Exploratory Clinical Trial of a Depression Diagnostic Software That Integrates Stress Biomarkers and Composite Psychometrics.

OBJECTIVE: This study evaluated the clinical effectiveness of Minds.NAVI, a depression screening kit combining psychometric measures and stress hormone biomarkers, in a prospective clinical trial. The objective was to assess its potential as a depression screening tool and investigate the associations between psychological assessments, salivary hormone staging, and depression severity. METHODS: Thirty-five participants with major depressive disorder and 12 healthy controls (HCs) were included. The Minds.NAVI software, utilizing the PROtective and Vulnerable factors battEry Test (PROVE) and salivary cortisol/dehydroepiandrosterone (DHEA) analysis, was employed. The PROVE test is a comprehensive self-report questionnaire that assesses depressive symptoms, suicide risk, attachment style, adverse childhood experiences, mentalization capacity, and resilience. In addition, salivary cortisol and DHEA levels were measured to evaluate the functional stage of the hypothalamic-pituitary-adrenal (HPA) axis. RESULTS: Minds.NAVI exhibited 100% sensitivity, 91.7% specificity, and 97.9% accuracy in distinguishing depression from HCs within an exploratory small group. Salivary stress hormone phases showed changes with depression stage (p=0.030), and the proportion of patients with "adrenal exhaustion stage" was higher in the moderate/severe depression group (p=0.038). Protective/vulnerable factors differed significantly between controls and depressed groups (p<0.001). Cortisol awakening response inversely correlated with depressive symptom severity (r=-0.31, p=0.034). CONCLUSION: This study suggested possible clinical effectiveness of Minds.NAVI, a depression screening tool that integrates psychometric measures and stress hormone biomarkers. The findings support the potential association between depression, chronic stress, and HPA axis hyporesponsiveness.

The Prevalence and Clinical Characteristics of Borderline Personality Disorder in South Korea Using National Health Insurance Service Customized Database.

PURPOSE: The purpose of the present study was to identify the prevalence and clinical characteristics of borderline personality disorder (BPD) in South Korea using the Korean National Health Insurance database (DB). MATERIALS AND METHODS: We used the National Health Insurance Service (NHIS)'s research DB (NHIS-2021-1-790) from January 1, 2010 to December 31, 2019, to make customized DB including sociodemographic information and absence or presence of BPD and other psychiatric disorders. The prevalence and the age of onset of BPD was estimated. To compare medical service utilization between the BPD group and the control group, a 1:1:1 propensity score matching was employed, and the regression analysis was conducted. RESULTS: The prevalence of BPD per 10000 people was 0.96 in 2010 and 1.06 in 2019. The prevalence ratio of males to females was 1:1.38 in 2010 and 1:1.65 in 2019, showing that BPD was more prevalent in females. The patients' overall average age of onset was 33.19±14.6 years, with the highest prevalence shown in 8503 people in their 20s. By administrative district, the highest prevalence of BPD per 10000 people was shown in Seoul with 8.71 and the lowest in Jeollanam-do with 2.35. The BPD patients showed a pattern of extensive use of general and mental healthcare services. CONCLUSION: This study identified the prevalence of BPD on a national DB set in South Korea. Although the prevalence of BPD in South Korea was relatively low compared to other countries, there was a steady increase in the number of BPD patients over a decade, which may be possibly due to an increased awareness of mental health and campaigns among healthcare providers and users in the country.

Neurophysiological insights into impaired mentalization in borderline personality disorder an electroencephalography study.

Introduction: Borderline personality disorder (BPD) is characterized by interpersonal and emotional instabilities, recurring suicidal tendencies, and feelings of emptiness. Childhood adverse event is reported in 70%-80% of cases involving BPD. Furthermore, the deficiency in mentalization capacity plays a significant role in emotion dysregulation and social interaction problems within individuals with BPD. This study explored the relationship among childhood adverse experiences, mentalization capacity, and neurophysiological activity in patients with BPD. Methods: Resting-state electroencephalography was used to identify the neural correlates associated with childhood adversity and mentalization deficits. The participants included 45 patients with BPD and 15 healthy controls. Results: The BPD group exhibited reduced alpha activity during eyes-closed rest, indicating heightened arousal even during relaxation. Correlations were found between the power spectral density (PSD) and mentalization capacity in the delta and theta ranges, suggesting an association between PSD and emotional awareness and expression. Gamma activity negatively correlated with psychic equivalence, implying a blurring of the boundaries between internal mental experiences and the external world. Conclusion: These findings offer insights into the pathophysiology of BPD, provide potential diagnostic markers, and suggest personalized treatment approaches based on mentalization traits.

The Factors Associated with Attempted Smoking Cessation and Successful Four-Week Smoking Abstinence According to the Types of Disability in Seoul, Korea.

This study investigated smoking behaviors by disability type among people with disabilities in Korea and identified factors associated with attempted smoking cessation and successful four-week smoking abstinence. Data were collected between 1 January 2018 and 31 December 2019. Predictors of attempted smoking cessation and successful four-week smoking abstinence were analyzed by disability type in 557 participants. Compared to people with mental health disorders, people with physical disabilities or brain lesions were more likely to attempt smoking cessation, and people with physical or internal disabilities were more likely to successfully abstain for four weeks. Common predictors of smoking cessation attempts and four-week abstinence were education level and CO level. Employment status predicted attempted cessation, while confidence in smoking cessation predicted four-week abstinence. To provide effective smoking cessation services for people with disabilities, disability type should be considered, and comprehensive and sustainable community-based programs need to be developed. Furthermore, a standardized survey of people with disabilities should be conducted to examine socioeconomic factors, including health status, employment, and education level, and to explore fundamental measures needed to address the problem of smoking among people with disabilities.

Korean Translation and Psychometric Evaluation of Korean Version EORTC QLQ-BRECON23.

The purpose of this study was to evaluate the psychometric properties of the Korean version of the European Organization for Research and Treatment of Cancer Quality of Life-QLQ-BRECON23 in women diagnosed and treated for breast cancer undergoing all types of breast reconstruction. METHODS: A total of 148 Korean women who underwent breast reconstruction were recruited from the breast cancer center to participate in the study. After performing forward and backward translation of the original English version of the questionnaire into Korean, its validity (construct, known-group validity, concurrent) and reliability were assessed. A structural equation model (SEM) was used to assess construct validity. RESULTS: The mean age of the patients was 52 years, and 89.8% underwent implant-based reconstruction. Construct validity using confirmatory factor analysis showed a good fit, and the effect size was small-to-medium regarding known-group validity. Concurrent validity was confirmed by the significant correlation between the QLQ-BRECON23 and the QLQ-BR23. The reliability of the QLQ-BRECON23 symptom and function scales ranged from 0.61 to 0.87. CONCLUSION: The Korean QLQ-BRECON23 can be applied to assess quality of life and its related factors, and also to internationally compare the level of quality of life in breast cancer patients undergoing breast reconstruction.

Functionalized graphene oxide for clinical glucose biosensing in urine and serum samples.

A novel clinical glucose biosensor fabricated using functionalized metalloid-polymer (silver-silica coated with polyethylene glycol) hybrid nanoparticles on the surface of a graphene oxide nanosheet is reported. The cyclic voltammetric response of glucose oxidase modification on the surface of a functionalized graphene oxide electrode showed a surface-confined reaction and an effective redox potential near zero volts, with a wide linearity of 0.1-20 mM and a sensitivity of 7.66 µA mM(-1) cm(-2). The functionalized graphene oxide electrode showed a better electrocatalytic response toward oxidation of H(2)O(2) and reduction of oxygen. The practical applicability of the functionalized graphene oxide electrode was demonstrated by measuring the peak current against multiple urine and serum samples from diabetic patients. This new hybrid nanoarchitecture combining a three-dimensional metalloid-polymer hybrid and two-dimensional graphene oxide provided a thin solid laminate on the electrode surface. The easy fabrication process and retention of bioactive immobilized enzymes on the functionalized graphene oxide electrode could potentially be extended to detection of other biomolecules, and have broad applications in electrochemical biosensing.

Rapid identification and preparative isolation of antioxidant components in licorice.

This study employed the online HPLC-2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate radical cation (ABTS(+*)) bioassay to rapidly determine antioxidant compounds occurring in the licorice extract of Glycyrrhiza uralensis. The negative peaks of the ABTS(+*) radical scavenging detection system, which indicated the presence of antioxidant activity, were monitored by measuring the decrease in absorbance at 734 nm. The ABTS(+)-based antioxidant activity profile showed that three peaks exhibited antioxidant activity, and then the high-speed counter-current chromatography technique of preparative scale was successfully applied to separate the three peaks I-III in one step from the licorice extract. The high-speed counter-current chromatography was performed using a two-phase solvent system composed of n-hexane-ethyl acetate-methanol-water (6.5:5.5:6:4, v/v). Yields of the three peaks, dehydroglyasperin C (I, 95.1% purity), dehydroglyasperin D (II, 96.2% purity), and isoangustone A (III, 99.5% purity), obtained were 10.33, 10.43, and 6.7% respectively. Chemical structures of the purified dehydroglyasperin C (I), dehydroglyasperin D (II), and isoangustone A (III) were identified by ESI-MS and (1)H- and (13)C-NMR analysis.

The anti-inflammatory effects of a methanolic extract from Radix Isatidis in murine macrophages and mice.

Radix Isatidis is the dried root of the plant Isatidis indigotica Fort (family Cruciferae) and traditionally used as an anti-viral, anti-bacterial, anti-endotoxic, and immune regulatory agent in the folk medicine of Korea and China. The aim of the present study was to determine the anti-inflammatory effects of methanolic extracts of Radix Isatidis (RIME) in lipopolysaccharide (LPS)-stimulated murine macrophages and in a TPA-induced ear edema animal model. Anti-inflammatory effects of RIME were examined in LPS-stimulated RAW 264.7 macrophages. In order to investigate the effects of RIME in vivo, activation of myeloperoxidase, and histological assessment were examined in the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced mouse ear edema model. RIME significantly inhibited the release from macrophages of inflammatory mediators such as nitric oxide, prostaglandin E(2), and pro-inflammatory cytokines. Topical administration of RIME at 1-5 mg/ear resulted in reduction of ear inflammation in mice. Thus, our results indicate that the anti-inflammatory effects of RIME involve decreased production of inflammatory mediators, which suggests that RIME may have therapeutic potential in a variety of inflammation-related diseases.

Oral administration of 3,3'-diindolylmethane inhibits lung metastasis of 4T1 murine mammary carcinoma cells in BALB/c mice.

3,3'-diindolylmethane (DIM) is the major in vivo product of the acid-catalyzed oligomerization of indole-3-carbinol present in cruciferous vegetables, and it has been shown to exhibit anticancer properties. In this study, we assessed the effects of DIM on the metastasis of 4T1 mouse mammary carcinoma cells. In vitro culture studies showed that DIM dose-dependently inhibited the migration, invasion, and adhesion of 4T1 cells at concentrations of 0-10 micromol/L without attendant changes in cell viability. In an in vivo lung metastasis model, 4T1 cells (2 x 10(5) cells/mouse) were injected into the tail veins of syngeneic female BALB/c mice. Beginning on the second day, the mice were subjected to gavage with 0-10 mg DIM/(kg body weight x d) for 13 d. Oral DIM administration resulted in a marked reduction in the number of pulmonary tumor nodules. DIM treatment significantly reduced the levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and vascular cell adhesion molecule (VCAM)-1 and increased TIMP-2 levels in the sera and lungs of mice injected with 4T1 cells. Additionally, DIM treatment reduced the serum concentrations of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)alpha. We have demonstrated that DIM profoundly inhibits the lung metastasis of 4T1 cells, which was accompanied by reduced levels of MMP, adhesion molecules, and proinflammatory cytokines. These results indicate that DIM has potential as an antimetastatic agent for the treatment of breast cancer.

3,3'-diindolylmethane attenuates colonic inflammation and tumorigenesis in mice.

BACKGROUND: 3,3-Diindolylmethane (DIM) is a major in vivo product of acid-catalyzed oligomerization of indole-3-carbinol (I3C) derived from Brassica food plants. Although DIM is known as a chemopreventive and chemotherapeutic phytochemical, the effects of DIM on inflammation in vivo are still unknown. In the present study we investigated the antiinflammatory effects of DIM on experimental colitis and colitis-associated colorectal carcinogenesis. METHODS: To determine if DIM has an antiinflammatory effect in vivo, we examined the therapeutic effects of DIM in dextran sodium sulfate (DSS)-induced experimental colitis and colitis-associated colon carcinogenesis induced by azoxymethane (AOM)/DSS in BALB/c mice. RESULTS: Treatment with DIM significantly attenuated loss of body weight, shortening of the colon, and severe clinical signs in a colitis model. This was associated with a remarkable amelioration of the disruption of the colonic architecture and a significant reduction in colonic myeloperoxidase activity and production of prostaglandin E(2), nitric oxide, and proinflammatory cytokines. Further, DIM administration dramatically decreased the number of colon tumors in AOM/DSS mice. CONCLUSIONS: These results suggest that DIM-mediated antiinflammatory action at colorectal sites may be therapeutic in the setting of inflammatory bowel disease and colitis-associated colon cancer.

The anti-inflammatory effects of methylsulfonylmethane on lipopolysaccharide-induced inflammatory responses in murine macrophages.

Methylsulfonylmethane (MSM), also known as dimethyl sulfone and methyl sulfone, is an organic sulfur-containing compound that occurs naturally in a variety of fruits, vegetables, grains, and animals, including humans. In the present study, we demonstrated the anti-inflammatory effects of MSM in lipopolysaccharide (LPS)-stimulated murine macrophages, RAW264.7 cells. MSM significantly inhibited the release of nitric oxide and prostaglandin E(2) by alleviating the expression of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-stimulated RAW264.7 cells. Furthermore, the levels of interleukin-6 and tumor necrosis factor-alpha were decreased by MSM treatment in cell culture supernatants. Further study indicated that the translocation of the p65 subunit of nuclear factor (NF)-kappaB to the nucleus was inhibited by MSM treatment in LPS-stimulated RAW264.7 cells, in which it helped block degradation of inhibitor of NF-kappaB. In addition, in vivo studies demonstrated that topical administration of MSM at 500-1250 microg/ear resulted in similar inhibitory activities in 12-O-tetradecanoylphorbol 13-acetate-induced mouse ear edema. Collectively, theses results indicate that MSM inhibits LPS-induced release of pro-inflammatory mediators in murine macrophages through downregulation of NF-kappaB signaling.

Cuscuta chinensis extract promotes osteoblast differentiation and mineralization in human osteoblast-like MG-63 cells.

The aim of the present study was to investigate whether the aqueous extract of To-Sa-Za (TSZ-AE), the seed of Cuscuta chinensis Lam., which is a traditional medicinal herb commonly used in Korea and other oriental countries, could induce osteogenic activity in human osteoblast-like MG-63 cells. TSZ-AE treatment mildly promoted the proliferation of MG-63 cells at doses of 500 and 1,000 microg/mL in the 24-hour culture period. Dose-dependent increases in alkaline phosphatase (ALP) activity and collagen synthesis were shown at 48 and 72 hours of incubation. The release of bone morphogenetic protein (BMP)-2 but not osteocalcin in the MG-63 cells was induced by TSZ-AE at 72 hours (100-1,000 microg/mL). In addition, TSZ-AE markedly increased mRNA expression of ALP, collagen, and BMP-2 in the MG-63 cells in a dose-dependent manner. Mineralization in the culture of MG-63 cells was significantly induced at 500 and 1,000 microg/mL TSZ-AE treatment. In conclusion, this study shows that TSZ-AE enhanced ALP activity, collagen synthesis, BMP-2 expression, and mineralization in MG-63 cells. These results strongly suggest that C. chinensis can play an important role in osteoblastic bone formation and may possibly lead to the development of bone-forming drugs.

Chrysin, a natural flavone, improves murine inflammatory bowel diseases.

Chrysin (5,7-dihydroxyflavone) is a natural flavone commonly found in many plants. It has previously been shown to be an anti-tumor agent. In this study, we investigated whether chrysin could alleviate the symptoms of dextran sodium sulfate (DSS)-induced colitis in mice and whether chrysin has an inhibitory effect on nuclear factor (NF)-kappaB activation in vitro. A significant blunting of weight loss and clinical signs was observed in DSS-exposed, chrysin-treated mice when compared to vehicle-treated mice. This was associated with a remarkable amelioration of the disruption of the colonic architecture, a significant reduction in colonic myeloperoxidase (MPO) activity, and a decrease in the production of inflammatory mediators such as nitric oxide (NO), prostaglandin (PG) E(2), and pro-inflammatory cytokines. In addition, chrysin inhibited tumor necrosis factor (TNF)-alpha-induced activation of NF-kappaB in IEC-6 cells. These findings suggest that chrysin exerts potentially clinically useful anti-inflammatory effects mediated through the suppression of NF-kappaB activation.

Apoptosis of DU145 human prostate cancer cells induced by dehydrocostus lactone isolated from the root of Saussurea lappa.

Saussurea lappa (SL) is a plant regularly utilized in traditional herbal medicine, and in vitro cell culture studies have demonstrated that SL has anti-ulcer, anti-inflammatory, and anti-tumor properties. In order to explore the possibility that SL exerts chemopreventive effects in androgen-independent prostate cancer, we attempted to determine whether the hexane extract of SL (HESL) induces apoptosis of DU145 cells, as well as the mechanisms underlying this effect. HESL substantially reduced the number of viable cells and induced apoptosis in DU145 cells in a dose-dependent manner. HESL-induced the cleavage of poly (ADP-ribose) polymerase (PARP) and caspases 8, 9, 7, and 3. HESL increased the protein levels of Bax, Bak, Bok, Bik, truncated Bid (t-Bid), and Bmf with a concomitant increase in the permeability of the mitochondrial membrane and in the release of cytochrome c from the mitochondria. The active fraction of HESL was isolated by column chromatography and the structure of the active compound dehydrocostus lactone (DHCL) was identified via (1)H NMR and (13)C NMR. DHCL promoted apoptosis with increased activation of caspases 8, 9, 7, 3, enhanced PARP cleavage, decreased Bcl-xL expression and increased levels of Bax, Bak, Bok, Bik, Bmf, and t-Bid. We have demonstrated that HESL and its active principle, DHCL, inhibit cell growth and induce apoptosis in DU145 cells.

Licochalcone A isolated from licorice suppresses lipopolysaccharide-stimulated inflammatory reactions in RAW264.7 cells and endotoxin shock in mice.

Licochalcone A (LicA), a major phenolic constituent of the licorice species Glycyrrhiza inflata, exhibits various biological properties, including chemopreventive, anti-bacterial, and anti-spasmodic activity. We report that LicA inhibits inflammatory reactions in macrophages and protects mice from endotoxin shock. Our in vitro experiments showed that LicA suppressed not only the generation of nitric oxide (NO) and prostaglandin (PG)E(2), but also the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 induced by lipopolysaccharide (LPS) in RAW264.7 cells. Similarly, LicA inhibited the production of inflammatory cytokines induced by LPS in RAW264.7 cells, including IL-1 beta and IL-6. In an animal model, LicA protected BALB/c mice from LPS-induced endotoxin shock, possibly through inhibiting the production of inflammatory cytokines and NO. Collectively, LicA inhibited the production of inflammatory mediators and may be a potential target for treatment of various inflammatory diseases.

Protein glycation inhibitors from the fruiting body of Phellinus linteus.

To characterize active principles for prevention and treatment of diabetic complications, the isolation of protein glycation inhibitors from the fruiting body of Phellinus linteus was conducted in vitro using the model systems of hemoglobin-delta-gluconolactone (early stage), bovine serum albumin-methylglyoxal (middle stage), and N(alpha)-acetyl-glycyl-lysine methyl ester-D-ribose (last stage) assays. Nine compounds were isolated from the active ethylacetate fraction of the fruiting body and identified as protocatechuic acid (1), protocatechualdehyde (2), caffeic acid (3), ellagic acid (4), hispidin (5), davallialactone (6), hypholomine B (7), interfungins A (8), and inoscavin A (9) by spectroscopic analyses. At the early stage of protein glycation, compounds 6, 8, and 9 exhibited inhibitory activity on hemoglobin A(1C) formation. For the middle stage, compounds 2, 6, and 9 showed a significant inhibitory effect on methylglyoxal-medicated protein modification and their IC(50) values were 144.28, 213.15, and 158.66 muM, respectively. At the last stage of glycation, compound 8 was found to be a potent inhibitor of the cross-linking of proteins, which was more effective than that of aminoguanidine, a well-known inhibitor for advanced glycation end products. Consequently, compound 8 showed the most potent inhibitory effects at each stage of protein glycation. This mechanism may help to provide a protective effect against hyperglycemia-mediated protein damage.

Inhibitory constituents of aldose reductase in the fruiting body of Phellinus linteus.

In an effort to characterize active principles for diabetic complication from medicinal mushroom, aldose reductase inhibitors were isolated from the fruiting body of Phellinus linteus and identified as hispidin (5), phelligridimer A (6), davallialactone (7), methyldavallialactone (8), hypholomine B (9), interfungins A (10), and inoscavin A (11), together with protocatechuic acid (1), protocatechualdehyde (2), caffeic acid (3), and ellagic acid (4). Their structures were elucidated by spectroscopic analyses. Among them, davallialactone (7), hypholomine B (9), and ellagic acid (4) exhibited potent rat lens aldose reductase and human recombinant aldose reductase inhibitory activity with IC50 values of 0.33, 0.82, 0.63 microM and 0.56, 1.28, 1.37 microM, respectively.

Characterization and electrocatalytic properties of Prussian blue electrochemically deposited on nano-Au/PAMAM dendrimer-modified gold electrode.

Gold electrode was modified with 3-mercaptopropionic acid (MPA) and further reacted with poly(amidoamine) (PAMAM) dendrimer (generation 4.0) then attached the nano-Au to obtain films on which Prussian blue (PB) was electrochemically deposited to afford much wider pH adaptive range, much better electrochemical stability and excellent electrochemical response. The microstructure and electrochemical behavior of Au/MPA/PAMAM/nano-Au/PB electrode were investigated by scanning electron microscopy (SEM) and cyclic voltammetry. The electrochemical response of the Au/MPA/PAMAM/nano-Au/PB-modified electrode for the electrocatalytic reduction of hydrogen peroxide was investigated, and it was found that the sensitivity as well as the corresponding detection limits were improved as compared to the voltammetric response of a Au/PB-modified electrode and Au/MPA/PAMAM/PB electrode. Based on this, a new electrochemical sensor for determination of hydrogen peroxide has been developed.

Antiinflammatory activities of Rubus coreanus depend on the degree of fruit ripening.

The dried unripe fruit of Rubus coreanus, which is well-known in Korea and referred to as 'Bok-bun-ja', has been employed as a traditional medicine for centuries. This crude drug is utilized in Korea for the management of impotence, spermatorrhea, enuresis, asthma and allergic diseases. The principal objective of the present study was to conduct a comparison of the antiinflammatory effects of ethanol extracts of the unripe (URCE), half-ripened (HRCE) and ripe fruits (RCE) of Rubus coreanus. URCE and HRCE were found to reduce the production of nitric oxide (NO) and prostaglandin E2 (PGE2) as well as pro-inflammatory cytokines, in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages. However, RCE exerted no inhibitory effects against the production of NO and IL-6. The results of the study show that the degree of fruit ripening of Rubus coreanus affects the production of inflammatory mediators such as NO, PGE2 and inflammatory cytokines.

Induction of apoptosis in HT-29 colon cancer cells by phloretin.

Phloretin, which is present in apples and pears, has been found to inhibit the growth of several cancer cells and induce apoptosis of B16 melanoma and HL60 human leukemia cells. The present study examined whether and how phloretin induces apoptosis of HT-29 human colon cancer cells. Phloretin (0-100 micromol/L) substantially decreased viable cell number and induced apoptosis of HT-29 cells in a dose-dependent manner. Western blot analysis of total cell lysates revealed that phloretin increased the protein levels of Bax but had no effect on Bcl-2. In addition, phloretin induced cleavage of caspase-8, -9, -7, and -3 and poly(ADP-ribose) polymerase. Furthermore, phloretin increased the levels of cytochrome c and Smac/Diablo in the cytosol. The present results indicate that phloretin inhibits HT-29 cell growth by inducing apoptosis, which may be mediated through changes in mitochondrial membrane permeability and activation of the caspase pathways.