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Cellular Injury IV: Necrosis01:16

Cellular Injury IV: Necrosis

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Necrosis is a form of irreversible cell death caused by severe injury such as ischemia, toxins, or trauma. Unlike programmed cell death, it is an uncontrolled, pathological process that typically provokes inflammation in surrounding tissues.Pathophysiologic ChangesNecrosis begins when cells sustain critical damage, leading to swelling of organelles, particularly mitochondria, and rapid ATP depletion. As energy levels decline, membrane ion pumps fail, leading to calcium influx and eventually,...
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Intracellular calcium-induced ROS generation promotes squaraine phototoxicity.

Giorgia Chinigò1, Carlotta Pontremoli2, Francesca Bianco3

  • 1University of Torino, Department of Life Sciences and Systems Biology, Via Accademia Albertina 13, 10123 Turin, Italy.

Biochimica Et Biophysica Acta. Molecular Cell Research
|September 1, 2025
PubMed
Summary
This summary is machine-generated.

New squaraine photosensitizers enhance photodynamic therapy (PDT) efficacy. Modifications like bromine or sulfur incorporation boost phototoxicity by modulating calcium and ROS signaling pathways, improving cancer treatment potential.

Keywords:
Ca(2+) signalPhotodynamic therapyPhototoxicityROSSignal transductionSquaraines

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Area of Science:

  • Biochemistry
  • Photochemistry
  • Cell Biology

Background:

  • Photodynamic therapy (PDT) is an FDA-approved cancer treatment.
  • Developing novel photosensitizers (PSs) is crucial for enhancing PDT efficacy and minimizing side effects.
  • Understanding PS photo-activation signaling pathways can optimize treatment outcomes.

Purpose of the Study:

  • To synthesize and evaluate squaraine (SQ) derivatives with modified indolenine rings for PDT applications.
  • To investigate the structure-activity relationships of these SQs concerning phototoxicity and intracellular signaling.
  • To elucidate the roles of calcium (Ca2+) and reactive oxygen species (ROS) in SQ-mediated phototoxicity.

Main Methods:

  • Synthesis of a series of SQ derivatives with varying indolenine ring modifications.
  • Assessment of phototoxic activity through in vitro assays.
  • Measurement of photo-induced cytoplasmic Ca2+ signals and ROS generation.
  • Localization studies of SQs within cellular compartments (endoplasmic reticulum and mitochondria).

Main Results:

  • Unsubstituted SQ showed phototoxic activity, enhanced by bromine (Br-SQ-C4) or sulfur (SQ-S-C4) modifications.
  • Phototoxicity correlated positively with Ca2+ signaling and ROS generation.
  • Br-SQ-C4 localized to the ER, inducing Ca2+ release and subsequent ROS generation.
  • SQ-S-C4 localized to mitochondria, causing basal Ca2+/ROS dynamics perturbation.

Conclusions:

  • SQ derivatives exhibit promising phototoxic potential for PDT.
  • Substituent-dependent modulation of intracellular Ca2+ and ROS signaling pathways dictates phototoxicity.
  • These findings provide insights into SQ-mediated signaling, guiding the development of more effective PDT agents.