IND-2, a pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline derivative, circumvents multi-drug resistance and causes apoptosis in colon cancer cells.

Naturally occurring condensed quinolines have anticancer properties. In efforts to find active analogues, we designed and synthesized eight polycyclic heterocycles with a pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline framework (IND series). The compounds were evaluated for activity against colon (HCT-116 and S1-MI-80), prostate (PC3 and DU-145), breast (MCF-7 and MDAMB-231), ovarian (ov2008 and A2780), and hepatocellular (HepG2) cancer cells and against non-cancerous Madin Darby canine kidney (MDCK), mouse embryonic fibroblast (NIH/3T3), and human embryonic kidney cells (HEK293). IND-2, a 4-chloro-2-methyl pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline, exhibited more than ten-fold selectivity and potent cytotoxic activity against colon cancer cells relative to the other cancer and non-cancer cells. With five additional colon cancer cell lines (HT-29, HCT-15, LS-180, LS-174, and LoVo), IND-2 had similar cytotoxicity and selectivity, and sub-micromolar concentrations caused changes in the morphology of HCT-116 and HCT-15 cells. IND-2 did not activate the transactivating function of the pregnane X receptor (PXR), indicating that it does not induce PXR-regulated ABCB1 or ABCG2 transporters. Indeed, IND-2 was not a substrate of ABCB1 or ABCG2, and it induced cytotoxicity in HEK293 cells overexpressing ABCB1 or ABCG2 to the same extent as in normal HEK293 cells. IND-2 was cytotoxic to resistant colon carcinoma S1-MI-80 cells, approximately three- and five-fold more than SN-38 and topotecan, respectively. In HCT-116 colon cancer cells, IND-2 produced concentration-dependent changes in mitochondrial membrane potential, leading to apoptosis, and sub-micromolar concentrations caused chromosomal DNA fragmentation. These findings suggest that, by increasing apoptosis, IND-2 has potential therapeutic efficacy for colorectal cancer.

A 2023 nationwide study on adjustment disorder among first year MBBS students in India.

Amidst the complex transition to medical college, encompassing a myriad of academic, social, and personal adjustments, MBBS students in India confront multifaceted challenges that can precipitate adjustment disorder, a phenomenon understudied within the Indian context. Therefore, it is of interest to assess adjustment disorder among first-year MBBS students within six months of enrolment. We used a Google form encompassing adjustment disorder new-module 20 for data collection and found that 67% of the 401 responses from first-year medical students exhibited adjustment disorder. The top stressors identified included time pressure, work pressure, financial problems, moving to a new home, and termination of important leisure activities. Female gender, age group 21-25, conflicts in working life, financial problems, own serious illness, family conflicts, pressure to meet deadlines, and excessive workload showed significant associations with adjustment disorder.

The dopamine D3 receptor antagonists PG01037, NGB2904, SB277011A, and U99194 reverse ABCG2 transporter-mediated drug resistance in cancer cell lines.

The ATP - binding cassette (ABC) family G2 (ABCG2) transporters are known to produce multidrug resistance (MDR) in cancer, thereby limiting the clinical response to chemotherapy. Molecular modeling data indicated that certain dopamine (DA) D3 receptor antagonists had a significant binding affinity for ABCG2 transporter. Therefore, in this in vitro study, we determined the effect of the D3 receptor antagonists PG01037, NGB2904, SB277011A, and U99194 on MDR resulting from the overexpression of ABCG2 transporters. The D3 receptor antagonists, at concentrations >100 µM, did not significantly affect the viability of H460-MX20, S1M1-80, A549-MX10 or wild type ABCG2 overexpressing (HEK293-R2) cells. However, at concentrations ranging from 0.01 to 10 µM, the D3 receptor antagonists PG01037, NGB2904, SB-277011A, and U99194 significantly increased the efficacy of the anticancer drugs mitoxantrone and doxorubicin in ABCG2-overexpressing MDR cells. Efflux studies indicated that both PG01037 and NGB2904, at a concentration of 5 µM, significantly decreased the efflux of rhodamine 123 from H460-MX20 cells. Interestingly, 5 µM of PG01037 or NGB2904 significantly decreased the expression levels of the ABCG2 protein, suggesting that these compounds inhibit both the function and expression of ABCG2 transporters at non-toxic concentrations.

Immunosuppressive therapy in children.

The treatment of auto-immune diseases is evolving and newer agents become available. This review will outline treatment options in children with auto-immune disorders. Treatment with current corticosteroids and azathioprine works in majority but issues of intolerance and incomplete response arise, which led to window of newer immunosuppressants including mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus, and various antibodies of human and animal origin. The newer agents have been studied in fewer numbers of children, so they are not first-line treatment yet but do have a clear role in patients with intolerance or incomplete response to standard therapy.

Free radical injury and blood-brain barrier permeability in hypoxic-ischemic encephalopathy.

OBJECTIVES: The purpose of this work was to evaluate the extent of free radical injury in newborns with hypoxic ischemic encephalopathy by measuring plasma levels of malondialdehyde and nitric oxide and to assess the blood-brain barrier permeability by measuring the cerebrospinal fluid albumin/plasma albumin ratio. METHODS: This prospective observational study was conducted over a period of 2 years at Sir Sundarlal Hospital, Banaras Hindu University. The study population consisted of 43 term neonates with perinatal asphyxia who subsequently developed hypoxic ischemic encephalopathy. Twenty normal gestational age- and gender-matched healthy infants without any perinatal asphyxia served as control subjects. Peripheral venous blood samples were analyzed for malondialdehyde, total plasma nitrates/nitrites, and albumin levels between 12 and 24 hours of life. To assess the blood-brain barrier permeability, the cerebrospinal fluid albumin/plasma albumin ratio was measured. Correlation among the levels of malondialdehyde, nitrates/nitrites, and blood-brain barrier permeability was calculated. Data were analyzed by using SPSS 10 software. RESULTS: Plasma malondialdehyde and nitrate/nitrite levels were significantly higher in infants with hypoxic ischemic encephalopathy compared with control subjects. Although there was a progressive increment in plasma levels of malondialdehyde with increasing severity of hypoxic ischemic encephalopathy, the differences were not statistically significant. Plasma nitrate/nitrite levels were almost similar in all stages of hypoxic ischemic encephalopathy. Plasma albumin levels were comparable in infants with hypoxic ischemic encephalopathy and control subjects, whereas cerebrospinal fluid albumin levels and blood-brain barrier permeability were significantly higher in infants with hypoxic ischemic encephalopathy. Significant correlation was observed between plasma malondialdehyde and nitrate/nitrite levels with blood-brain barrier permeability. CONCLUSIONS: Increased plasma levels of malondialdehyde and nitrates/nitrites are found to be associated with hypoxic ischemic encephalopathy, indicating the possible role of free radical injury in its causation. Increased blood-brain barrier permeability may be another contributory factor to the progression of the disease.