Hypericin Enhances Paclitaxel-Induced B16-F10 Cell Apoptosis by Activating a Cytochrome c Release–Dependent Pathway

The enhanced inhibitory effect of paclitaxel (PTX) combined with hypericin (HY) on B16-F10 cells may be realized through the ROS-related cytochrome c release pathway. The apoptotic characteristics of the B16-F10 cells, such as DNA fragmentation, chromatin condensation, and apoptotic body formation, were all enhanced in the combined treatment group. Further investigation showed that the combination of paclitaxel and HY could increase the level of mitochondrial damage and the concentration of cytochrome c, causing the expression of caspase-3 and the cleavage of PARP.1. Compared with paclitaxel or HY alone, the level of reactive oxygen species (ROS) increased significantly, while glutathione reductase (GR) activity and intracellular glutathione (GSH) levels decreased significantly in the combination group.

Apoptotic body–mediated intercellular delivery for enhanced drug penetration and whole tumor destruction

Chemotherapeutic nanomedicines can exploit the neighboring effect to increase tumor penetration. However, the neighboring effect is limited, likely by the consumption of chemotherapeutic agents and resistance of internal hypoxic tumor cells. Here, we first propose and demonstrate that apoptotic bodies (ApoBDs) could carry the remaining drugs to neighboring tumor cells after apoptosis. To enhance the ApoBD-based neighboring effect, we fabricated disulfide-linked prodrug nanoparticles consisting of camptothecin (CPT) and hypoxia-activated prodrug PR104A. CPT kills external normoxic tumor cells to produce ApoBDs, while PR104A remains inactive. The remaining drugs could be effectively delivered into internal tumor cells via ApoBDs. Although CPT exhibits low toxicity to internal hypoxic tumor cells, PR104A could be activated to exert strong cytotoxicity, which further facilitates deep penetration of the remaining drugs. Such a synergic approach could overcome the limitations of the neighboring effect to penetrate deep into solid tumors for whole tumor destruction.

“Don’t eat me/eat me”-combined apoptotic body analogues for efficient targeted therapy of triple-negative breast cancer

For the purpose of efficient targeted therapies, suppressing the phagocytosis by mononuclear phagocyte system (MPS), enhancing the “active” targeted delivery, and meeting clinical production criteria are extremely critical for the...

Pathology of Intestinal Transplantation: Rejection and a Case of Tolerance

Small bowel transplants are less common than other organ transplants. Histological criteria for rejection of the transplanted small intestine were proposed at the 8th International Symposium on Small Intestinal Transplantation 2003-2004 [1, 2]. The Banff Conference on Transplant Disease Pathology, an international conference on the rejection of small bowel transplants, was held in 2019, and unifying diagnostic criteria were discussed (https://banfffoundation.org/pittsburgh-2019/). These histological criteria are expected to be standardized in the near future. This review outlines new findings such as apoptosis and apoptotic-body phagocytic findings in the lamina propria and behavior of natural killer T (NKT) cells, in addition to previously known crypt Fas-related apoptosis in acute cellular rejection. Furthermore, we review the case of a recipient who has shown no rejection for 5 years after transplantation. In the transplanted small intestine of this patient, the lymphocytes were replaced by those of another male patient.

How many serial sections are needed to detect apoptosis in endoscopic biopsies with gastrointestinal graft versus host disease?

AimsThe hallmark histological feature of acute gastrointestinal graft versus host disease (GI GVHD) is epithelial apoptosis. This is the first formal evaluation of how many serial sections are required to consistently detect apoptotic bodies in endoscopic biopsies from various GI locations in patients with clinically validated GI GVHD.Methods, results and conclusionsAssessment of 1008 serial sections showed that apoptotic bodies are uniformly distributed among such sections of gastric, duodenal and colorectal biopsies from these patients. Assessment of 59 further biopsies showed that assessing 12 serial sections should suffice to detect GVHD in gastric, duodenal and colorectal biopsies using thresholds of one apoptotic body per biopsy fragment or one apoptotic body per 4 mm2. Assessing 12 serial sections should also suffice to detect GVHD in duodenal and colorectal biopsies using the threshold of 6 apoptotic bodies per 10 contiguous crypts, but it remains uncertain whether this assessment and threshold can be applied to gastric biopsies.

TIM-1 As a Signal Receptor Triggers Dengue Virus-Induced Autophagy

Dengue virus (DENV) infection triggers the activation of autophagy to facilitate the viral replication cycle from various aspects. Although a number of stimulators are proposed to activate autophagy, none of them appears prior to the uncoating process. Given that T-cell immunoglobulin and mucin domain 1 (TIM-1) receptor is a putative DENV receptor and promotes apoptotic body clearance by autophagy induction, it raises the possibility that TIM-1 may participate in the activation of DENV-induced autophagy. In this study, confocal images first revealed the co-localization of TIM-1 with autophagosomes in DENV-induced autophagy rather than rapamycin-induced autophagy, suggesting the co-transportation of TIM-1 with DENV during infection. The treatment of siRNA to knockdown TIM-1 expression in DENV-infected GFP-microtubule-associated protein light chain 3 (LC3)-Huh7.5 cells revealed that TIM-1 is required not only for DENV cellular internalization but also for autophagy activation. Furthermore, knockdown p85, a subunit of phosphoinositide 3-kinases (PI3Ks), which is co-localized with TIM-1 at rab5-positive endosomes caused the reduction of autophagy, indicating that TIM-1-mediated DENV-induced autophagy requires p85. Taken together, the current study uncovered TIM-1 as a novel factor for triggering autophagy in DENV infection through TIM-1-p85 axis, in addition to serving as a DENV receptor.

Apoptosis and apoptotic body: disease message and therapeutic target potentials

Apoptosis is widely known as programmed cell death eliciting no inflammatory responses. The intricacy of apoptosis has been a focus of an array of researches, accumulating a wealth of knowledge which led to not only a better understanding of the fundamental process, but also potent therapies of diseases. The classic intrinsic and extrinsic signaling pathways of apoptosis, along with regulatory factors have been well delineated. Drugs and therapeutic measures designed based on current understanding of apoptosis have long been employed. Small-molecule apoptosis inducers have been clinically used for eliminating morbid cells and therefore treating diseases, such as cancer. Biologics with improved apoptotic efficacy and selectivity, such as recombinant proteins and antibodies, are being extensively researched and some have been approved by the FDA. Apoptosis also produces membrane-bound vesicles derived from disassembly of apoptotic cells, now known as apoptotic bodies (ApoBDs). These little sealed sacs containing information as well as substances from dying cells were previously regarded as garbage bags until they were discovered to be capable of delivering useful materials to healthy recipient cells (e.g., autoantigens). In this review, current understandings and knowledge of apoptosis were summarized and discussed with a focus on apoptosis-related therapeutic applications and ApoBDs.