Chlamydia Infection Remodels Host Cell Mitochondria to Alter Energy Metabolism and Subvert Apoptosis.

Chlamydia infection represents an important cause for concern for public health worldwide. Chlamydial infection of the genital tract in females is mostly asymptomatic at the early stage, often manifesting as mucopurulent cervicitis, urethritis, and salpingitis at the later stage; it has been associated with female infertility, spontaneous abortion, ectopic pregnancy, and cervical cancer. As an obligate intracellular bacterium, Chlamydia depends heavily on host cells for nutrient acquisition, energy production, and cell propagation. The current review discusses various strategies utilized by Chlamydia in manipulating the cell metabolism to benefit bacterial propagation and survival through close interaction with the host cell mitochondrial and apoptotic pathway molecules.

Recent Development of Nanomaterials for Transdermal Drug Delivery.

Nano-engineered medical products first appeared in the last decade. The current research in this area focuses on developing safe drugs with minimal adverse effects associated with the pharmacologically active cargo. Transdermal drug delivery, an alternative to oral administration, offers patient convenience, avoids first-pass hepatic metabolism, provides local targeting, and reduces effective drug toxicities. Nanomaterials provide alternatives to conventional transdermal drug delivery including patches, gels, sprays, and lotions, but it is crucial to understand the transport mechanisms involved. This article reviews the recent research trends in transdermal drug delivery and emphasizes the mechanisms and nano-formulations currently in vogue.

Recent Advancement of Medical Patch for Transdermal Drug Delivery.

Transdermal patches are a non-invasive method of drug administration. It is an adhesive patch designed to deliver a specific dose of medication through the skin and into the bloodstream throughout the body. Transdermal drug delivery has several advantages over other routes of administration, for instance, it is less invasive, patient-friendly, and has the ability to bypass first-pass metabolism and the destructive acidic environment of the stomach that occurs upon the oral ingestion of drugs. For decades, transdermal patches have attracted attention and were used to deliver drugs such as nicotine, fentanyl, nitroglycerin, and clonidine to treat various diseases or conditions. Recently, this method is also being explored as a means of delivering biologics in various applications. Here, we review the existing literatures on the design and usage of medical patches in transdermal drug delivery, with a focus on the recent advances in innovation and technology that led to the emergence of smart, dissolvable/biodegradable, and high-loading/release, as well as 3D-printed patches.

Chlamydia trachomatis plasmid-encoding Pgp3 protein induces secretion of distinct inflammatory signatures from HeLa cervical epithelial cells.

BACKGROUND: Genital Chlamydia trachomatis infection is the most common bacterial sexual transmitted disease that causes severe complications including pelvic inflammatory disease, ectopic pregnancy, and infertility in females. The Pgp3 protein encoded by C. trachomatis plasmid has been speculated to be an important player in chlamydial pathogenesis. However, the precise function of this protein is unknown and thus remains to be thoroughly investigated. METHODS: In this study, we synthesized Pgp3 protein for in vitro stimulation in the Hela cervical carcinoma cells. RESULTS AND CONCLUSION: We showed that Pgp3 induced prominent expression of host inflammatory cytokine genes including interleukin-6 (IL-6), IL-8, tumor necrosis factor alpha-induced protein 3 (TNFAIP3), and chemokine C-X-C motif ligand 1 (CXCL1), implying a possible role of Pgp3 in modulating the inflammatory reaction in the host.

Current Development of Chemical Penetration Enhancers for Transdermal Insulin Delivery.

The use of the transdermal delivery system has recently gained ample recognition due to the ability to deliver drug molecules across the skin membrane, serving as an alternative to conventional oral or injectable routes. Subcutaneous insulin injection is the mainstay treatment for diabetes mellitus which often leads to non-compliance among patients, especially in younger patients. Apart from its invasiveness, the long-term consequences of insulin injection cause the development of physical trauma, which includes lipohypertrophy at the site of administration, scarring, infection, and sometimes nerve damage. Hence, there is a quest for a better alternative to drug delivery that is non-invasive and easily adaptable. One of the potential solutions is the transdermal delivery method. However, the stratum corneum (the top layer of skin) is the greatest barrier in transporting large molecules like insulin. Therefore, various chemical enhancers have been proposed to promote stratum corneum permeability, or they are designed to increase the permeability of the full epidermis, such as the use of ionic liquid, peptides, chemical pre-treatment as well as packaging insulin with carriers or nanoparticles. In this review, the recent progress in the development of chemical enhancers for transdermal insulin delivery is discussed along with the possible mechanistic of action and the potential outlook on the proposed permeation approaches in comparison to other therapeutical drugs.

Immune Recognition versus Immune Evasion Systems in Zika Virus Infection.

The reemergence of the Zika virus (ZIKV) infection in recent years has posed a serious threat to global health. Despite being asymptomatic or mildly symptomatic in a majority of infected individuals, ZIKV infection can result in severe manifestations including neurological complications in adults and congenital abnormalities in newborns. In a human host, ZIKV is primarily recognized by RIG-like receptors and Toll-like receptors that elicit anti-viral immunity through the secretion of type I interferon (IFN) to limit viral survival, replication, and pathogenesis. Intriguingly, ZIKV evades its host immune system through various immune evasion strategies, including suppressing the innate immune receptors and signaling pathways, mutation of viral structural and non-structural proteins, RNA modulation, or alteration of cellular pathways. Here, we present an overview of ZIKV recognition by the host immune system and the evasion strategies employed by ZIKV. Characterization of the host-viral interaction and viral disease mechanism provide a platform for the rational design of novel prophylactic and therapeutic strategies against ZIKV infection.

Influx of podoplanin-expressing inflammatory macrophages into the genital tract following Chlamydia infection.

Genital Chlamydia trachomatis infection remains a major health issue as it causes severe complications including pelvic inflammatory disease, ectopic pregnancy and infertility in females as a result of infection-associated chronic inflammation. Podoplanin, a transmembrane receptor, has been previously reported on inflammatory macrophages. Thus, strategies that specifically target podoplanin might be able to reduce local inflammation. This study investigated the expression level and function of podoplanin in a C. trachomatis infection model. C57BL/6 mice infected with the mouse pathogen Chlamydia muridarum were examined intermittently from days 1 to 60 using flow cytometry analysis. Percentages of conventional macrophages (CD11b+ CD11c- F4/80+ ) versus inflammatory macrophages (CD11b+ CD11c+ F4/80+ ), and the expression of podoplanin in these cells were investigated. Subsequently, a podoplanin-knockout RAW264.7 cell was used to evaluate the function of podoplanin in C. trachomatis infection. Our findings demonstrated an increased CD11b+ cell volume in the spleen at day 9 after the infection, with augmented podoplanin expression, especially among the inflammatory macrophages. A large number of podoplanin-expressing macrophages were detected in the genital tract of C. muridarum-infected mice. Furthermore, analysis of the C. trachomatis-infected patients demonstrated a higher percentage of podoplanin-expressing monocytes than that in the noninfected controls. Using an in vitro infection in a transwell migration assay, we identified that macrophages deficient in podoplanin displayed defective migratory function toward C. trachomatis-infected HeLa 229 cells. Lastly, using immunoprecipitation-mass spectrometry method, we identified two potential podoplanin interacting proteins, namely, Cofilin 1 and Talin 1 actin-binding proteins. The present study reports a role of podoplanin in directing macrophage migration to the chlamydial infection site. Our results suggest a potential for reducing inflammation in individuals with chronic chlamydial infections by targeting podoplanin.

A Systematic Review of Molecular Hydrogen Therapy in Cancer Management.

BACKGROUND: Cancer remains a challenging target to cure, with present therapeutic methods unable to exhibit restorative outcomes without causing severe negative effects. Molecular hydrogen (H2) has been reported to be a promising adjunctive therapy for cancer treatment, having the capability to induce anti-proliferative, anti-oxidative, pro-apoptotic and anti-tumoural effects. This review summarises the findings from various articles on the mechanism, treatment outcomes, and overall effectiveness of H2 therapy on cancer management. METHODS: Using Cochrane, PubMed, and Google Scholar as the search engines, full-text articles in the scope of the study, written in English and within 10 years of publication were selected. RESULTS: Out of the 677 articles, 27 articles fulfilled the eligibility criteria, where data was compiled into a table, outlining the general characteristics and findings. Throughout the different forms of H2 administration, study design and types of cancers reported, outcomes were found to be consistent. CONCLUSION: From our analysis, H2 plays a promising therapeutic role as an independent therapy as well as an adjuvant in combination therapy, resulting in an overall improvement in survivability, quality of life, blood parameters, and tumour reduction. Although more comprehensive research is needed, given the promising outcomes, H2 is worth considering for use as a complement to current cancer therapy.

Tualang and Kelulut Honey Reduced Lipopolysaccharidesstimulated Inflammatory Responses of Mic

@#Microglial activity is crucial in maintaining the central nervous system (CNS) homeostasis. However, prolonged microglial activation have been implicated in the pathology of neurodegenerative diseases. Activated microglia will increase the production of inflammatory cytokines, reactive oxygen species (ROS) and alter their surface marker expression levels. This study used Malaysian honey, Tualang honey (TH), and Kelulut honey (KH) to determine lipopolysaccharide (LPS)-stimulated inflammatory responses of microglia. TH and KH at 0.1% were used in the current study as our findings showed no significant difference in the cell viability between BV2 cells treated with 0.1 % of TH and KH and control group. TH and KH reduced the ROS level significantly by 41.62±1.06% and 49.16±0.63%, respectively, and slightly reduced the expression of co-stimulatory molecules, CD40 and CD11b in LPS-activated BV2 cells. Our preliminary findings proposed an in-depth future study on the anti-inflammatory effect of TH and KH on microglial activation.

Helicobacter pylori Infection Elicits Type I Interferon Response in Human Monocytes via Toll-Like Receptor 8 Signaling.

Helicobacter pylori colonization and persistence could precede gastric adenocarcinoma. Elucidating immune recognition strategies of H. pylori is therefore imperative to curb chronic persistence in the human host. Toll-like receptor 7 (TLR7) and TLR8 are widely known as viral single-stranded RNA (ssRNA) sensors yet less studied in the bacteria context. Here, we investigated the involvement of these receptors in the immunity to H. pylori. Human THP-1 monocytic cells were infected with H. pylori, and the expression levels of human Toll-like receptors (TLRs) were examined. The roles of TLR7 and TLR8 in response to H. pylori infection were further investigated using receptor antagonists. Among all TLR transcripts examined, TLR8 exhibited the most prominent upregulation, followed by TLR7 in the THP-1 cells infected with H. pylori J99 or SS1 strains. H. pylori infection-mediated IFN-α and IFN-ß transactivation was significantly abrogated by the TLR7/8 (but not TLR7) antagonist. Additionally, TLR7/8 antagonist treatment reduced H. pylori infection-mediated phosphorylation of interferon regulatory factor 7 (IRF7). Our study suggests a novel role of TLR8 signaling in host immunity against H. pylori through sensing live bacteria to elicit the production of type I interferon.

Immune Checkpoint Molecules and Glucose Metabolism in HIV-Induced T Cell Exhaustion.

The progressive decline of CD8+ cytotoxic T cells in human immunodeficiency virus (HIV)-infected patients due to infection-triggered cell exhaustion and cell death is significantly correlated with disease severity and progression into the life-threatening acquired immunodeficiency syndrome (AIDS) stage. T cell exhaustion is a condition of cell dysfunction despite antigen engagement, characterized by augmented surface expression of immune checkpoint molecules such as programmed cell death protein 1 (PD-1), which suppress T cell receptor (TCR) signaling and negatively impact the proliferative and effector activities of T cells. T cell function is tightly modulated by cellular glucose metabolism, which produces adequate energy to support a robust reaction when battling pathogen infection. The transition of the T cells from an active to an exhausted state following pathogen persistence involves a drastic change in metabolic activity. This review highlights the interplay between immune checkpoint molecules and glucose metabolism that contributes to T cell exhaustion in the context of chronic HIV infection, which could deliver an insight into the rational design of a novel therapeutic strategy.

Zika Virus Vaccine: The Current State of Affairs and Challenges Posed by Antibody-Dependent Enhancement Reaction.

Infection caused by the Zika virus (ZIKV) can lead to serious neurological complications such as microcephaly in neonates. At present, no approved ZIKV vaccine is available, but few vaccine candidates are undergoing clinical trial. One major challenge faced is antibody-dependent enhancement (ADE) reaction that may provoke severe outcome in subsequent infection by ZIKV or other flaviviruses. Thus, more efforts should be dedicated to understanding ADE in designing a safe and effective vaccine to minimize the consequence of the potentially fatal infection's complications and to tackle potential ZIKV reemergence. This review discusses different types of ZIKV vaccine candidates that are currently underway in various stages of preclinical and clinical evaluations.

Regulatory network of BLIMP1, IRF4, and XBP1 triad in plasmacytic differentiation and multiple myeloma pathogenesis.

Antibody secreting plasma cell plays an indispensable role in humoral immunity. As activated B cell undergoes germinal center reaction and develops into plasma cell, it gradually loses B cell characteristics and embraces functional changes associated with immunoglobulins production. Differentiation of B cell into plasma cell involves drastic changes in cell structure, granularity, metabolism, gene expression and epigenetic regulation that couple with the mounting capacity for synthesis of a large quantity of antigen-specific antibodies. The interplay between three hallmark transcriptional regulators IRF4, BLIMP1, and XBP1, is critical for supporting the cellular reprograming activities during B to plasma cell transition. IRF4 promotes plasma cell generation by directing immunoglobulin class switching, proliferation and survival; BLIMP1 serves as a transcriptional repressor that extinguishes B cell features; whereas XBP1 controls unfolded protein response that relieves endoplasmic reticulum stress and permits antibody release during terminal differentiation. Intriguingly, high expression of IRF4, BLIMP1, and XBP1 molecules have been reported in myeloma cells derived from multiple myeloma patients, which negatively impact treatment outcome, prognosis, and relapse frequency. Despite the introduction of immunomodulatory drugs in recent years, multiple myeloma is still an incurable disease with poor survival rate. An in-depth review of IRF4, BLIMP1, and XBP1 triad molecules in plasma cell generation and multiple myeloma tumorigenesis may provide clues to the possibility of targeting these molecules in disease management.

A Comprehensive Review of the Evolution of Insulin Development and Its Delivery Method.

The year 2021 marks the 100th anniversary of the momentous discovery of insulin. Through years of research and discovery, insulin has evolved from poorly defined crude extracts of animal pancreas to recombinant human insulin and analogues that can be prescribed and administered with high accuracy and efficacy. However, there are still many challenges ahead in clinical settings, particularly with respect to maintaining optimal glycemic control whilst minimizing the treatment-related side effects of hypoglycemia and weight gain. In this review, the chronology of the development of rapid-acting, short-acting, intermediate-acting, and long-acting insulin analogues, as well as mixtures and concentrated formulations that offer the potential to meet this challenge, are summarized. In addition, we also summarize the latest advancements in insulin delivery methods, along with advancement to clinical trials. This review provides insights on the development of insulin treatment for diabetes mellitus that may be useful for clinicians in meeting the needs of their individual patients. However, it is important to note that as of now, none of the new technologies mentioned have superseded the existing method of subcutaneous administration of insulin.

Innate Immunity Crosstalk with Helicobacter pylori: Pattern Recognition Receptors and Cellular Responses.

Helicobacter pylori is one of the most successful gastric pathogens that has co-existed with human for centuries. H. pylori is recognized by the host immune system through human pattern recognition receptors (PRRs), such as toll-like receptors (TLRs), C-type lectin like receptors (CLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs), which activate downstream signaling pathways. Following bacterial recognition, the first responders of the innate immune system, including neutrophils, macrophages, and dendritic cells, eradicate the bacteria through phagocytic and inflammatory reaction. This review provides current understanding of the interaction between the innate arm of host immunity and H. pylori, by summarizing H. pylori recognition by PRRs, and the subsequent signaling pathway activation in host innate immune cells.

Non-toxic nature of chebulinic acid on biochemical, hematological and histopathological analysis in normal Sprague Dawley rats.

Chebulinic acid (CA) is an ellagitannins isolated from the dried fruits of Terminalia chebula with diverse pharmacological activities. The present study focused on the acute toxicity of CA in normal Sprague Dawley (SD) rats. CA was administered via oral gavage to different groups in 300 and 2000 mg/kg body weight and vehicle respectively. All the animals were monitored carefully for any physiological or behavioral changes for 14 days. On day 15th animals were euthanized and blood was collected for hematological and biochemical analysis. Different tissues were collected for histopathological study using four different staining techniques (hematoxylin and eosin, Masson's trichrome, periodic acid Schiff and picro sirius red) to observe any pathological alterations. The results highlighted no morbidity and mortality after oral ingestion of CA (300 and 2000 mg/kg). Food and water consumption, body weight, relative organ weight, hematological and biochemical parameters were normal without any gross pathological lesions in harvested tissues. The outcome of the current study supported safety of CA even at high dose. However, further detailed study is required on experimentally disease model to unfold its therapeutic potential in laboratory animals.

Corrigendum: Podoplanin Drives Motility of Active Macrophage via Regulating Filamin C During Helicobacter pylori Infection.

[This corrects the article DOI: 10.3389/fimmu.2021.702156.].

An Overview of Helicobacter pylori Survival Tactics in the Hostile Human Stomach Environment.

Helicobacter pylori is well established as a causative agent for gastritis, peptic ulcer, and gastric cancer. Armed with various inimitable virulence factors, this Gram-negative bacterium is one of few microorganisms that is capable of circumventing the harsh environment of the stomach. The unique spiral structure, flagella, and outer membrane proteins accelerate H. pylori movement within the viscous gastric mucosal layers while facilitating its attachment to the epithelial cells. Furthermore, secretion of urease from H. pylori eases the acidic pH within the stomach, thus creating a niche for bacteria survival and replication. Upon gaining a foothold in the gastric epithelial lining, bacterial protein CagA is injected into host cells through a type IV secretion system (T4SS), which together with VacA, damage the gastric epithelial cells. H. pylori does not only establishes colonization in the stomach, but also manipulates the host immune system to permit long-term persistence. Prolonged H. pylori infection causes chronic inflammation that precedes gastric cancer. The current review provides a brief outlook on H. pylori survival tactics, bacterial-host interaction and their importance in therapeutic intervention as well as vaccine development.

Defining the Role of GLI/Hedgehog Signaling in Chemoresistance: Implications in Therapeutic Approaches.

Insight into cancer signaling pathways is vital in the development of new cancer treatments to improve treatment efficacy. A relatively new but essential developmental signaling pathway, namely Hedgehog (Hh), has recently emerged as a major mediator of cancer progression and chemoresistance. The evolutionary conserved Hh signaling pathway requires an in-depth understanding of the paradigm of Hh signaling transduction, which is fundamental to provide the necessary means for the design of novel tools for treating cancer related to aberrant Hh signaling. This review will focus substantially on the canonical Hh signaling and the treatment strategies employed in different studies, with special emphasis on the molecular mechanisms and combination treatment in regard to Hh inhibitors and chemotherapeutics. We discuss our views based on Hh signaling's role in regulating DNA repair machinery, autophagy, tumor microenvironment, drug inactivation, transporters, epithelial-to-mesenchymal transition, and cancer stem cells to promote chemoresistance. The understanding of this Achilles' Heel in cancer may improve the therapeutic outcome for cancer therapy.

Podoplanin Drives Motility of Active Macrophage via Regulating Filamin C During Helicobacter pylori Infection.

Podoplanin (Pdpn) is a mucin-type transmembrane protein that has been implicated in multiple physiological settings including lymphangiogenesis, platelet aggregation, and cancer metastasis. Here, we reported an absence of Pdpn transcript expression in the resting mouse monocytic macrophages, RAW264.7 cells; intriguingly, a substantial upregulation of Pdpn was observed in activated macrophages following Helicobacter pylori or lipopolysaccharide stimulation. Pdpn-knockout macrophages demonstrated intact phagocytic and intracellular bactericidal activities comparable to wild type but exhibited impaired migration due to attenuated filopodia formation. In contrast, an ectopic expression of Pdpn augmented filopodia protrusion in activated macrophages. NanoString analysis uncovered a close dependency of Filamin C gene on the presence of Pdpn, highlighting an involvement of Filamin C in modulation of actin polymerization activity, which controls cell filopodia formation and migration. In addition, interleukin-1ß production was significantly declined in the absence of Pdpn, suggesting a role of Pdpn in orchestrating inflammation during H. pylori infection besides cellular migration. Together, our findings unravel the Pdpn network that modulates movement of active macrophages.