, may contribute to sepsis mortality.
On the basis of the boron neutron capture therapy (BNCT) modality, we have designed and synthesized a zinc gallate (ZnGa2O4)-based nanoformulation for developing an innovative theranostic approach for cancer treatment. Initially, the (ZnGa1.995Cr0.005O4 or ZnGa2O4:(0.5%)Cr persistent luminescence nanoparticles (PLNPs) embedded on silica matrix were synthesized. Their surface functionalization was performed using organic synthesis strategies to attach the amine functional moieties which were further coupled with poly(vicinal diol). These diols were helpful for conjugation with 10B(OH)3, which subsequently served to couple with an in-house-synthesized variant of pH-(low)-insertion peptide (pHLIP) finally giving a tumor-targeting nanoformulation. Most importantly, the polymeric diols helped in conjugation of a substantial number of 10B to provide the therapeutic dose required for effective BNCT. This nanoformulation internalized substantially (∼80%) to WEHI-164 cancer cells within 6 h. Tumor homing studies indicated that the accumulation of this formulation at the acidic tumor site was within 2 h. The in vitro evaluation of the formulation against WEHI-164 cancer cells followed by neutron irradiation revealed its potent cytotoxicity with IC50 ∼ 25 μM. In the case of studies on animal models, the melanoma-induced C57BL/6 and fibrosarcoma-induced BALB/c mice were treated with formulations through intratumoral and intravenous injections, respectively, followed by neutron irradiation, leading to a significant killing of the cancer cells, which was evidenced by a reduction in tumor volume (75–80%) as compared with a control tumor. Furthermore, the histopathological studies confirmed a damaging effect only on tumor cells, while there was no sign of damage to the vital organs in treated mice as well as in controls.
During sepsis along with the manifestation of symptoms, there are many biochemical and physiological changes in the host. To mark a few are, Presence of bacteria, changes in overall proteomics of blood, which is termed acute phase response and organ failure leading to death in extreme cases. In search of biomarkers during early bacterial infection, we could identify a prominent biomarker Neutrophil gelatinase-associated lipocalin (NGAL) and its involvement in bacterial infection. NGAL is a 25 kDa protein secreted by neutrophils, whose importance is well studied in kidney injury and cancer, whereas its role during bacterial infection is less sorted. To evaluate its role, human whole blood cells (HWBC) induced with bacterial E. coli LPS were analyzed for changes in NGAL expression. NGAL transcripts were observed to be upregulated very early, <4 h of induction and continued to be detected until 18 h, after which its levels rapidly decreased by 24 h. Treatment of HWBC with steroid hormones such as estrogen (β Estradiol), testosterone, progesterone, and adrenaline confirmed the mode of action of NGAL as pro-inflammatory. Further, immunoblotting of lysates from HWBC treated with retinol and LPS revealed that upregulation of NGAL in the presence of retinol was reversed on induction with LPS. Organic extracts from the root of the plant Desmotrichum fimbriatum (DF) were explored for their effect on bacterial infection by E. coli (ATCC25922) and effect on NGAL. HWBC pre-treated with DF and induced with E. coli inhibited bacterial growth and multiplication combined with elevated NGAL and protected cells from undergoing apoptosis. This demonstrates the role of NGAL, suggesting its necessity in the host to mount antibacterial action and aid host survival. Accordingly, NGAL can be categorized as an acute phase pro-inflammatory polypeptide necessary for establishing an early immune response toward invading bacterial infection by exerting antibacterial activity necessary for cell survival.
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