Basveshwar Gawali

Hematopoietic acute radiation syndrome (H-ARS) results from bone marrow (BM) damage, leading to depletion of myeloid and lymphoid cells and increasing infection, hemorrhage, and mortality risks. Imidazolyl ethanamide pentandioic acid (IEPA), an orally bioavailable molecule, alleviates chemotherapy-induced myelosuppression and may similarly mitigate H-ARS. This study examines whether IEPA, alone or with granulocyte-monocyte colony-stimulating factor (GM-CSF), promotes recovery of hematopoietic stem and progenitor cells (HSCs/HPCs) after sublethal total body irradiation (TBI). Mice received 5 Gy TBI followed by vehicle, IEPA (days 1-3), GM-CSF (days 1-5), or IEPA+GM-CSF. Recovery was assessed by body weight, blood counts, flow cytometry, clonogenic assays, BM megakaryocytes, and splenic CD34⁺ cells. IEPA increased body weight 2.5-fold by day 7, while IEPA+GM-CSF showed 2.5-fold and 3.3-fold increases on days 7 and 21, respectively. IEPA promoted recovery of HSCs/HPCs, multipotent progenitors (MPP2), myeloid and lymphoid progenitors, BM megakaryocytes, and splenic CD34+ cells. IEPA+GM-CSF improved in vitro self-renewal but offered no major in vivo advantage over IEPA alone, except for a 159-fold recovery in erythroid progenitors. All treatments reduced γ-H2AX expression in Lin- and HPCs on day 21, indicating less DNA damage. Our results reveal that IEPA attenuated radiation-induced DNA damage and improved recovery of HSCs/HPCs, myeloid as well as lymphoid progenitors, accompanied by increases in platelets in blood, megakaryocytes in BM and splenic CD34⁺ cells. IEPA shows promise as a radiation mitigator, with no significant benefit observed from adding GM-CSF.

The heart is one of the organs that is sensitive to developing delayed adverse effects of ionizing radiation (IR) exposure. Radiation-induced heart disease (RIHD) occurs in cancer patients and cancer survivors, as a side effect of radiation therapy of the chest, with manifestation several years post-radiotherapy. Moreover, the continued threat of nuclear bombs or terrorist attacks puts deployed military service members at risk of exposure to total or partial body irradiation. Individuals who survive acute injury from IR will experience delayed adverse effects that include fibrosis and chronic dysfunction of organ systems such as the heart within months to years after radiation exposure. Toll-like receptor 4 (TLR4) is an innate immune receptor that is implicated in several cardiovascular diseases. Studies in preclinical models have established the role of TLR4 as a driver of inflammation and associated cardiac fibrosis and dysfunction using transgenic models. This review explores the relevance of the TLR4 signaling pathway in radiation-induced inflammation and oxidative stress in acute as well as late effects on the heart tissue and the potential for the development of TLR4 inhibitors as a therapeutic target to treat or alleviate RIHD.

Retinoblastoma (Rb) is the most critical and severe intraocular malignancy occurring in children. The clinical management of retinoblastoma is still challenging due to failure in early detection and control despite the advancements in medical strategies. Early-stage Rb tumors do not occupy major visual fields, so chemo/photothermal therapy (PTT) with biocompatible materials can be a practical approach. Herein, we report multifunctional polymeric nanoparticles (PNPs) entrapped with an FDA-approved anticancer drug, Palbociclib (PCB), and a near-infrared dye, IR820 (IR), as chemo/photothermal agents. These PCB/IR PNPs were evaluated for the combinational effect in the retinoblastoma cell line. Further, the in vivo photoacoustic imaging efficacy and acute toxicity profile of the PNPs were studied in a mice model. The results indicated that the PCB/IR PNPs exhibited a significant cytotoxic effect (86.5 ± 2.3%) in Y79 cell lines than the respective control groups upon exposure to NIR light. Qualitative and quantitative analyses indicated that PCB/IR PNPs with NIR light induction resulted in DNA damage followed by apoptosis. PCB/IR PNPs, when tested in vivo, showed optimal photoacoustic signals. Thus, the combination of PCB and PTT can emerge as a translational modality for retinoblastoma therapy.

Conventional systemic chemotherapeutic regimens suffer from challenges such as non-specificity, shorter half-life, clearance of drugs and dose-limiting toxicity. Localized delivery of chemotherapeutic drugs through non-invasive spatiotemporally controllable stimuli-responsive drug delivery systems could overcome these drawbacks while utilizing drugs approved for cancer treatment. In this regard, we developed photo-electro active nanocomposite silk-based drug delivery systems (DDS) exhibiting, on-demand drug release in vivo. A functionally modified single-walled carbon nanotube loaded with doxorubicin was embedded within cross-linker free silk hydrogel. The resultant nanocomposite silk hydrogel showed electrical field responsiveness and near-infrared (NIR) laser-induced hyperthermal effect. The remote application of these stimuli in tandem or independent manner led to the increased thermal and electrical conductivity of nanocomposite hydrogel, which effectively triggered the intermittent on-demand drug release. In a proof-of-concept in vivo tumor regression study, the nanocomposite hydrogel was administered in a minimally invasive way at the periphery of the tumor by covering most of it. During the 21-day study, drastic tumor regression was recorded upon regular stimulation of nanocomposite hydrogel with simultaneous or individual external application of an electric field and NIR laser. Tumor cell death marker expression analysis uncovered the induction of apoptosis in tumor cells leading to its shrinkage. Heart ultrasound and histology revealed no cardiotoxicity associated with localized DOX treatment. To our knowledge, this is also the first report to show the simultaneous application of electric field and NIR laser in vivo for localized tumor therapy, and our results suggested that such strategy might have high clinical translational potential.

Type 2 diabetes is a multifactorial disorder coupled with impaired glucose tolerance, diminished insulin sensitivity and hyperlipidemia. Incessant hyperglycemia and hyperlipidemia led a towering risk to develop cardiovascular hitches with end-stage renal failure. Leaves of Nyctanthes arbor-tristis L. (NAT) (family: Oleaceae) is traditionally used by tribes of Assam for various ailments without proper scientific validation and appropriate mechanism of action for its activity. Hence, we aimed to evaluate the mechanism involved in the hypoglycemic and hypolipidemic effects of NAT leaves in high-fat diet (HFD)–streptozotocin (STZ)-induced diabetic rats. Male Sprague–Dawley rats were fed with in-house prepared high-fat diet (HFD) for a period of 4 weeks to create insulin resistance. Streptozotocin was injected intraperitoneally to these rats to cause β-cell destructions to create a model of type 2 diabetes. Our results have shown that NAT extract has a dose-dependent hypoglycemic and hypolipidemic activity in controlling the early biochemical parameters of kidney and lipids. Moreover, the extract has anti-oxidant and anti-inflammatory activities which were more pronounced at a dose of 400 mg/kg body weight. NAT treatment group also restored the normal architecture of the kidney and aorta tissue. GC–MS data analysis revealed the presence of several active compounds which are directly or indirectly responsible for its anti-diabetic and anti-hyperlipidemic activity. The apparent mechanism of NAT for its nephroprotection may be due to the suppression of hyperglycemia-mediated oxidative stress and amelioration of inflammatory cascades allied with NF-kB activation.