Novel drug delivery strategies for antidepressant active ingredients from natural medicinal plants: the state of the art.

Depression is a severe mental disorder among public health issues. Researchers in the field of mental health and clinical psychiatrists have long been faced with difficulties in slow treatment cycles, high recurrence rates, and lagging efficacy. These obstacles have forced us to seek more advanced and effective treatments. Research has shown that novel drug delivery strategies for natural medicinal plants can effectively improve the utilization efficiency of the active molecules in these plants and therefore improve their efficacy. Currently, with the development of treatment technologies and the constant updating of novel drug delivery strategies, the addition of natural medicinal antidepressant therapy has given new significance to the study of depression treatment against the background of novel drug delivery systems. Based on this, this review comprehensively evaluates and analyses the research progress in novel drug delivery systems, including nanodrug delivery technology, in intervention research strategies for neurological diseases from the perspective of natural medicines for depression treatment. This provided a new theoretical foundation for the development and application of novel drug delivery strategies and drug delivery technologies in basic and clinical drug research fields.

Geographical distribution and pathogenesis of ticks and tick-borne viral diseases.

Ticks are obligatory hematophagous arthropods that harbor and transmit infectious pathogens to humans and animals. Tick species belonging to Amblyomma, Ixodes, Dermacentor, and Hyalomma genera may transmit certain viruses such as Bourbon virus (BRBV), Dhori virus (DHOV), Powassan virus (POWV), Omsk hemorrhagic fever virus (OHFV), Colorado tick fever virus (CTFV), Crimean-Congo hemorrhagic fever virus (CCHFV), Heartland virus (HRTV), Kyasanur forest disease virus (KFDV), etc. that affect humans and certain wildlife. The tick vectors may become infected through feeding on viraemic hosts before transmitting the pathogen to humans and animals. Therefore, it is vital to understand the eco-epidemiology of tick-borne viruses and their pathogenesis to optimize preventive measures. Thus this review summarizes knowledge on some medically important ticks and tick-borne viruses, including BRBV, POWV, OHFV, CTFV, CCHFV, HRTV, and KFDV. Further, we discuss these viruses' epidemiology, pathogenesis, and disease manifestations during infection.

Occurrence of extended- spectrum ß-lactamase harboring K. pneumoniae in various sources: a one health perspective.

This study was designed to investigate the occurrence and dissemination of extended-spectrum ß-lactamase (ESBL) harboring Klebsiella pneumoniae in various ecological niches under the one health approach. A total of 793 samples were collected from animals, humans, and the environment. The findings of the study revealed the occurrence of K. pneumoniae as follows: animals (11.6%), humans (8.4%), and associated environments (7.0%), respectively. A high occurrence rate of ESBL genes was found in animals compared to human and environmental isolates. A total of 18 distinct sequence types (STs) and 12 clonal complexes of K. pneumoniae were observed. Overall, six STs of K. pneumoniae were identified in commercial chickens, and three were found in rural poultry. The majority of K. pneumoniae STs found in this study were positive for blaSHV, while the positivity of other ESBL-encoding genes combinations was different in different STs. The high occurrence rate of ESBL-harboring K. pneumoniae found in animals as compared to other sources is alarming and has the potential to be disseminated to the associated environment and community.

Co-Occurrence of mcr-1 and Carbapenem Resistance in Avian Pathogenic E. coli Serogroup O78 ST95 from Colibacillosis-Infected Broiler Chickens.

Avian pathogenic Escherichia coli (APEC) is responsible for significant economic losses in the poultry industry. This study aimed to molecularly detect carbapenem-resistant co-harboring mcr-1 avian pathogenic E. coli in broiler chickens infected with colibacillosis. A total of 750 samples were collected from colibacillosis-infected broilers, and conventional microbiological techniques were used to isolate and identify APEC. MALDI-TOF and virulence-associated genes (VAGs) were used for further identification. Phenotypic carbapenem resistance profiling was followed by molecular detection of carbapenem resistance genes (CRGs) and other resistance genes through PCR using specific primers. Isolates were also subjected to PCR for O typing, followed by allele-specific PCR to detect sequence type (ST) 95. Results showed that 154 (37%) isolates were confirmed as APEC, with 13 (8.4%) isolates found to be carbapenem-resistant (CR)-APEC. Among CR-APEC isolates, 5 (38%) were observed to co-harbor mcr-1. All CR-APEC showed the presence of five markers (ompT, hylF, iutA, iroN, and iss) APEC VAGs, and 89% of CR-APEC isolates displayed O78 type. Furthermore, 7 (54%) CR-APEC isolates were observed with ST95, all displaying O78 type. These results suggest that the improper use of antibiotics in poultry production systems is contributing to the emergence of pathogens such as CR-APEC co-harboring the mcr-1 gene.

Distribution of mcr-1 Harboring Hypervirulent Klebsiella pneumoniae in Clinical Specimens and Lytic Activity of Bacteriophage KpnM Against Isolates.

Background: The World Health Organization (WHO) has declared the multi-drug resistant (MDR) Klebsiella pneumoniae as one of the critical bacterial pathogens. The dearth of new antibiotics and inadequate therapeutic options necessitate finding alternative options. Bacteriophages are known as enemies of bacteria and are well-recognized to fight MDR pathogens. Methods: A total of 150 samples were collected from different clinical specimens through a convenient sampling technique. Isolation, identification, and antibiotic susceptibility testing (AST) of K. pneumoniae were done by standard and validated microbiological procedures. Molecular identification of virulence factors and antibiotic resistance genes (ARGs) was carried out through polymerase chain reaction (PCR) by using specific primers. For bacteriophage isolation, hospital sewage samples were processed for phage enrichment, purification, and further characterization ie, transmission electron microscopy (TEM) and stability testing, etc. followed by evaluation of the lytic potential of the phage. Results: Overall, a total of 41% of isolates of K. pneumoniae were observed as hypervirulent K. pneumoniae (hvKp). Among hvKp, a total of 12 (42%) were detected as MDR hvKp. A total of 37% of all MDR isolates were found resistant to colistin, and 66% of the colistin resistance isolates were recorded as mcr-1 positive. Isolated phage KpnM had shown lytic activity against 53 (79%) K. pneumoniae isolates. Remarkably, all 8 mcr-1 harboring MDR hvKp and non-hvKp isolates were susceptible to KpnM phage. Conclusion: Significant distribution of mcr-1 harboring hypervirulent Klebsiella pneumoniae was observed in clinical specimens, which is worrisome for the health system of the country. Characterized phage KpnM exhibited encouraging results and showed the lytic activity against the mcr-1 harboring hvKp isolates, which may be used as a prospective alternative control strategy to fight this ominous bacterium.

Distribution and genetic diversity of multi-drug-resistant Klebsiella pneumoniae at the human-animal-environment interface in Pakistan.

Klebsiella pneumoniae is ubiquitous and known to be a notorious pathogen of humans, animals, and plant-based foods. K. pneumoniae is a recognized trafficker of antibiotic resistance genes (ARGs) between and from different ecological niches. A total of 775 samples (n = 775) were collected from September 2017 to August 2019 from humans, animals, and environmental sources by applying the random convenient sampling technique. A total of 120 (15.7%) samples were confirmed as K. pneumoniae. The distribution of K. pneumoniae among humans, the environment, and animals was 17.1, 12.38, and 10%, respectively. Isolates have shown significant resistance against all the subjected antibiotics agents except colistin. ARGs profiling revealed that the highest percentage prevalence (67.5%) of bla CTX-M was estimated in the isolates, and various carbapenem resistance genes that were found in the study were bla NDM-1 (43.3%), bla OXA-48 (38%), and (1.67%) bla KPC-2. Overall, 21 distinct sequence types (ST) and 13 clonal complexes (CCs) were found through the multi-locus sequence typing (MLST) analysis. Taking together, the distribution of multi-drug resistance (MDR) K. pneumoniae clones in the community and associated environment is alarming for the health care system of the country. Health policymakers should consider the role of all the integral parts of humans, animals, and the associated environment intently to cope with this serious public and animal health concern.

Human Coronavirus Spike Protein Based Multi-Epitope Vaccine against COVID-19 and Potential Future Zoonotic Coronaviruses by Using Immunoinformatic Approaches.

Zoonotic coronaviruses (CoV) have emerged twice and have caused severe respiratory diseases in humans. Due to the frequent outbreaks of different human coronaviruses (HCoVs), the development of a pan-HCoV vaccine is of great importance. Various conserved epitopes shared by HCoVs are reported to induce cross-reactive T-cell responses. Therefore, this study aimed to design a multi-epitope vaccine, targeting the HCoV spike protein. Genetic analysis revealed that the spike region is highly conserved among SARS-CoV-2, bat SL-CoV, and SARS-CoV. By employing the immunoinformatic approach, we prioritized 20 MHC I and 10 MHCII conserved epitopes to design a multi-epitope vaccine. This vaccine candidate is anticipated to strongly elicit both humoral and cell-mediated immune responses. These results warrant further development of this vaccine into real-world application.

Pathogenesis of SARS-CoV-2 and Mycobacterium tuberculosis Coinfection.

Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is an infectious disease that poses severe threats to global public health and significant economic losses. The COVID-19 global burden is rapidly increasing, with over 246.53 million COVID-19 cases and 49.97 million deaths reported in the WHO 2021 report. People with compromised immunity, such as tuberculosis (TB) patients, are highly exposed to severe COVID-19. Both COVID-19 and TB diseases spread primarily through respiratory droplets from an infected person to a healthy person, which may cause pneumonia and cytokine storms, leading to severe respiratory disorders. The COVID-19-TB coinfection could be fatal, exacerbating the current COVID-19 pandemic apart from cellular immune deficiency, coagulation activation, myocardial infarction, and other organ dysfunction. This study aimed to assess the pathogenesis of SARS-CoV-2-Mycobacterium tuberculosis coinfections. We provide a brief overview of COVID19-TB coinfection and discuss SARS-CoV-2 host cellular receptors and pathogenesis. In addition, we discuss M. tuberculosis host cellular receptors and pathogenesis. Moreover, we highlight the impact of SARS-CoV-2 on TB patients and the pathological pathways that connect SARS-CoV-2 and M. tuberculosis infection. Further, we discuss the impact of BCG vaccination on SARS-CoV-2 cases coinfected with M. tuberculosis, as well as the diagnostic challenges associated with the coinfection.

A Mouse-Adapted Model of HCoV-OC43 and Its Usage to the Evaluation of Antiviral Drugs.

The human coronavirus OC43 (HCoV-OC43) is one of the most common causes of common cold but can lead to fatal pneumonia in children and elderly. However, the available animal models of HCoV-OC43 did not show respiratory symptoms that are insufficient to assist in screening antiviral agents for respiratory diseases. In this study, we adapted the HCoV-OC43 VR-1558 strain by serial passage in suckling C57BL/6 mice and the resulting mouse-adapted virus at passage 9 (P9) contained 8 coding mutations in polyprotein 1ab, spike (S) protein, and nucleocapsid (N) protein. Pups infected with the P9 virus significantly lost body weight and died within 5 dpi. In cerebral and pulmonary tissues, the P9 virus replication induced the production of G-CSF, IFN-γ, IL-6, CXCL1, MCP-1, MIP-1α, RANTES, IP-10, MIP-1ß, and TNF-α, as well as pathological alterations including reduction of neuronal cells and typical symptoms of viral pneumonia. We found that the treatment of arbidol hydrochloride (ARB) or Qingwenjiere Mixture (QJM) efficiently improved the symptoms and decreased n gene expression, inflammatory response, and pathological changes. Furthermore, treating with QJM or ARB raised the P9-infected mice's survival rate within a 15 day observation period. These findings suggested that the new mouse-adapted HCoV-OC43 model is applicable and reproducible for antiviral studies of HCoV-OC43.

Emergence of Carbapenem-Resistant ST244, ST292, and ST2446 Pseudomonas aeruginosa Clones in Burn Patients in Yunnan Province.

Introduction: The prevalence of carbapenem-resistant Pseudomonas aeruginosa is increasing persistently, particularly in burn ward isolates. Here, we investigate the prevalence of carbapenem-resistant Pseudomonas aeruginosa in a burn ward of a provincial-level hospital at Kunming, Yunnan province, China. Methods: A total of 118 P. aeruginosa strains were isolated from 57 hospitalized patients, and their MICs were measured. Carbapenem-resistant isolates were selected for multilocus sequence typing (MLST). Carbapenem-resistance mechanisms were identified by examining carbapenemase genes and OprD protein and Carba-NP testing. Representative isolates were further characterized by de novo sequencing for carbapenemase molecular background. Results: Among 118 P. aeruginosa isolates, 54 (54/118,45.8%) were carbapenem-resistant Pseudomonas aeruginosa, and 3 genotypes were found (ST292, ST244, and ST2446). Non-carbapenemase-producing ST292 was the most prevalent ST, followed by ST2446 and ST244. A novel 13-bp oprD deletion was found in the ST292 clone, which formed the truncated outer membrane protein and may cause carbapenem resistance. ST244 and ST2446 harbored blaIMP-45 and blaIMP-87, respectively. blaIMP-45 is located in a megaplasmid, together with aac(6')-Ib3, blaOXA-1, catB3, qnrVC6, armA, msr(E), mph(E), aph(3')-Ia, tetC/tetR, aac(6')-Ib3, floR, mexC-mexD-oprJ, fosA and lead to extensive drug resistance. ST2446 contains a carbapenem-resistant gene blaIMP-87 on the chromosome and is acquired by a novel gene cassette array (blaIMP-87-ant(2")-Ia-blaOXA-10-aac(6')-Ib3) of class 1 integron. Discussion: For the first time, ST244, ST292 and ST2446 are reported emerging in burn patients, with distinctive carbapenem-resistance mechanisms, respectively. The obtained results highlight the need to surveillance carbapenem-resistant isolates in burn patients.

The diversity of vaginal microbiome in women infected with single HPV and multiple genotype HPV infections in China.

Introduction: The human papillomavirus (HPV) is the leading cause of cervical cancer globally. However, its microbial composition and association with the types of HPV infection remain elusive. Methods: This study was designed to characterize the vaginal microbiota of 53 HPV-infected and 16 normal women (control group) by using high-throughput sequencing with the Illumina platform. Results: In this study, the five leading phyla were Firmicutes (73.9%), Actinobacteriota (12.8%), Proteobacteria (6.2%), Fusobacteria (3.5%), and Bacteroidota (3.1%). We found that single HPV genotype-positive women had higher α-microbial diversity compared with HPV-negative and multiple HPV-positive women. In women with a single HPV genotype infection, the HPV-16 infection had significantly higher α-diversity than other genotype infections. In multiple HPV genotype-positive women, the highest α-diversity was found in women positive for HR-HR HPV genotype infection, compared with other infections. Furthermore, in single- and multiple-genotype infections, the abundance of s_unclassified_g_Lactobacillus decreased whereas the abundance of s_Gardnerella_vaginalis increased compared with control. Additionally, s_unclassified_f_Rhizobiaceae and s_sneathia_sanguinegens were only found in HPV-infected women. Conclusion: This study showed that the type of HPV infection was associated with the composition of the vaginal microbiota. Further studies on HPV genotypes and vaginal microbiota are necessary to uncover more mysteries of their association and provide a promising therapeutic target as well as low-cost future therapeutic strategies.

Cross-species transmission, evolution and zoonotic potential of coronaviruses.

Coronaviruses (CoVs) continuously evolve, crossing species barriers and spreading across host ranges. Over the last two decades, several CoVs (HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2) have emerged in animals and mammals, causing significant economic and human life losses. Due to CoV cross-species transmission and the evolution of novel viruses, it is critical to identify their natural reservoiurs and the circumstances under which their transmission occurs. In this review, we use genetic and ecological data to disentangle the evolution of various CoVs in wildlife, humans, and domestic mammals. We thoroughly investigate several host species and outline the epidemiology of CoVs toward specific hosts. We also discuss the cross-species transmission of CoVs at the interface of wildlife, animals, and humans. Clarifying the epidemiology and diversity of species reservoirs will significantly impact our ability to respond to the future emergence of CoVs in humans and domestic animals.

Antibiotic Resistance: One Health One World Outlook.

Antibiotic resistance (ABR) is a growing public health concern worldwide, and it is now regarded as a critical One Health issue. One Health's interconnected domains contribute to the emergence, evolution, and spread of antibiotic-resistant microorganisms on a local and global scale, which is a significant risk factor for global health. The persistence and spread of resistant microbial species, and the association of determinants at the human-animal-environment interface can alter microbial genomes, resulting in resistant superbugs in various niches. ABR is motivated by a well-established link between three domains: human, animal, and environmental health. As a result, addressing ABR through the One Health approach makes sense. Several countries have implemented national action plans based on the One Health approach to combat antibiotic-resistant microbes, following the Tripartite's Commitment Food and Agriculture Organization (FAO)-World Organization for Animal Health (OIE)-World Health Organization (WHO) guidelines. The ABR has been identified as a global health concern, and efforts are being made to mitigate this global health threat. To summarize, global interdisciplinary and unified approaches based on One Health principles are required to limit the ABR dissemination cycle, raise awareness and education about antibiotic use, and promote policy, advocacy, and antimicrobial stewardship.

The Impact of Mutations on the Pathogenic and Antigenic Activity of SARS-CoV-2 during the First Wave of the COVID-19 Pandemic: A Comprehensive Immunoinformatics Analysis.

An in-depth analysis of first-wave SARS-CoV-2 genome is required to identify various mutations that significantly affect viral fitness. In the present study, we performed a comprehensive in silico mutational analysis of 3C-like protease (3CLpro), RNA-dependent RNA polymerase (RdRp), and spike (S) proteins with the aim of gaining important insights into first-wave virus mutations and their functional and structural impact on SARS-CoV-2 proteins. Our integrated analysis gathered 6000 SARS-CoV-2 sequences and identified 92 mutations in S, 37 in RdRp, and 11 in 3CLpro regions. The impact of these mutations was also investigated using various in silico approaches. Among these, 32 mutations in S, 15 in RdRp, and 3 in 3CLpro proteins were found to be deleterious in nature and could alter the structural and functional behavior of the encoded proteins. The D614G mutation in spike and the P323Lmutation in RdRp are the globally dominant variants with a high frequency. Most of the identified mutations were also found in the binding moiety of the viral proteins which determine their critical involvement in host-pathogen interactions and may represent drug targets. Furthermore, potential CD4+ and CD8+ T cell epitopes were predicted, and their overlap with genetic variations was explored. This study also highlights several hot spots in which HLA and drug selective pressure overlap. The findings of the current study may allow a better understanding of COVID-19 diagnostics, vaccines, and therapeutics.

Transcriptional Response of Multidrug-Resistant Klebsiella pneumoniae Clinical Isolates to Ciprofloxacin Stress.

BACKGROUND: The term "persisters" refers to a small bacterial population that persists during treatment with high antibiotic concentration or dose in the absence of genetic resistance. The present study was designed to investigate the transcriptional response in indigenous Klebsiella pneumoniae under the ciprofloxacin stress. METHODS: Isolation and identification of K. pneumoniae were carried out through standard microbiological protocols. The characterization of quinolone resistance was performed by estimating the quinolone susceptibility testing, MIC estimation, and detecting the QRDR and PMQR. Transcriptional response of the isolates to ciprofloxacin was determined using qPCR. RESULTS: Among 34 isolates, 23 (67%) were resistant to ciprofloxacin. Both QRDR (gyrA and gyrB) and PMQR (qnrA, qnrB, and qnrS) were detected in the isolates, and all were found resistant to ciprofloxacin. The mRNA levels of both mutS and euTu under the influence of ciprofloxacin were significantly increased. On ciprofloxacin exposure, the mRNA levels of the DNA damage response element (mutS) were raised in a time-dependent fashion. K. pneumoniae showed high-level resistance to ciprofloxacin in the presence of mutations in QRDR and PMQR genes. CONCLUSION: The transcriptional response revealed the upregulation of DNA repair and protein folding elements (mutS and euTu) in ciprofloxacin stress and delayed cell division. The ciprofloxacin was found to trigger various stress responses in a time- and concentration-dependent manner.

Establishment of Tree Shrew Animal Model for Kaposi's Sarcoma-Associated Herpesvirus (HHV-8) Infection.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the most common cause of Kaposi's sarcoma (KS) and other malignant growths in humans. However, the lack of a KSHV-infected small animal model has hampered understanding of the mechanisms of KSHV infection, virus replication, pathogenesis, and persistence. This study was designed to explore the susceptibility of tree shrews as a possible KSHV-infected small animal model. A recombinant GFP (latent)/RFP (lytic)-positive rKSHV.219 strain was used to infect primary cells cultured from different tissues of tree shrews as an in vitro model and adult tree shrews as an in vivo model. KSHV latent nuclear antigen (LANA) and DNA were successfully detected in primary cells of tree shrews. Among them, tree shrew kidney epithelial cells (TSKEC) were the most susceptible cells to KSHV infection compared to other cells. KSHV genomic DNA, mRNA, and KSHV-specific proteins were readily detected in the TSKEC cultured up to 32 dpi. Moreover, KSHV DNA and mRNA transcription were also readily detected in the peripheral blood mononuclear cells (PBMCs) and various tissues of tree shrews infected with KSHV. Haematoxylin and eosin (HE) staining showed lymphocyte infiltration, lymphoid tissue focal aggregation, alveolar wall thickening, hepatocyte edema, hepatic necrosis in the spleen, lung, and liver of KSHV-infected animals. Additionally, immune-histochemical (IHC) staining showed that LANA or ORF62-positive cells were present in the spleen, lung, liver, and kidney of KSHV-infected tree shrews. Here, we have successfully established in vitro and in vivo KSHV latent infection in tree shrews. This small animal model is not only useful for studying the pathogenesis of KSHV in vivo but can also be a useful model to study transmission routes of viral infection and a useful platform to characterize the novel therapeutics against KSHV.

The role of microbiota in respiratory health and diseases, particularly in tuberculosis.

Trillions of beneficial and hostile microorganisms live in the human respiratory and gastrointestinal tracts, which act as gatekeepers in maintaining human health, i.e., protecting the body from pathogens by colonizing mucosal surfaces with microbiota-derived antimicrobial metabolites such as short-chain fatty acids or host-derived cytokines and chemokines. It is widely accepted that the microbiome interacts with each other and with the host in a mutually beneficial relationship. Microbiota in the respiratory tract may also play a crucial role in immune homeostasis, maturation, and maintenance of respiratory physiology. Anti-TB antibiotics may cause dysbiosis in the lung and intestinal microbiota, affecting colonization resistance and making the host more susceptible to Mycobacterium tuberculosis (M. tuberculosis) infection. This review discusses recent advances in our understanding of the lung microbiota composition, the lungs and intestinal microbiota related to respiratory health and diseases, microbiome sequencing and analysis, the bloodstream, and the lymphatic system that underpin the gut-lung axis in M. tuberculosis-infected humans and animals. We also discuss the gut-lung axis interactions with the immune system, the role of the microbiome in TB pathogenesis, and the impact of anti-TB antibiotic therapy on the microbiota in animals, humans, and drug-resistant TB individuals.

Malaria: elimination tale from Yunnan Province of China and new challenges for reintroduction.

BACKGROUND: Eradication of infectious disease is the sanctified public health and sustainable development goal around the world. MAIN BODY: Three antimalarial barriers were developed to control imported malarial cases, and an effective surveillance strategy known as the "1-3-7 approach" was developed to eliminate malaria from the Chinese population. From 2011 to 2019, 5254 confirmed malaria cases were reported and treated in Yunnan Province, China. Among them, 4566 cases were imported from other countries, and 688 cases were indigenous from 2011 to 2016. Since 2017, no new local malarial case has been reported in China. Thus, malaria has been completely eliminated in Yunnan Province. However, malaria is detected in overseas travellers on a regular basis, such as visitors from neighbouring Myanmar. CONCLUSION: Hence, the strategies should be further strengthened to maintain a robust public health infrastructure for disease surveillance and vector control programs in border areas. Such programs should be supported technically and financially by the government to avert the possibility of a malarial resurgence in Yunnan Province.