A COVID-19 Silver Lining-Decline in Antibiotic Resistance in Ischemic Leg Ulcers during the Pandemic: A 6-Year Retrospective Study from a Regional Tertiary Hospital (2017-2022).

Antibiotic resistance (AR) associated with chronic limb-threatening ischemia (CLTI) poses additional challenges for the management of ischemic leg ulcers, increasing the likelihood of severe outcomes. This study assessed AR prevalence in bacteria isolated from CLTI-associated leg ulcers before (1 January 2017-10 March 2020; n = 69) and during (11 March 2020-31 December 2022; n = 59) the COVID-19 pandemic from patients admitted with positive wound cultures to a regional hospital in Chiang Mai (Thailand). There was a marked reduction in AR rates from 78% pre-pandemic to 42% during the pandemic (p < 0.0001), with rates of polymicrobial infections 22 percentage points lower (from 61% to 39%, respectively; p = 0.014). There were reduced AR rates to amoxicillin/clavulanate (from 42% to 4%; p < 0.0001) and ampicillin (from 16% to 2%; p = 0.017), as well as multidrug resistance (19% to 8%; p = 0.026). Factors associated with increased AR odds were polymicrobial infections (adjusted odds ratio (aOR) 5.6 (95% CI 2.1, 15.0); p = 0.001), gram-negative bacteria (aOR 7.0 (95% CI 2.4, 20.5); p < 0.001), and prior use of antibiotics (aOR 11.9 (95% CI 1.1, 128.2); p = 0.041). Improvements in infection control measures and hygiene practices in the community during the pandemic were likely key factors contributing to lower AR rates. Thus, strategic public health interventions, including community education on hygiene and the informed use of antibiotics, may be crucial in mitigating the challenges posed by AR in CLTI. Further, advocating for more judicious use of empirical antibiotics in clinical settings can balance effective treatment against AR development, thereby improving patient outcomes.

Hydrosoluble Perylene Monoimide-Based Telomerase Inhibitors with Diminished Cytotoxicity.

Telomerase is essential for the immortality characteristics of most cancers. Telomerase-specific inhibitors should render cancer cells to replicative senescence without acute cytotoxicity. Perylene-based G-quadruplex (G4) ligands are widely studied as telomerase inhibitors. Most reported perylene-based G4 ligands are perylene diimides (PDIs), which often suffer from self-aggregation in aqueous solutions. Previously, we found that PM2, a perylene monoimide (PMI), exhibited better solubility, G4 binding affinity, and telomerase inhibition than PIPER, the prototypic PDI. However, the acute cytotoxicity of PM2 was about 20-30 times more than PIPER in cancer cells. In this report, we replaced the piperazine side chain of PM2 with ethylenediamine to yield PM3 and replaced the N,N-diethylethylenediamine side chain of PM2 with the 1-(2-aminoethyl) piperidine to yield PM5. We found that asymmetric PMIs with two basic side chains (PM2, PM3, and PM5) performed better than PIPER (the prototypic PDI), in terms of hydrosolubility, G4 binding, in vitro telomerase inhibition, and suppression of human telomerase reverse transcriptase (hTERT) expression and telomerase activity in A549 cells. However, PM5 was 7-10 times less toxic than PM2 and PM3 in three cancer cell lines. We conclude that replacing the N,N-diethylethylenediamine side chain with the 2-aminoethylpiperidine on PMIs reduces the cytotoxicity in cancer cells without impacting G4 binding and telomerase inhibition. This study paves the way for synthesizing new PMIs with drug-like properties for selective telomerase inhibition.

Superiority of an Asymmetric Perylene Diimide in Terms of Hydrosolubility, G-Quadruplex Binding, Cellular Uptake, and Telomerase Inhibition in Prostate Cancer Cells.

Perylene diimide (PDI) derivatives have been studied as G-quadruplex ligands that suppress telomerase activity by facilitating G-quadruplex formation of telomeric DNA and the hTERT promoter. PIPER, the prototypical PDI, reduces telomerase activity in lung and prostate cancer cells, leading to telomere shortening and cellular senescence of these cells. However, PIPER suffers from poor hydrosolubility and the propensity to aggregate at neutral pH. In this report, we synthesized a new asymmetric PDI, aPDI-PHis, which maintains one N-ethyl piperidine side chain of PIPER and has histidine as another side chain. The results show that aPDI-PHis is superior to its symmetric counterparts, PIPER and PDI-His, in terms of hydrosolubility, G-quadruplex binding, cellular uptake, and telomerase inhibition in prostate cancer cells. These results suggest that one N-ethyl piperidine side chain of PDI is sufficient for G-quadruplex binding, while another side chain can be tuned to elicit desirable properties. These findings might lead to better PDIs for use as anticancer drugs.

Curcuminoid derivatives enhance telomerase activity in an in vitro TRAP assay.

The length of telomeres controls the life span of eukaryotic cells. Telomerase maintains the length of telomeres in certain eukaryotic cells, such as germline cells and stem cells, and allows these cells to evade replicative senescence. Here, we report for the first time a number of curcuminoid derivatives that enhance telomerase activity in an in vitro TRAP assay. A preliminary analysis of structure-activity relationships found that the minimal requirement for this enhanced telomerase activity is a curcuminoid core with at least one n-pentylpyridine side chain, while curcuminoids with two such side chains exhibit even greater activity. The finding here might lead to a new class of telomerase activators that act directly or indirectly on telomerase, rather than through the reactivation of the telomerase reverse transcriptase (TERT) gene associated with other telomerase activators found in the literature.

Aristolactam-type alkaloids from Orophea enterocarpa and their cytotoxicities.

A new aristolactam, named enterocarpam-III (10-amino-2,3,4,6-tetramethoxy phenanthrene-1-carboxylic acid lactam, 1) together with the known alkaloid stigmalactam (2), were isolated from Orophea enterocarpa. Their structures were elucidated on the basis of interpretation of their spectroscopic data. Compounds 1 and 2 exhibited significant cytotoxicities against human colon adenocarcinoma (HCT15) cell line with IC(50) values of 1.68 and 1.32 µM, respectively.