In Harrison’s Principles of Internal Medicine, human understanding is emphasized as one of three necessary characteristics that a physician must have. Inflammation, which is caused by inflammatory inducers (inf-ids), is a fundamental feature of disease at the cellular and molecular levels. Inflammation protects the body, but excessive or prolonged inflammation can be damaging and can cause disease. Humans are repeatedly exposed to external and internal environmental factors that generate inf-ids throughout their lives. External environmental factors include microbial and non-microbial inf-ids, as well as stressors that inevitably arise during social interactions. Internal environmental factors include the adaptive physiological response that is present from birth. Inf-ids may also be produced by the four-step habit loop, which consists of a cue (e.g., stressor), emotions, routine act (adaptive response), and a reward. Immune cells in the circulatory system and in tissues may have positive and negative effects in inflammatory responses. However, low-grade inflammation may be difficult to detect. We propose a model of disease development that integrates external and internal environmental factors from the perspective of human understanding.

Purpose: To evaluate the therapeutic effect of repeated injections of mesenchymal stem cell (MSC)-derived exosomes on the erectile dysfunction (ED) of bilateral cavernous nerve injury (BCNI) rat model and to identify potential target genes of these injections. Materials and Methods: MSC-derived exosomes were isolated using an aqueous two-phase system. Rats were randomly assigned into four groups: Normal, BCNI, exosome once, and exosome-repeat groups. After four weeks, we measured the intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio to evaluate erectile function and examined cavernous nerve tissues for histological and molecular analyses. RNA sequencing in penile tissues was used to determine differentially expressed genes and was verified by quantitative polymerase chain reaction. Human umbilical vein endothelial cells (HUVECs) were used for in vitro studies to analyze biological roles. Results: The ICP/MAP ratios in the exosome-once and exosome-repeat groups were significantly increased compared to those in the BCNI group. Interestingly, the ICP/MAP ratio showed a greater increase in the exosome-repeat group, which also showed significantly increased smooth muscle/collagen ratio, α-smooth muscle actin and neuronal nitric oxide synthase expression, and cyclic guanosine monophosphate level compared to the BCNI and exosome-once groups. Three genes were significantly differentially expressed in the exosome group, among which Ras homolog family member B promoted cell proliferation and angiogenesis of HUVECs. Conclusions Repeated injections of MSC-derived exosomes can be effective in the treatment of rat models with ED induced by cavernous nerve injury.

Purpose: The primary goal of this study is to evaluate the effect of the non-invasive radiofrequency hyperthermia (RFHT) device on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) rat model and investigate the underlying mechanism. Materials and Methods: In this study, Sprague-Dawley rats were randomly distributed into three groups: (1) normal control group, (2) CP/CPPS group, and (3) RFHT group. CP/CPPS rat models were induced by 17β-estradiol and dihydrotestosterone for 4 weeks and RFHT was administered for 5 weeks after model establishment. During RFHT administration, core body temperatures were continuously monitored with a rectal probe. After administering RFHT, we assessed pain index for all groups and collected prostate tissues for Western blot analysis, immunofluorescence, and immunohistochemistry. We also collected adjacent organs to the prostate including urinary bladder, testes, and rectum for safety assessment via H&E staining along with a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay. Results: After administering RFHT, pain in rats was significantly alleviated compared to the CP/CPPS group. RFHT reduced high-mobility group box 1 (HMGB1) expression and improved inflammation by downregulating subsequent proinflammatory cytokines through inhibition of the toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-κB) pathway. In prostate-adjacent organs, no significant histological alteration or inflammatory infiltration was detected. The area of cell death also did not increase significantly after RFHT. Conclusions In conclusion, RFHT demonstrated anti-inflammatory effects by inhibiting the HMGB1-TLR4-NF-κB pathway in CP/CPPS rat models. This suggests that RFHT could serve as a safe and promising therapeutic strategy for CP/CPPS.

Purpose: To evaluate the therapeutic effect of repeated injections of mesenchymal stem cell (MSC)-derived exosomes on the erectile dysfunction (ED) of bilateral cavernous nerve injury (BCNI) rat model and to identify potential target genes of these injections. Materials and Methods: MSC-derived exosomes were isolated using an aqueous two-phase system. Rats were randomly assigned into four groups: Normal, BCNI, exosome once, and exosome-repeat groups. After four weeks, we measured the intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio to evaluate erectile function and examined cavernous nerve tissues for histological and molecular analyses. RNA sequencing in penile tissues was used to determine differentially expressed genes and was verified by quantitative polymerase chain reaction. Human umbilical vein endothelial cells (HUVECs) were used for in vitro studies to analyze biological roles. Results: The ICP/MAP ratios in the exosome-once and exosome-repeat groups were significantly increased compared to those in the BCNI group. Interestingly, the ICP/MAP ratio showed a greater increase in the exosome-repeat group, which also showed significantly increased smooth muscle/collagen ratio, α-smooth muscle actin and neuronal nitric oxide synthase expression, and cyclic guanosine monophosphate level compared to the BCNI and exosome-once groups. Three genes were significantly differentially expressed in the exosome group, among which Ras homolog family member B promoted cell proliferation and angiogenesis of HUVECs. Conclusions Repeated injections of MSC-derived exosomes can be effective in the treatment of rat models with ED induced by cavernous nerve injury.

Purpose: The primary goal of this study is to evaluate the effect of the non-invasive radiofrequency hyperthermia (RFHT) device on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) rat model and investigate the underlying mechanism. Materials and Methods: In this study, Sprague-Dawley rats were randomly distributed into three groups: (1) normal control group, (2) CP/CPPS group, and (3) RFHT group. CP/CPPS rat models were induced by 17β-estradiol and dihydrotestosterone for 4 weeks and RFHT was administered for 5 weeks after model establishment. During RFHT administration, core body temperatures were continuously monitored with a rectal probe. After administering RFHT, we assessed pain index for all groups and collected prostate tissues for Western blot analysis, immunofluorescence, and immunohistochemistry. We also collected adjacent organs to the prostate including urinary bladder, testes, and rectum for safety assessment via H&E staining along with a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay. Results: After administering RFHT, pain in rats was significantly alleviated compared to the CP/CPPS group. RFHT reduced high-mobility group box 1 (HMGB1) expression and improved inflammation by downregulating subsequent proinflammatory cytokines through inhibition of the toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-κB) pathway. In prostate-adjacent organs, no significant histological alteration or inflammatory infiltration was detected. The area of cell death also did not increase significantly after RFHT. Conclusions In conclusion, RFHT demonstrated anti-inflammatory effects by inhibiting the HMGB1-TLR4-NF-κB pathway in CP/CPPS rat models. This suggests that RFHT could serve as a safe and promising therapeutic strategy for CP/CPPS.

In Harrison’s Principles of Internal Medicine, human understanding is emphasized as one of three necessary characteristics that a physician must have. Inflammation, which is caused by inflammatory inducers (inf-ids), is a fundamental feature of disease at the cellular and molecular levels. Inflammation protects the body, but excessive or prolonged inflammation can be damaging and can cause disease. Humans are repeatedly exposed to external and internal environmental factors that generate inf-ids throughout their lives. External environmental factors include microbial and non-microbial inf-ids, as well as stressors that inevitably arise during social interactions. Internal environmental factors include the adaptive physiological response that is present from birth. Inf-ids may also be produced by the four-step habit loop, which consists of a cue (e.g., stressor), emotions, routine act (adaptive response), and a reward. Immune cells in the circulatory system and in tissues may have positive and negative effects in inflammatory responses. However, low-grade inflammation may be difficult to detect. We propose a model of disease development that integrates external and internal environmental factors from the perspective of human understanding.