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ABSTRACT Background: The increasing incidence of multidrug-resistant tuberculosis (MDR-TB) infections has created a need for new effective drugs that also target extensively drug-resistant tuberculosis (XDR-TB) and/or augment the activities of [...]

The continued spread of drug-resistant tuberculosis is one of the most pressing and complex challenges facing tuberculosis management worldwide. Therefore, developing a new class of drugs is necessary and urgently needed to cope with the increasing threat of drug-resistant tuberculosis. This study aims to discover a potential new class of tuberculosis drug candidates different from existing tuberculosis drugs. By screening a library of compounds, methyl (S)-1-((3-alkoxy-6,7-dimethoxyphenanthren-9-yl)methyl)-5-oxopyrrolidine-2-carboxylate (PP) derivatives with antitubercular activity were discovered. MIC ranges for PP1S, PP2S, and PP3S against clinically isolated drug-resistant Mycobacterium tuberculosis strains were 0.78 to 3.13, 0.19 to 1.56, and 0.78 to 6.25 μg/ml, respectively. PPs demonstrated antitubercular activities in macrophage and tuberculosis mouse models, showing no detectable toxicity in all assays tested. PPs specifically inhibited M. tuberculosis without significantly changing the intestinal microbiome in mice. Mutants selected in vitro suggest that the drug targets the PE-PGRS57, which has been found only in the genomes of the M. tuberculosis complex, highlighting the specificity and safety potency of this compound. As PPs show an excellent safety profile and highly selective toxicity specific to M. tuberculosis, PPs are considered a promising new candidate for the treatment of drug-resistant tuberculosis while maintaining microbiome homeostasis. This study identifies a new class of PP derivatives as Mycobacterium tuberculosis-targeting antimicrobials with microbiome-safe properties that do not disrupt normal flora, making them a promising candidate for the treatment of drug-resistant tuberculosis. [ABSTRACT FROM AUTHOR]

Objectives: Sosihotang (SSH) is an herbal medicine traditionally used against the common cold, and hepatic and gastric diseases, in Northeast Asia. In this study, we investigated whether SSH extract can protect against UVB‐induced skin damage and photoageing. Methods: HaCaT cells were treated with SSH extract and exposed UVB irradiation at 20 mJ/cm2. Hairless mice were orally administered SSH extract (100 mg/kg per mouse) as UVB irradiation was increased from 60 to 120 mJ/cm2 over the course of 12 weeks. Key findings: Treatment with SSH extract inhibited the upregulation of MMP‐1 and MMP‐9 expression in UVB‐irradiated HaCaT cells. In UVB‐irradiated hairless mice, treatment with SSH extract restored the levels of factors instrumental in skin hydration (TEWL, capacitance, HA and TGF‐β) and those regulating collagen content (procollagen, MMP‐1 and MMP‐9). This activity inhibited epidermal thickening and disorganization of collagen fibres. Administration of SSH extract also ameliorated the expression of UVB‐induced pro‐inflammatory cytokines (TNF‐α, IL‐1β and IL‐6) and phosphorylation of MAPK family members (MEK, JNK, ERK and p38) by upregulating the activity of antioxidant enzymes (SOD, CAT, Nrf‐2, HO‐1 and NQO‐1). Conclusions: These results indicate that SSH extract can be used therapeutically for the treatment of UVB‐induced skin damage and photoageing. [ABSTRACT FROM AUTHOR]

Inflammation is a pathological process that is known to be involved in numerous diseases. Microbial infection or tissue injury activates inflammatory responses, resulting in the induction of proinflammatory proteins including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS).Aster yomenais used in traditional Korean remedies to treat cough, asthma, and insect bites. Here, we investigated the effects ofA. yomenaextract (EAY) on the expression of COX-2 and iNOS induced by LPS. EAY inhibited NF-κB activation and IκBα degradation induced by LPS. EAY suppressed LPS-induced COX-2 and iNOS expression which are the target genes regulated through NF-κB activation in macrophages. EAY also suppressed LPS-induced nitrite production. These results suggest that EAY has the potential to be developed as a potent anti-inflammatory drug. [ABSTRACT FROM AUTHOR]

We investigated the photoprotective activity of phloroglucinol on ultraviolet B ( UVB)-induced deleterious effects in hairless mice in vivo. To assess the photoprotective effect of phloroglucinol, phloroglucinol-treated HR-1 hairless male mice were exposed to UVB irradiation. The inhibitory activity of phloroglucinol on wrinkle formation was determined by analysis of skin replicas, epidermal thickness based on histological examination and collagen damage. Matrix metalloproteinase-1 ( MMP-1), matrix metalloproteinase-9 ( MMP-9) and tissue inhibitor of metalloproteinase ( TIMP) mRNA levels were measured by real-time PCR. UVB induced transcription of proinflammatory cytokines, including interleukin-1 beta ( IL-1 β, IL-6) and IL-8 ( IL-8). The protective effects of phloroglucinol on UVB-induced skin photoaging were examined by measuring protein levels of MMPs and mitogen-activated protein ( MAP) kinases. The results of these experiments suggest that phloroglucinol has a significant beneficial effect on the barrier function of the skin. In hairless mice, signs of photoaging and photodamage, including coarse wrinkle formation, epidermal thickness and elastic fiber degeneration, were reduced in severity by phloroglucinol application. The phloroglucinol-treated group showed remarkably decreased mRNA levels of MMP-1, MMP-9 and inflammatory cytokines in comparison with those of the UVB-induced group. Oral administration of phloroglucinol attenuated phosphorylation of MAP kinases, including extracellular signal-regulated kinase, c-Jun N-terminal kinase and p38. [ABSTRACT FROM AUTHOR]

Polydeoxyribonucleotide (PDRN) is an agonist of the A2A adenosine receptors. We evaluated the effects of PDRN on liver regeneration induced by partial hepatectomy (PH) in rats, focusing on cell proliferation. Proliferating cell nuclear antigen (PCNA) as an indicator of cell proliferation was targeted to determine whether PDRN treatment could promote proliferation of hepatic cells in regenerating liver. Male Sprague-Dawley rats were divided into three groups: normal group (n= 3) without PH (sham operated), control groups (n= 12) with saline injection after PH, and experimental groups (n= 12) with i.p. injection of 8 mg/kg of PDRN immediately after PH. Light microscopically, liver regeneration induced by PH involved proliferation of various hepatic cells including parenchymal cells and Kupffer cells. The disintegration (1 or 2 days after PH) and remodeling (4 days after PH) of hepatic plate and increase of sinusoids (6 days after PH) were sequentially observed. These regenerative processes occurred relatively earlier in the experimental groups. By western blotting, the expression of PCNA increased in the early stage, reached its peak at 1 and 2 days after PH, and decreased thereafter. By immunohistochemistry, the intensities of PCNA staining in the experimental groups were more obvious at various days after PH. By electron microscopy using immunogold labeling for PCNA, the gold particles were largely observed in heterochromatin and nucleolus in hepatic cells. The results of immunochemistry and western blotting for PCNA showed the similar pattern in most groups. These findings suggest that PDRN treatment to hepatectomized rat could accelerate liver regeneration through rapid cell proliferation. [ABSTRACT FROM PUBLISHER]

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The mechanism underlying the wogonin-mediated increase in the expression of suppressor of cytokine signaling 3 (SOCS3) is unclear. Promoter deletion assay results revealed that wogonin-induced SOCS3 expression is dependent on the AP-1 consensus sequences and two STAT responsive elements (TTACAAGAA and TTCCAGGAA) in the 5′-flanking region of the SOCS3 gene in SH-SY5Y cells. Wogonin-induced SOCS3 expression was blocked by inhibitors of PI3K, Akt, Raf, p38, JNK, MEK, and STAT3, respectively. However, JAK2 inhibitors did not inhibit wogonin-induced SOCS3 expression. These results indicate that SOCS3-inducing effect of wogonin is caused by the activation of PI3K-mediated MAPK signaling pathways (Akt, ERK1/2, p38, and JNK), and the subsequent activation of AP-1 consensus sequences and STAT responsive elements in SH-SY5Y cells. [ABSTRACT FROM AUTHOR]

Astragaloside IV (AS-IV) is one of the major bio-active ingredients of huang qi which is the dried root of Astragalus membranaceus (a traditional Chinese medicinal plant). The pharmacological effects of AS-IV, including anti-oxidative, anti-cancer, and anti-diabetic effects have been actively studied, however, the effects of AS-IV on liver regeneration have not yet been fully described. Thus, the aim of this study was to explore the effects of AS-IV on regenerating liver after 70% partial hepatectomy (PHx) in rats. Differentially expressed mRNAs, proliferative marker and growth factors were analyzed. AS-IV (10 mg/kg) was administrated orally 2 h before surgery. We found 20 core genes showed effects of AS-IV, many of which were involved with functions related to DNA replication during cell division. AS-IV down-regulates MAPK signaling, PI3/Akt signaling, and cell cycle pathway. Hepatocyte growth factor (HGF) and cyclin D1 expression were also decreased by AS-IV administration. Transforming growth factor β1 (TGFβ1, growth regulation signal) was slightly increased. In short, AS-IV down-regulated proliferative signals and genes related to DNA replication. In conclusion, AS-IV showed anti-proliferative activity in regenerating liver tissue after 70% PHx. [ABSTRACT FROM AUTHOR]

The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome has been implicated in a variety of diseases, including atherosclerosis, neurodegenerative diseases, and infectious diseases. Thus, inhibitors of NLRP3 inflammasome have emerged as promising approaches to treat inflammation-related diseases. The aim of this study was to explore the effects of juglone (5-hydroxyl-1,4-naphthoquinone) on NLRP3 inflammasome activation. The inhibitory effects of juglone on nitric oxide (NO) production were assessed in lipopolysaccharide (LPS)-stimulated J774.1 cells by Griess assay, while its effects on reactive oxygen species (ROS) and NLRP3 ATPase activity were assessed. The expression levels of NLRP3, caspase-1, and pro-inflammatory cytokines (IL-1β, IL-18) and cytotoxicity of juglone in J774.1 cells were also determined. Juglone was non-toxic in J774.1 cells when used at 10 μM (p < 0.01). Juglone treatment inhibited the production of ROS and NO. The levels of NLRP3 and cleaved caspase-1, as well as the secretion of IL-1β and IL-18, were decreased by treatment with juglone in a concentration-dependent manner. Juglone also inhibited the ATPase activities of NLRP3 in LPS/ATP-stimulated J774.1 macrophages. Our results suggested that juglone could inhibit inflammatory cytokine production and NLRP3 inflammasome activation in macrophages, and should be considered as a therapeutic strategy for inflammation-related diseases. [ABSTRACT FROM AUTHOR]

Due to the emergence of multidrug-resistant and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis , new antituberculosis drugs are urgently required to improve the efficacy of current tuberculosis (TB) treatment. To achieve this goal, ca. 1000 chemical compounds were screened for potential antimycobacterial activity, among which methyl 5-(2-diethylaminoethoxy)-7,12-dioxo-7,12 dihydrodinaphtho[1,2- b ;2′,3′- d ]furan-6-carboxylate (DNF-3) showed strong activity against all of the tested drug-susceptible and -resistant M. tuberculosis strains, with 50% minimum inhibitory concentrations (MIC 50 values) of 0.02–0.39 µg/mL both in culture broth and within murine RAW 264.7 macrophage cells. When DNF-3 was used in combination with rifampicin or streptomycin, it exhibited direct synergy against XDR-TB and an additive effect against M. tuberculosis H37Rv. DNF-3 displayed a long post-antibiotic effect (PAE) that was comparable with rifampicin but was superior to isoniazid, streptomycin and ethambutol. Importantly, DNF-3 showed no cytotoxicity to any cell line tested, with a selectivity index (SI) of >32. DNF-3 was also active against 27 nontuberculous mycobacteria (NTM) strains, Staphylococcus spp. and Streptococcus spp. Taken together, these results indicate that DNF-3 is a promising new candidate drug for treating TB. Further studies are warranted to establish the in vivo effect and therapeutic potential of DNF-3. [ABSTRACT FROM AUTHOR]

Background/objectives: Curcuma zedoaria R. ( Zingiberaceae ) has been used to treat headache, fever, and hypertension-related symptoms in Asian countries, including Korea, China, and Japan. We investigated whether dietary intake of a C. zedoaria extract (CzE) affected atherosclerosis in vivo ., Materials/methods: Apolipoprotein E-deficient (ApoE -/- ) mice (n = 32) were fed a normal diet (ND), a high-cholesterol diet (HCD), an HCD containing CzE (100 mg/kg/day), or an HCD containing simvastatin (10 mg/kg/day) for 12 weeks. The anti-atherosclerotic effects were evaluated by observing changes in fatty streak lesions, immunohistochemical analysis, ex vivo fluorescence imaging, lipid profiles, and western blot analysis., Results: The CzE-fed group showed a 41.6% reduction of atherosclerosis. Furthermore, CzE significantly reduced the levels of serum triglyceride, high-density lipoprotein, the chemokine (C-X3-C-motif) ligand 1, the adhesion molecules vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and E-selectin; down-regulation of tumor necrosis factor-α, interleukin-6, high mobility group box-1, and cathepsin levels in the aortic sinuses and aortas of ApoE -/- mice were also observed., Conclusions: The results suggest that the inclusion of a water extract of C. zedoaria in a HCD is closely correlated with reducing the risk of vascular inflammatory diseases in an ApoE mouse model., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interests., (©2021 The Korean Nutrition Society and the Korean Society of Community Nutrition.)

Tuberculosis, one of the world's major health problems, has become more serious due to the emergence of multi-drug resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (MTB). In this study, we performed three anti-MTB assays to evaluate the anti-mycobacterial activity of naphthofuroquinone derivatives against drug-resistant MTB. Among them, methyl 5-[2-(dimethylamino)ethoxy]-7,12-dioxo-7,12-dihydrodinaphtho[1,2-b:2',3'-d]furan-6-carboxylate (DFC2) exhibited strong anti-mycobacterial activity against MTB H37Ra, H37Rv and four drug-resistant MTB strains. The MIC of DFC2 ranged from 0.19-0.39 μg/ml to 0.78-1.56 μg/ml against all tested MTB strains. Moreover, DFC2 showed low cytotoxicity against fibroblast cells (L929) at concentrations 10-40-fold higher than their MICs. The IC 50 value of DFC2 against L929 cells was 15.218 μg/ml. In addition, DFC2 reduced the number of intracellular M. tuberculosis in macrophages in a dose-dependent manner. Taken together, our results indicate DFC2 to be promising new candidate agents for the treatment of tuberculosis.

DFC-2, a methyl 5-[2-(dimethylamino)ethoxy]-7,12-dioxo-7,12-dihydrodinaphtho[1,2-b:2',3'-d]furan-6-carboxylate, is reported to have antitubercular effects against Mycobacterium tuberculosis . At concentrations ranging from 0.19 to 0.39 μg/ml, DFC-2 inhibited both drug-susceptible and -resistant strains of M. tuberculosis . Microarray analyses were employed to gain insights into the molecular mechanisms of DFC-2's action in M. tuberculosis . The most affected functional gene category was "lipid biosynthesis," which is involved in mycolic acid synthesis. The decrease in transcription of genes related to mycolic acid synthesis was confirmed by RT-PCR. Furthermore, we found that DFC-2 triggered a reduction in mycolic acid levels, showing a similar pattern to that of mycolic acid synthesis inhibitor isoniazid. These results may explain how this compound kills mycobacteria efficiently by inhibiting mycolic acid synthesis.

Background: Human tuberculosis, which is caused by the pathogen Mycobacterium tuberculosis, remains a major public health concern. Increasing drug resistance poses a threat of disease resurgence and continues to cause considerable mortality worldwide, which necessitates the development of new drugs with improved efficacy. Thymoquinone (TQ), an essential compound of Nigella sativa, was previously reported as an active anti-tuberculosis agent., Methods: In this study, the effects of TQ on intracellular mycobacterial replication are examined in macrophages. In addition, its effect on mycobacteria-induced NO production and pro-inflammatory responses were investigated in Mycobacterium tuberculosis (MTB)-infected Type II human alveolar and human myeloid cell lines., Results: TQ at concentrations ranging from 12.5 to 25 μg/mL and 6.25 to 12.5 μg/mL reduced intracellular M. tuberculosis H37Rv and extensively drug-resistant tuberculosis (XDR-TB) 72 h post-infection in RAW 264.7 cells. TQ treatment also produced a concentration-dependent reduction in nitric oxide production in both H37Rv and XDR-TB infected RAW 264.7 cells. Furthermore, TQ reduced the expression of inducible nitric oxide synthase (iNOS) and pro-inflammatory molecules such as tumor necrosis factor-alpha (TNF-α) and interlukin-6 (IL-6) in H37Rv-infected cells and eventually reduced pathogen-derived stress in host cells., Conclusions: TQ inhibits intracellular H37Rv and XDR-TB replication and MTB-induced production of NO and pro-inflammatory molecules. Therefore, along with its anti-inflammatory effects, TQ represents a prospective treatment option to combat Mycobacterium tuberculosis infection.

Ursolic acid (3-β-3-hydroxy-urs-12-ene-28-oic-acid; UA) is a triterpenoid carboxylic acid with various pharmaceutical properties. It is commonly found in apples, basil, berries, rosemary, peppermint, lavender, oregano, thyme, hawthorn and prunes. In the present study, the activities of UA against the Mycobacterium tuberculosis H37Rv‑induced release of a panel of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 from RAW 264.7 murine macrophages, A549 alveolar epithelial cells and in concanavalin A (Con A)-stimulated rat splenocytes were investigated. In addition, the present study examined the ability of UA to reduce the expression levels of the inflammatory mediators, cyclooxygenase‑2 (COX‑2) and inducible nitric oxide synthase (iNOS) in the stimulated cells. The reduction of nitric oxide (NO) release by UA was also examined in the stimulated cells. UA significantly inhibited the mRNA expression levels of TNF‑α, IL‑1β and IL‑6 in the stimulated cells. The expression levels of COX‑2 and iNOS were also suppressed by UA, as was the release of NO at a significant level. The data indicated the potency of UA on different cell types, which may assist in the development of anti‑inflammatory drugs. In the case of adjunct host‑directed immune therapy for tuberculosis, UA may be used, in addition to established antibiotic therapies, to improve treatment efficacy and outcome due to their anti‑inflammatory potential. Further detailed investigations are required to establish its use as an anti-inflammatory.

Alveolar epithelial cells have been functionally implicated in Mycobacterium tuberculosis infection. This study investigated the role of ursolic acid (UA)-a triterpenoid carboxylic acid with potent antioxidant, anti-tumor, anti-inflammatory, and anti-tuberculosis properties in mycobacterial infection of alveolar epithelial A549 cells. We observed that M. tuberculosis successfully entered A549 cells. Cytotoxi-city was mediated by nitric oxide (NO). A549 toxicity peaked along with NO generation 72 h after infection. The NO generated by mycobacterial infection in A549 cells was insufficient to kill mycobacteria, as made evident by the mycobacteria growth indicator tube time to detect (MGIT TTD) and viable cell count assays. Treatment of mycobacteria-infected cells with UA reduced the expression of inducible nitric oxide synthase, NO generation, and eventually improved cell viability. Moreover, UA was found to quench the translocation of the transcription factor, nuclear factor kappa B (NF-κB), from the cytosol to the nucleus in mycobacteria-infected cells. This study is the first to demonstrate the cytotoxic role of NO in the eradication of mycobacteria and the role of UA in reducing this cytotoxicity in A549 cells.

Recently, it has become a struggle to treat tuberculosis with the current commercial antituberculosis drugs because of the increasing emergence of multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis. We evaluated here the antimycobacterial activity of tamoxifen, known as a synthetic anti-estrogen, against eight drug-sensitive or resistant strains of Mycobacterium tuberculosis (TB), and the active intracellular killing of tamoxifen on TB in macrophages. The results showed that tamoxifen had antituberculosis activity against drug-sensitive strains (MIC, 3.125-6.25 μg/ml) as well as drug-resistant strains (MIC, 6.25 to 12.5 μg/ml). In addition, tamoxifen profoundly decreased the number of intracellular TB in macrophages in a dose-dependent manner.

Tuberculosis is one of the most threatening infectious diseases to public health all over the world, for which Mycobacterium tuberculosis (MTB) is the etiological agent of pathogenesis. Ursolic acid (UA) has immunomodulatory function and exhibits antimycobacterial activity. However, the intracellular killing effect of UA has yet to be elucidated. The aim of this study was to evaluate the intracellular killing effect of UA during mycobacterial infection. The intracellular killing activity of UA was evaluated in the macrophage cell line THP-1 by the MGIT 960 system as well as by CFU count. The production of reactive oxygen species (ROS) and the level of nitric oxide (NO) were measured using DCF-DA and Griess reagent, respectively. Phagocytosis was observed by a fluorescence-based staining method, and the colony forming units were enumerated on 7H11 agar medium following infection. In addition, MRP8 mRNA expression was measured by qRT-PCR. UA significantly decreased the number of intracellular Mycobacterium through generation of ROS and NO. In addition, it profoundly activated the phagocytosis process of THP-1 cells during MTB-infection. Furthermore, our data demonstrated that UA activated the phagocytosis process in human monocyte cells through MRP8 induction. These data suggest that UA firmly contributes to the intracellular killing effect of macrophages during mycobacterial infection.