Efficacy and safety of antibiotics for treatment of leptospirosis: a systematic review and network meta-analysis.

BACKGROUND: Leptospirosis, an important zoonotic bacterial disease, commonly affects resource-poor populations and results in significant morbidity and mortality worldwide. The value of antibiotics in leptospirosis remains unclear, as evidenced by the conflicting opinions published. METHODS: We conducted a search in the PubMed, Web of Science, and Cochrane Library databases for studies. These studies included clinical trials and retrospective studies that evaluated the efficacy or safety of antibiotics for leptospirosis treatment. The primary outcomes assessed were defervescence time, mortality rate, and hospital stays. Subgroup analyses were performed based on whether there were cases involving children and whether there were cases of severe jaundice. Safety was defined as the prevalence of adverse events associated with the use of antibiotics. p scores were utilized to rank the efficacy of the antibiotics. RESULTS: There are included 9 randomized controlled trials (RCTs), 1 control trial (CT), and 3 retrospective studies (RS) involving 920 patients and 8 antibiotics. Six antibiotics resulted in significantly shorter defervescence times compared to the control, namely cefotaxime (MD, - 1.88; 95% CI = - 2.60 to - 1.15), azithromycin (MD, - 1.74; 95% CI = - 2.52 to - 0.95), doxycycline (MD, - 1.53; 95% CI = - 2.05 to - 1.00), ceftriaxone (MD, - 1.22; 95% CI = - 1.89 to - 0.55), penicillin (MD, - 1.22; 95% CI = - 1.80 to - 0.64), and penicillin or ampicillin (MD, - 0.08; 95% CI = - 1.01 to - 0.59). The antibiotics were not effective in reducing the mortality and hospital stays. Common adverse reactions to antibiotics included Jarisch-Herxheimer reaction, rash, headache, and digestive reactions (nausea, vomiting, diarrhea, abdominal pain, and others). CONCLUSIONS: Findings recommend that leptospirosis patients be treated with antibiotics, which significantly reduced the leptospirosis defervescence time. Cephalosporins, doxycycline, and penicillin are suggested, and azithromycin may be a suitable alternative for drug-resistant cases. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022354938.

Prevalence of Borrelia burgdorferi in Ixodidae Tick around Asia: A Systematic Review and Meta-Analysis.

Lyme disease (LD) is a common arthropod-borne inflammatory disorder prevalent in the northern hemisphere. LD is caused by a spirochete named Borrelia burgdorferi s.l., which is transmitted to humans by ticks. Climate, environment, and other factors affect land use; recreational-behavior changes affect human contact with infected ticks. Studies in Europe and North America have looked at these aspects, but studies in Asia have not. We searched databases to identify all relevant abstracts published until March 2021. A meta-analysis was undertaken using the standard methods and procedures established by the Cochrane Collaboration. Ninety-one articles were included in our meta-analysis. The literature search identified data from nine countries (China, Japan, Malaysia, Mongolia, Pakistan, Russia Siberia region, South Korea, Thailand and Turkey). Furthermore, 53,003 ticks from six genera (Amblyomma, Dermacentor, Haemaphysalis, Hyalomma, Ixodes and Rhipicephalus) were inspected for infection with B. burgdorferi. The pooled prevalence was 11.1% (95% CI = 8.3-14.2%). Among the nine countries, China had the most studies (56) and Malaysia had the highest infection rate (46.2%). Most infected ticks were from the genera Ixodes and Haemaphysalis. Ticks of the genus Ixodes had the highest infection rate (16.9%). Obvious heterogeneity was noted in our meta-analysis. We analyzed the heterogeneity with regard to countries, genera, time points, and detection methods. This study suggests that Ixodes, Haemaphysalis and Dermacentor may be the most common tike of B. burgdorferi-positive in Asia. The highest proportion of ticks infected by B. burgdorferi were from the genus Ixodes. This meta-analysis is the first attempt to explain the B. burgdorferi infection of hard-body ticks in Asia. The infection rate for each country and infection rate of different tick genera were analyzed: there were large differences between them. The literature is concentrates mainly on East Asia, and data are limited. Our study can provide a reference for a more comprehensive and in-depth investigation of ticks in Asia infected by B. burgdorferi spirochetes.

Effects of betulinic acid on synovial inflammation in rats with collagen-induced arthritis.

Betulinic acid (BA) inhibits the migration, invasion, and cytoskeletal reorganization of fibroblast-like synoviocytes (RA-FLS) in patients with rheumatoid arthritis. Here, to further explore the mechanism of action of BA in collagen-induced arthritis (CIA) rats, we investigated the pharmacodynamic effects of BA on synovial inflammation in a rat model of type II CIA. After inducing hind paw swelling, the rats were divided into four groups: healthy controls (normal), and rats that underwent CIA and received methotrexate treatment (MTX), BA treatment (BA), or no treatment (CIA). Body weight and hind paw swelling were determined regularly, and arthritis scores were calculated weekly. On day 35, rats were sacrificed and their hind ankle joints sectioned and stained with hematoxylin and eosin for histopathological evaluation. BA significantly reduced CIA-induced hind paw swelling, synovial tissue proliferation, cartilage destruction, and vasospasm. BA treatment also decreased serum interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha (TNF-α) levels in rats with CIA. The CCK-8 assay was used to detect the proliferation of isolated vimentin+CD68- RA-FLS; RA-FLS were stimulated with TNF-α in vitro. BA significantly inhibited TNF-α-stimulated RA-FLS proliferation, as well as IL-1ß and IL-6 secretion. BA also downregulated the transcription of vascular endothelial growth factor (VEGF) and transforming growth factor ß (TGF-ß) and decreased the expression of the NF-кB pathway proteins (NF-kB-P65, IkBα, and IKKα/ß) in the TNF-α-stimulated RA-FLS. These results indicate that BA alleviated the symptoms of CIA by inhibiting synoviocyte proliferation, modifying TNF-α- and NF-кB-related inflammatory pathways, and downregulating inflammatory mediators and growth factors including IL-1ß, IL-6, VEGF, and TGF-ß.

Anti-inflammatory effects of Eucommia ulmoides Oliv. male flower extract on lipopolysaccharide-induced inflammation.

BACKGROUND: Eucommia ulmoides Oliv. is a medicinal plant native to China, with its bark (Eucommiae Cortex) traditionally being used for medicinal purposes. Previous research has shown that Eucommia male flowers can exert anti-inflammatory, analgesic, antibacterial, and other pharmacological effects, including immune regulation. This study explored the anti-inflammatory effects of the 70% ethanol extract of male flowers (EF) of E. ulmoides in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and LPS-administered mice. METHODS: Cytotoxicity of EF for RAW 264.7 cells was investigated using Cell Counting Kit-8. The production of proinflammatory mediators, nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 was determined using enzyme-linked immunosorbent assays. IL-17, IL-23, and IL-10 mRNA levels were determined using quantitative real-time polymerase chain reaction. Activation of the nuclear factor (NF)-κB pathway in RAW 264.7 cells was investigated via Western blotting. In vivo anti-inflammatory effects of EF were studied in an LPS-induced acute inflammation mouse model by analyzing lung tissue histopathology, serum TNF-α and IL-6 levels, and myeloperoxidase (MPO) activity in lung tissue. RESULTS: EF showed no significant cytotoxicity at concentrations from 10 to 60 µg/mL (cell viability > 80%) in the CCK-8 cell viability assay. EF inhibited the RAW 264.7 cell proliferation (EF 60 µg/mL, 120 µg/mL, and 250 µg/mL vs. negative control: 87.31 ±â€Š2.39% vs. 100.00 ±â€Š2.50%, P = 0.001; 79.01 ±â€Š2.56 vs. 100.00 ±â€Š2.50%, P < 0.001; and 64.83 ±â€Š2.50 vs. 100.00 ±â€Š2.50%, P < 0.001), suppressed NO (EF 20 µg/mL and 30 µg/mL vs. LPS only, 288.81 ±â€Š38.01 vs. 447.68 ±â€Š19.07 µmol/L, P = 0.004; and 158.80 ±â€Š45.14 vs. 447.68 ±â€Š19.07 µmol/L, P < 0.001), TNF-α (LPS+EF vs. LPS only, 210.20 ±â€Š13.85 vs. 577.70 ±â€Š5.35 pg/mL, P < 0.001), IL-1ß (LPS+EF vs. LPS only, 193.30 ±â€Š10.80 vs. 411.03 ±â€Š42.28 pg/mL, P < 0.001), and IL-6 (LPS+EF vs. LPS only, 149.67 ±â€Š11.60 vs. 524.80 ±â€Š6.24 pg/mL, P < 0.001) secretion, and downregulated the mRNA expression of IL-17 (LPS+EF vs. LPS only, 0.23 ±â€Š0.02 vs. 0.43 ±â€Š0.12, P < 0.001), IL-23 (LPS+EF vs. LPS only, 0.29 ±â€Š0.01 vs. 0.42 ±â€Š0.06, P=0.002), and IL-10 (LPS+EF vs. LPS only, 0.30 ±â€Š0.01 vs. 0.47 ±â€Š0.01, P=0.008) in LPS-stimulated RAW 264.7 cells. EF inhibited the LPS-induced NF-κB p65 (LPS+EF 20 µg/mL and 30 µg/mL vs. LPS only: 0.78 ±â€Š0.06 vs. 1.17 ±â€Š0.08, P < 0.001; and 0.90 ±â€Š0.06 vs. 1.17 ±â€Š0.08, P =0.002) and inhibitor of kappa B (IκBα) phosphorylation (LPS+EF 20 µg/mL and 30 µg/mL vs. LPS only: 0.25 ±â€Š0.01 vs. 0.63 ±â€Š0.03, P < 0.001; and 0.31 ±â€Š0.01 vs. 0.63 ±â€Š0.03, P < 0.001), LPS+EF 30 µg/mL inhibited IκB kinase (IKKα/ß) phosphorylation (LPS+EF 30 µg/mL vs. LPS only, 1.12 ±â€Š0.14 vs. 1.71 ±â€Š0.25, P = 0.002) in RAW 264.7 cells. Furthermore, EF 10 mg/kg and EF 20 mg/kg inhibited lung tissue inflammation in vivo and suppressed the serum TNF-α (LPS+EF 10 mg/kg and 20 mg/kg vs. LPS only, 199.99 ±â€Š186.49 vs. 527.90 ±â€Š263.93 pg/mL, P=0.001; and 260.56 ±â€Š175.83 vs. 527.90 ±â€Š263.93 pg/mL, P = 0.005), and IL-6 (LPS+EF 10 mg/kg and 20 mg/kg vs. LPS only, 41.26 ±â€Š30.42 vs. 79.45 ±â€Š14.16 pg/ ml, P = 0.011; and 42.01 ±â€Š26.26 vs. 79.45 ±â€Š14.16 pg/mL, P = 0.012) levels and MPO (LPS+EF 10 mg/kg and 20 mg/kg vs. LPS only, 3.19 ±â€Š1.78 vs. 5.39 ±â€Š1.51 U/g, P = 0.004; and 3.32 ±â€Š1.57 vs. 5.39 ±â€Š1.51 U/g, P = 0.006) activity in lung tissue. CONCLUSIONS: EF could effectively inhibit the expression of inflammatory factors and overactivation of neutrophils. Further investigation is needed to evaluate its potential for anti-inflammation therapy.

Salp15, a Multifunctional Protein From Tick Saliva With Potential Pharmaceutical Effects.

Ixodes ticks are the main vectors for a number of zoonotic diseases, including Lyme disease. Ticks secrete saliva directly into a mammalian host while feeding on the host's blood. This action serves to modulate host immunity and coagulation, thus allowing ticks to attach and feed upon their host. One of the most extensively studied components of tick saliva is Salp15. Research has shown that this protein binds specifically to CD4 molecules on the surface of T lymphocytes, interferes with TCR-mediated signaling transduction, inhibits CD4+ T cell activation and proliferation, and impedes the secretion of interleukin 2 (IL-2). Salp15 also binds specifically to dendritic cell dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) to up-regulate the expression of CD73 in regulatory T cells. Collectively, these findings render this salivary protein a potential candidate for a range of therapeutic applications. Here, we discuss our current understanding of Salp15 and the mechanisms that might be used to treat disease.

Comparative Studies of Different Extracts from Eucommia ulmoides Oliv. against Rheumatoid Arthritis in CIA Rats.

To compare efficacy of different extracts from Eucommia ulmoides Oliv. with both immune inflammation and joint destruction in collagen induced arthritis (CIA) rat model. Rats were divided into normal group (Nor), control group (CIA), TG group (treated with tripterygium glycoside), E70 group (treated with 70% ethanol extract from Eucommia ulmoides Oliv.), EA group (treated with ethyl acetate fraction from E70), and EN group (treated with n-butyl alcohol fraction from E70). All extracts from Eucommia ulmoides Oliv. could significantly inhibit ankle swelling, pathological manifestations, and cytokine levels in serum and spleen, by using foot volume measurement, H&E staining, ELISA, and RT-QPCR methods, respectively. All extracts could significantly inhibit rough joint surface and marginal osteophytes, improve RANKL/OPG ratio, and decrease MMP-9 expression, by using micro-CT and immunohistochemical staining. The activation of IKK/NF-κB signaling pathway was also inhibited by all extracts. In addition, ethyl acetate fraction from E70 presented better effect on RANKL/OPG system. This study identified effective extracts from Eucommia ulmoides Oliv. relieving immune inflammation and maintaining structural integrity of joints in CIA rats.

Chelerythrine Inhibits Human Hepatocellular Carcinoma Metastasis in Vitro.

Chelerythrine (CHE) is a type of benzophenanthridine alkaloid found in many herbs and is also the main alkaloid constituent of Toddalia asiatica (L.) LAM. It has been proven to have various activities including antitumor, antifungal, anti-inflammatory and anti-parasitic effects. We have previously demonstrated that CHE can inhibit proliferation and promote apoptosis in human hepatocellular carcinoma (HCC) cells. However, the effect of CHE on the metastasis of HCC and its related molecular mechanisms have yet to be validated. In this study, we investigated the effects of CHE on the migration and invasion of the HCC cell line Hep3B. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wounding healing, transwell migration and invasion assays and cytoskeleton staining demonstrated that CHE could inhibit the migration and invasion of Hep3B cells in a dose-dependent manner with change of cell structure. RNA interference studies made a knockdown of matrix metalloproteinase (MMP)-2/9 respectively in Hep3B cells. And the results of wounding healing and transwell invasion assay with the treatment of small interfering RNA (siRNA) investigated that MMP-2/9 are positively associated with Hep3B cell metastasis. The results of enzyme-linked immunosorbent assay (ELISA), Western blotting and quantitative RT-PCR showed that CHE suppressed the expression of MMP-2/9 at both mRNA and protein levels. CHE also exhibited an inhibitory effect on the phosphorylation of Focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases (ERK) and p38. In summary, on Hep3B cells, CHE could change the cell cytoskeletal structures through reducing the expression of p-FAK and inhibit the metastasis of Hep3B cells by downregulating the expression of MMP-2/9 mainly through PI3K/Akt/mTOR signaling pathway.

Cambogin exerts anti-proliferative and pro-apoptotic effects on breast adenocarcinoma through the induction of NADPH oxidase 1 and the alteration of mitochondrial morphology and dynamics.

Cambogin, a bioactive polycyclic polyprenylated acylphoroglucinol (PPAP) derived from the Garcinia genus, possesses proapoptotic effect in medulloblastoma and breast cancer cells. We have previously demonstrated that the proapoptotic effect of cambogin is driven by the production of reactive oxygen species (ROS). Here we have shown that the inhibitory effect of cambogin on cell proliferation is associated with the loss of mitochondrial transmembrane potential (ΔΨm) and mitochondrial fragmentation. Cambogin also promotes the mutual complex formation of the membrane-bound subunit p22phox of NADPH oxidase 1 (NOX1), as well as the phosphorylation of the cytosolic subunit p47phox, subsequently enhancing membrane-bound NOX1 activity, which leads to increases in intracellular and mitochondrial levels of O2.- and H2O2. Pharmacological inhibition of NOX1 using apocynin (pan-NOX inhibitor), ML171 (NOX1 inhibitor) or siRNA against NOX1 prevents the increases in O2.- and H2O2 levels and the anti-proliferative effect of cambogin. Antioxidants, including SOD (superoxide dismutase), CAT (catalase) and EUK-8, are also able to restore cell viability in the presence of cambogin. Besides, cambogin increases the dissociation of thioredoxin-1 (Trx1) from ASK1, switching the inactive form of ASK1 to the active kinase, subsequently leads to the phosphorylation of JNK/SAPK, which is abolished upon ML171 treatment. The proapoptotic effect of cambogin in breast cancer cells is also aggravated upon knocking down Trx1 in MCF-7 cells. Taken in conjunction, these data indicate that the anti-proliferative and pro-apoptotic effect of cambogin is mediated via inducing NOX1-dependent ROS production and the dissociation of ASK1 and Trx1.

Pretreatment with Jieduxiezhuo decoction impedes elevations in serum uric acid levels in mice.

OBJECTIVE: To investigate whether Jieduxiezhuo decoction (JDXZD) can prevent serum uric acid elevations in mice. METHODS: Hyperuricemia in mice was induced by intraperitoneally administering uric acid (250 mg/ kg). Concentrations of uric acid in serum were determined using the uric acid enzyme method. Mice were treated with JDXZD for 4 days before uric acid was administered. RESULTS: After intraperitoneal injection of uric acid, serum uric acid concentrations in mice significantly increased. However, the levels of uric acid in groups pretreated with 16.25 or 4.06 g/kg of JDXZD were significantly lower than those in the model and normal groups. CONCLUSION: Pretreatment with JDXZD slowed increases in serum uric acid levels in mice intraperitoneally administered uric acid.

Multifunctional catalysis by Pd@MIL-101: one-step synthesis of methyl isobutyl ketone over palladium nanoparticles deposited on a metal-organic framework.

Palladium nanoparticles deposited on a chromium terephthalate MIL-101 is a highly efficient multifunctional catalyst for the one-step synthesis of methyl isobutyl ketone, with significantly higher activity than palladium on traditional materials, such as metal oxides and zeolites.